WO2021121210A1 - 并环类衍生物、其制备方法及其在医药上的应用 - Google Patents

并环类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2021121210A1
WO2021121210A1 PCT/CN2020/136431 CN2020136431W WO2021121210A1 WO 2021121210 A1 WO2021121210 A1 WO 2021121210A1 CN 2020136431 W CN2020136431 W CN 2020136431W WO 2021121210 A1 WO2021121210 A1 WO 2021121210A1
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group
cycloalkyl
aryl
alkyl
heteroaryl
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PCT/CN2020/136431
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English (en)
French (fr)
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杨方龙
韩吉慧
瞿健
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 WO2021121210A1 publication Critical patent/WO2021121210A1/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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused ring derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially for preparing treatment and/or Use in medicine for preventing 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 human body and maintaining metabolic homeostasis.
  • the three major functions of thyroid hormone (1) Promote growth and development. Thyroid hormone has the most obvious effect in promoting growth and development during infancy. It 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, the GH of the pituitary gland cannot play a role; (2) It affects metabolism and thermogenesis. Thyroid hormone can increase the oxygen consumption rate of most tissues and increase thermogenesis effect. This thermal effect may be due to the increase of Na on the cell membrane by thyroid hormone.
  • Thyroid hormone has an important role in the activities of some organs, for example, it has important significance in maintaining the excitability of the nervous system , Thyroid hormone can directly act on the myocardium, promote the release of Ca 2+ from the sarcoplasmic reticulum, increase myocardial contractility and increase heart rate.
  • the natural thyroid hormone T3 plays a physiological role by binding to the thyroid hormone receptor (THR).
  • THR ⁇ thyroid hormone receptor
  • THR ⁇ is mainly distributed in the liver
  • THR ⁇ is mainly distributed in the brain and heart tissues.
  • Natural thyroid hormone can act on THR ⁇ and THR ⁇ at the same time, without any selectivity.
  • the natural thyroid hormone T3 can significantly reduce cholesterol and low-density lipoprotein (LDL) in animal models and humans.
  • LDL low-density lipoprotein
  • T3 has side effects on the heart, and it cannot be used for the treatment of obesity, hypercholesterolemia and non-alcoholic fatty liver.
  • THR ⁇ thyroid hormone T3
  • THR ⁇ 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 non-alcoholic steatohepatitis without affecting heart rate and rhythm.
  • Thyroid hormone receptor ⁇ Thyroid hormone receptor ⁇ (THR ⁇ ) selective and/or tissue-selective thyroid hormone analogues have been synthesized. These compounds can appropriately reduce body weight, lipids, cholesterol and lipoproteins, and have significant effects on cardiovascular and hypothalamus/pituitary/ The normal function of the thyroid axis has little impact (Johan Malm, J. Med. Chem. 2003, 46, 1580-158; Martha J. Kelly, J. Med. Chem. 2014, 57, 3912-3923).
  • Patent applications of compounds that have been published as agonists of THR ⁇ include WO2006128055, WO2005051298, WO2007009913, WO2009037172 and the like.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, prodrug , Hydrate, or its mixture form, or its pharmaceutically acceptable salt:
  • G is CR 5 or N atom
  • Ring A is selected from aryl and heteroaryl
  • L is selected from alkylene, O atom and S atom; wherein said alkylene is optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 1 is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups Each independently is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in the aryl and heteroaryl groups;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -COOR 6 , cycloalkyl , Heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently Optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;
  • R 3 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups Each independently is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in the aryl and heteroaryl groups;
  • R 4 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group is optionally selected from the group consisting of hydroxy,- OC(O)R 7 and -OP(O)(OR 8 ) 2 are substituted by one or more substituents;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents in;
  • R 6 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 8 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3, or 4.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomers, mesosomes, racemates, enantiomers, and non-pairs Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (II) or tautomers, mesoisomers, exogenous Rotates, enantiomers, diastereomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 to R 4 , G, L and s are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (III), or tautomers, mesoisomers, and exoisomers thereof Racemates, enantiomers, diastereomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 to R 4 and s are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (IV) or tautomers, mesoisomers, and exogenous compounds Rotates, enantiomers, diastereomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 to R 4 and s are as defined in the general formula (I).
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, pro Drugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R m is an alkyl group
  • G is CR 5 or N atom
  • Ring A is selected from aryl and heteroaryl
  • L is selected from alkylene, O atom and S atom; wherein said alkylene is optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 1 is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups Each independently is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in the aryl and heteroaryl groups;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -COOR 6 , cycloalkyl , Heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently Optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;
  • R 3 are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups Each independently is optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in the aryl and heteroaryl groups;
  • R 4 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group is optionally selected from the group consisting of hydroxy,- OC(O)R 7 and -OP(O)(OR 8 ) 2 are substituted by one or more substituents;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents in;
  • R 6 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 7 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 8 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3, or 4.
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, pro Drugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IIA) or tautomers, mesosomes, racemates, enantiomers Conformers, diastereomers, or prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R m , R 1 to R 4 , G, L and s are as defined in the general formula (IA).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, pro Drugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIIA) or tautomers, mesosomes, racemates, enantiomers Conformers, diastereomers, or prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R m , R 1 to R 4 and s are as defined in the general formula (IA).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a prodrug, a hydrate, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIA) or a tautomer, meso, racemate, or enantiomer Isomers, diastereomers, or prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R m , R 1 to R 4 and s are as defined in the general formula (IA).
  • Typical compounds of the general 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, meso, racemate, enantiomer, non- Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which include the following steps:
  • the compound of general formula (IA) or its pharmaceutically acceptable salt undergoes an intramolecular reaction (intramolecular acylation reaction) to obtain a compound represented by general formula (I),
  • R m is an alkyl group
  • Rings A, G, L, R 1 to R 4 , n and s are as defined in the 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, meso, racemate, enantiomer, non- Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which include the following steps:
  • the compound of general formula (IIA) or its pharmaceutically acceptable salt undergoes an intramolecular reaction (intramolecular acylation reaction) to obtain a compound represented by general formula (II),
  • R m is an alkyl group
  • G, L, R 1 to R 4 and s are as defined in the 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, meso, racemate, enantiomer, non- Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which include the following steps:
  • the compound of general formula (IIIA) or its pharmaceutically acceptable salt undergoes an intramolecular reaction (intramolecular acylation reaction) to obtain a compound represented by general formula (III),
  • R m is an alkyl group
  • R 1 to R 4 and s are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the general formula (IV) according to the present disclosure or its tautomer, meso, racemate, enantiomer, non- Enantiomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, which include the following steps:
  • the compound of general formula (IVA) or its pharmaceutically acceptable salt undergoes an intramolecular reaction (intramolecular acylation reaction) to obtain a compound represented by general formula (IV),
  • R m is an alkyl group
  • R 1 to R 4 and s are as defined in the general formula (IV).
  • compositions which contains the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the compound represented by the general formula (I) according to the present disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers, Use of prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them in the preparation of THR ⁇ agonists.
  • the present disclosure further relates to the compound represented by the general formula (I) according to the present disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers,
  • the present disclosure further relates to the compound represented by the general formula (I) according to the present disclosure or its tautomers, mesosomes, racemates, enantiomers, diastereomers, Prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them are prepared for the treatment and/or prevention of obesity, hypothyroidism, thyroid cancer, diabetes mellitus modulated by thyroid hormones , Cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the present disclosure also relates to a method for stimulating THR ⁇ , which comprises administering to a desired patient a therapeutically effective amount of the compound represented by the general formula (I) according to the present disclosure or its tautomer, mesosome, exo Racemates, enantiomers, diastereomers, prodrugs, hydrates, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for treating and/or preventing diseases regulated by thyroid hormones, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I) according to the present disclosure or its mutual variation Conformer, mesosome, racemate, enantiomer, diastereomer, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a drug containing the same combination.
  • a compound represented by the general formula (I) according to the present disclosure or its mutual variation Conformer, mesosome, racemate, enantiomer, diastereomer, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a drug containing the same combination.
  • the present disclosure also relates to a treatment and/or prevention of obesity, hypothyroidism, thyroid cancer, diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, and non-alcoholic fat regulated by thyroid hormone
  • a method for hepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) which comprises administering to a desired patient a therapeutically effective amount of a compound represented by the general formula (I) according to the present disclosure or a tautomer thereof, Meso, racemate, enantiomer, diastereomer, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • the present disclosure further relates to a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer
  • a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer
  • the present disclosure further relates to a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer A body, a prodrug, a hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a THR ⁇ agonist.
  • the present disclosure further relates to a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Body, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a drug for the treatment and/or prevention of diseases regulated by thyroid hormone; preferably for use as Drugs for the treatment and/or prevention of metabolic diseases regulated by thyroid hormones.
  • a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Body, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a drug for the treatment and/or prevention of diseases regulated by thyroid hormone; preferably for use as Drugs for the treatment and/or prevention of metabolic diseases regulated by thyroid hormones.
  • the present disclosure further relates to a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer Body, prodrug, hydrate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment and/or prevention of obesity, hypothyroidism, and thyroid cancer regulated by thyroid hormones , Diabetes, cardiovascular disease, hyperlipidemia, hypercholesterolemia, atherosclerosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) drugs.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose.
  • the unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose may be 0.1-1000 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 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients for mixing suitable for preparing aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • dispersible powders and granules suitable for preparing water suspensions can provide active ingredients and dispersing agents, wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing agents, wetting agents and suspending agents. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids.
  • the emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injection preparation can be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing agents, wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode, such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be based on Traditional treatment plan to verify.
  • the present disclosure provides a highly selective THR ⁇ inhibitor, which is less distributed in the heart and is safer.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 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 More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • alkyl group 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups, One or more substituents of haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy
  • substituents of the group, cycloalkylthio group, heterocycloalkylthio group and oxo group are particularly preferred from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. It preferably contains 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably contains 2 to 8 carbon atoms. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently optionally selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, One or more substituents of hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • alkynyl refers to a straight or branched chain hydrocarbon, which has an alkyl compound having at least one carbon-carbon triple bond, wherein the definition of the alkyl group is as described above. It is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbons Atom, more preferably contains 2 to 8 carbon atoms.
  • Non-limiting examples of alkynyl groups include, but are not limited to, -C ⁇ CH, -CH 2 C ⁇ CH, -CH 2 C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 , -CH 2 C ⁇ CCH 2 CH 3 ,- C ⁇ CCH(CH 3 ) 2 , -C(CH 3 ) 2 C ⁇ CH, -C(CH 3 ) 2 C ⁇ CCH 3 and so on.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently optionally selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, One or more substituents of hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 (e.g. 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably 3 to 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 Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl 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 5-membered and 6-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro ring, fused ring and bridged ring) fused on an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) r (where r is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, wherein 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,3-dioxolane, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, Linyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) Heteroatoms of r (where r is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group 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.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) r (where r is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 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 5-membered 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) r (where r is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent
  • the rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g. 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from the parent ring atom, or two residues derived from the same ring atom or two different ring atoms of the parent
  • residues derived from the removal of two hydrogen atoms are "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, and "heteroarylene”.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tetrahydropyranyl.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or Or both with Two configurations.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, and has due biological activity.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • the structure of the present disclosure including replacing hydrogen with "deuterium” or “tritium”, or replacing fluorine with 18 F-fluorine label ( 18 F isotope), or enriching with 11 C-, 13 C- or 14 C- Compounds in which carbon atoms ( 11 C-, 13 C- or 14 C-carbon labels; 11 C-, 13 C- or 14 C- isotope
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • Deuterated compounds can generally retain the same activity as non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).
  • the various deuterated compounds of formula (I) in the present disclosure means that each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature.
  • deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents.
  • Deuterated reagents include, but are not limited to, deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • the position should be understood as having an abundance of deuterium (ie, at least 10%) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • the natural abundance of the compound in the example having greater than deuterium may be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium, or higher abundance of deuterium.
  • the compounds of the present disclosure may include all their rotamers and conformationally restricted states.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • Prodrug refers to a compound that can be transformed in the body under physiological conditions, such as by hydrolysis in the blood, to produce an active prodrug compound.
  • Hydrophilrate also known as hydrate, refers to a compound containing water, where water can be coordinated and connected to other parts, such as hydrated metal ions, or combined by covalent bonds, such as hydrated chloral.
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • R m is an alkyl group; preferably a C 1 -C 6 alkyl group;
  • Rings A, G, L, R 1 to R 4 , n and s are as defined in the general formula (I).
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • R m is an alkyl group; preferably a C 1 -C 6 alkyl group;
  • G, L, R 1 to R 4 and s are as defined in the general formula (II).
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • R m is an alkyl group; preferably a C 1 -C 6 alkyl group;
  • R 1 to R 4 and s are as defined in the general formula (III).
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • R m is an alkyl group; preferably a C 1 -C 6 alkyl group;
  • R 1 to R 4 and s are as defined in the general formula (IV).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, and n-butyllithium.
  • 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, lithium hydroxide and hydrates thereof; preferably sodium acetate and sodium hydroxide;
  • the reactions in Scheme 1 to Scheme 4 above are preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, glacial acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • High performance liquid chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.
  • 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 in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the specification of thin layer chromatography 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 known starting materials of the present invention can be synthesized by 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 all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses the 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 examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the first step raw material 3a was replaced with the raw material 4-amino-2,6-dibromophenol 6a (Shanghai Aladdin Biochemical Technology Co., Ltd.) to obtain the title compound 6b (470mg), Rate: 58.8%.
  • Disperse compound 7f (170mg, 0.40mmol) in 3mL concentrated hydrochloric acid, add 6mL water, cool to 0°C, dissolve sodium nitrite (42mg, 0.61mmol) in 1mL water, add to the above system, continue to stir 1 Hours, the obtained diazonium liquid is ready for use.
  • Dissolve compound 1i (63mg, 0.40mmol) in 3mL pyridine, add 4mL water, cool to 0°C, pour the prepared diazonium liquid into the reaction system, continue stirring at 0-5°C for 1 hour, and filter. After drying, 7 g (140 mg, yield: 59.2%) of the title compound was obtained.
  • Test Example 1 The agonistic effect of the compound of the present disclosure on THR ⁇ and THR ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • THR ⁇ thyroid hormone receptor ⁇
  • the compound was prepared with dimethyl sulfoxide (Sigma, #D2650), the initial concentration was 10 mM, T3 (sigma, T2877) was diluted 10 times, 9 dose points, and the test compound was diluted 3 times, 9 dose points. The compound was further diluted 20 times using DMEM/F12 (GE, #SH30023.01) medium containing 0.5% FBS (corning, #35-076-CV).
  • the constructed CHO-K1 cells (ATCC, catalog number CCL-61) expressing both DR4 response element and THR ⁇ or THR ⁇ were plated in a 96-well plate (Corning, #3903) at 5,000 cells/well, 37°C, 5% Incubate in a CO 2 incubator (thermo scientific, #HERAcell 240i) for 24 hours.
  • Table 1 EC 50 values of the agonistic effects of the compounds of the present disclosure on THR ⁇ and THR ⁇ .
  • Emax the maximum reading of the test compound group-the minimum reading of the T3 group) / (the maximum reading of the T3 group-the minimum reading of the T3 group) * 100; the T3 group refers to the control group with T3 added.
  • the compound of the present disclosure has high selectivity for THR ⁇ .

Abstract

涉及并环类衍生物、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)所示的并环类衍生物、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/或预防甲状腺激素受体调节的疾病的药物中的用途。其中通式(I)的各取代基与说明书中的定义相同。

Description

并环类衍生物、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)所示的并环类衍生物、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、高血脂症、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，其主要促进骨骼、脑和生殖器官的生长发育，如果没有甲状腺激素，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，例如其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THRɑ和THRβ。THRβ主要分布在肝脏中，而THRɑ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THRɑ和THRβ，没有任何选择性。天然甲状腺激素T3在动物模型和人中能够显著降低胆固醇、低密度脂蛋白(LDL)。然而，T3对心脏有副作用，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THRɑ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肥胖、高血脂症、甲状腺疾病、非酒精性脂肪肝炎的治疗，而不会对心率和心律有影响。
已经合成甲状腺激素受体β(THRβ)选择性和/或组织选择性作用的甲状腺激素类似物，这些化合物可以适当降低体重、脂类、胆固醇和脂蛋白，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.2003,46,1580-158；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申请包括WO2006128055、WO2005051298、WO2007009913、WO2009037172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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
Figure PCTCN2020136431-appb-000001
其中：
G为CR 5或N原子；
环A选自芳基和杂芳基；
L选自亚烷基、O原子和S原子；其中所述的亚烷基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、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；
R 1相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
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、氨基、硝基、羟基、羟烷基、-COOR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、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、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；
R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
R 4选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基任选被选自羟基、-OC(O)R 7、-OP(O)(OR 8) 2中的一个或多个取代基所取代；
R 5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、氨基、硝基、羟基、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、烷氧基、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、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；
R 6选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 7选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 8选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3或4；和
s为0、1、2、3或4。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中环A为苯基或噻吩基。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
Figure PCTCN2020136431-appb-000002
其中
R 1～R 4、G、L和s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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中L选自CH 2、O原子和S原子，优选地，L为S原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中L选自CH 2和S原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中G为CH或N原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
Figure PCTCN2020136431-appb-000003
其中：
R 1～R 4和s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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
Figure PCTCN2020136431-appb-000004
其中：
R 1～R 4和s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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 1相同或不同，且各自独立地为氢原子或卤素。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、卤素、氰基、C(O)OH和C 1-6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(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、卤素、氰基和烷基，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(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 3选自氢原子、卤素、烷基和环烷基；优选地，R 3为氢原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其前药、水合物、或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基和3至6元环烷基；优选地，R 3为氢原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 4为氢原子或烷基；优选地R 4为氢原子。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 4为氢原子或C 1-6烷基；优选地R 4为氢原子。
本公开的典型化合物包括但不限于：
Figure PCTCN2020136431-appb-000005
Figure PCTCN2020136431-appb-000006
Figure PCTCN2020136431-appb-000007
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
Figure PCTCN2020136431-appb-000008
其中：
R m为烷基；
G为CR 5或N原子；
环A选自芳基和杂芳基；
L选自亚烷基、O原子和S原子；其中所述的亚烷基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、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；
R 1相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
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、氨基、硝基、羟基、羟烷基、-COOR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、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、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；
R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、 卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
R 4选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基任选被选自羟基、-OC(O)R 7、-OP(O)(OR 8) 2中的一个或多个取代基所取代；
R 5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、氨基、硝基、羟基、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、烷氧基、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、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；
R 6选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 7选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
R 8选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3或4；和
s为0、1、2、3或4。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其为通式(IIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其前药、水合物、或其混合物形式、或其可药用的盐，
Figure PCTCN2020136431-appb-000009
其中
R m、R 1～R 4、G、L和s如通式(IA)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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其为通式(IIIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其前药、水合物、或其混合物形式、或其可药用的盐，
Figure PCTCN2020136431-appb-000010
其中
R m、R 1～R 4和s如通式(IA)中所定义。
本公开的另一方面涉及一种通式(IVA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其前药、水合物、或其可药用的盐，其为通式(IIIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其前药、水合物、或其混合物形式、或其可药用的盐，
Figure PCTCN2020136431-appb-000011
其中
R m、R 1～R 4和s如通式(IA)中所定义。
本公开通式(IA)的典型化合物包括但不限于：
Figure PCTCN2020136431-appb-000012
Figure PCTCN2020136431-appb-000013
Figure PCTCN2020136431-appb-000014
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其包括以下步骤：
Figure PCTCN2020136431-appb-000015
通式(IA)的化合物或其可药用的盐发生分子内反应(分子内的酰化反应)，得到通式(I)所示的化合物，
其中：
R m为烷基；
环A、G、L、R 1～R 4、n和s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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其包括以下步骤：
Figure PCTCN2020136431-appb-000016
通式(IIA)的化合物或其可药用的盐发生分子内反应(分子内的酰化反应)，得到通式(II)所示的化合物，
其中：
R m为烷基；
G、L、R 1～R 4和s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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其包括以下步骤：
Figure PCTCN2020136431-appb-000017
通式(IIIA)的化合物或其可药用的盐发生分子内反应(分子内的酰化反应)，得到通式(III)所示的化合物，
其中：
R m为烷基；
R 1～R 4和s如通式(III)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(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其包括以下步骤：
Figure PCTCN2020136431-appb-000018
通式(IVA)的化合物或其可药用的盐发生分子内反应(分子内的酰化反应)，得到通式(IV)所示的化合物，
其中：
R m为烷基；
R 1～R 4和s如通式(IV)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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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，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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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，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。
本公开治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者的体重和化合物的相对功效而改变。不过，作为一般性指导，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。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。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。
水悬浮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。
通过加入水可使适用于制备水混悬的可分散粉末和颗粒提供活性成分和用于混合的分散剂、湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂、湿润剂和悬浮剂。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
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、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、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。
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、药物的组合等；另外，最佳的治疗方式如治疗的模式、通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。
本公开提供了一种高选择性的THRβ抑制剂，其在心脏中分布少，更安全。
发明的详细说明
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，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，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、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。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，其独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个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，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、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，更优选为含有2至8个碳原子。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，其独立地任选选自氢原子、烷基、烷氧基、卤素、卤代烷基、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”指直链或支链烃，其具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。其为包含2至20个碳原子的直链或支链基团，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，更优选为含有2至8个碳原子。炔基的非限制性实例包括但不限于-C≡CH、-CH 2C≡CH、-CH 2C≡CCH 3、-C≡CCH 2CH 3、-CH 2C≡CCH 2CH 3、-C≡CCH(CH 3) 2、-C(CH 3) 2C≡CH、 -C(CH 3) 2C≡CCH 3等。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，其独立地任选选自氢原子、烷基、烷氧基、卤素、卤代烷基、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(例如3、4、5、6、7、8、9、10、11和12个)碳原子，更优选包含3至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元的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，但没有一个环具有完全共轭的π电子系统。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 PCTCN2020136431-appb-000019
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，但没有一个环具有完全共轭的π电子系统。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元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2020136431-appb-000020
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，但没有一个环具有完全共轭的π电子系统。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 PCTCN2020136431-appb-000021
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、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) r(其中r是整数0至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，其中1-3是杂原子；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、1,3-二氧戊环、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元的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、氧或S(O) r(其中r是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。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 PCTCN2020136431-appb-000022
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，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) r(其 中r是整数0至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元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2020136431-appb-000023
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，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) r(其中r是整数0至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 PCTCN2020136431-appb-000024
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 PCTCN2020136431-appb-000025
杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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“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 PCTCN2020136431-appb-000026
芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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“杂芳基”指包含1至4个(例如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 PCTCN2020136431-appb-000027
Figure PCTCN2020136431-appb-000028
杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、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。
上述环烷基、杂环基、芳基和杂芳基具有1个从母体环原子上除去一个氢原子所衍生的残基，或2个从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实例包含四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为四氢吡喃基。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
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“羟基”指-OH基团。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O。
本发明所述化合物的化学结构中，键
Figure PCTCN2020136431-appb-000029
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2020136431-appb-000030
可以为
Figure PCTCN2020136431-appb-000031
或
Figure PCTCN2020136431-appb-000032
或者同时包含
Figure PCTCN2020136431-appb-000033
和
Figure PCTCN2020136431-appb-000034
两种构型。
“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发生，该说明包括该事件或环境发生或不发生的场合。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，优选为最多5个，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。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验 或理论)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/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。
本公开的化合物还可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，包括用“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。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(如体内半衰期增加或剂量需求减少)。本公开的各种氘化形式的式(I)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式(I)化合物。在制备氘代形式的式(I)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。除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。
本公开的化合物可包含其所有方式的旋转异构体和构象上受限的状态。
针对药物或药理学活性剂而言，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。
“前药”是指可以在生理条件下，例如通过在血液中水解，在体内转化以产生活性原药化合物。
“水合物”又称水化物，指的是含有水的化合物，其中水可以是配位与其他部分相连，如水合金属离子，也可以是以共价键相结合，如水合三氯乙醛。
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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式或其可药用的盐的制备方法包括以下步骤：
Figure PCTCN2020136431-appb-000035
通式(IA)的化合物或其可药用的盐，在碱性条件下，发生分子内的亲核取代反应，得到通式(I)所示的化合物，
其中：
R m为烷基；优选C 1-C 6烷基；
环A、G、L、R 1～R 4、n和s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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式或其可药用的盐的制备方法包括以下步骤：
Figure PCTCN2020136431-appb-000036
通式(IIA)的化合物或其可药用的盐，在碱性条件下，发生分子内的亲核取代反应，得到通式(II)所示的化合物，
其中：
R m为烷基；优选C 1-C 6烷基；
G、L、R 1～R 4和s如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式或其可药用的盐的制备方法包括以下步骤：
Figure PCTCN2020136431-appb-000037
通式(IIIA)的化合物或其可药用的盐，在碱性条件下，发生分子内的亲核取代反应，得到通式(III)所示的化合物，
其中：
R m为烷基；优选C 1-C 6烷基；
R 1～R 4和s如通式(III)中所定义。
方案四
本公开通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式或其可药用的盐的制备方法包括以下步骤：
Figure PCTCN2020136431-appb-000038
通式(IVA)的化合物或其可药用的盐，在碱性条件下，发生分子内的亲核取代反应，得到通式(IV)所示的化合物，
其中：
R m为烷基；优选C 1-C 6烷基；
R 1～R 4和s如通式(IV)中所定义。
在上述方案一至方案四中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱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、醋酸钾、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；优选为乙酸钠和氢氧化钠；
上述方案一至方案四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、水或N,N-二甲基甲酰胺及其混合物。
具体实施方式
以下结合实施例进一步描述本公开，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，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高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备色谱法使用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，薄层层析色谱法(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。
硅胶柱层析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)。
本发明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，反应能够均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-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈1
Figure PCTCN2020136431-appb-000039
第一步
2-氰基-2-(2,6-二溴-4-硝基苯基)乙酸叔丁酯1c
将2-氰基乙酸叔丁酯1b(4.9g，34.7mmol，上海毕得医药科技有限公司)溶于N,N-二甲基甲酰胺(70mL)中，再将无水碳酸钾(9.61g，69.5mmol)和1,3-二溴-2-氟-5-硝基苯1a(10.4g，34.7mmol，韶远化学科技(上海)有限公司)加入上述反应体系，油浴加热至60℃，搅拌反应5小时。冷却至室温，反应液减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化，得到标题化合物1c(14g)，产率：95.8％。
MS m/z(ESI):420.9[M+1]。
第二步
2-(2,6-二溴-4-硝基苯基)乙腈1d
将化合物1c(14g，33.3mmol)置于反应瓶中，依次加入浓硫酸(5mL)、水(50mL)和乙酸(50mL)，反应体系加热至100℃搅拌1小时。冰水浴冷却下，向反应液加入水，有固体析出，过滤，真空干燥，得到标题化合物1d(8g)，产率：75％。
第三步
2-(4-氨基-2,6-二溴苯基)乙腈1e
将化合物1d(7.7g，24.1mmol)分散于300mL乙醇和水(V/V＝2/1)的混合溶剂中，再将铁粉(6.7g，120.0mmol)和氯化铵(6.4g，120.0mmol)加入上述反应体系，油浴加热至90℃，搅拌反应1小时。减压浓缩，向所得残余物中加入乙酸乙酯(100mL)，打浆，过滤；向滤液中加入水(50mL)，搅拌，静置分层，收集有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系A纯化，得到标题化合物1e(6g)，产率：86％。
MS m/z(ESI):288.8[M+1]。
第四步
2-(4-氨基-2,6-二溴苯基)-2-(4-氯酞嗪-1-基)乙腈1g
将化合物1e(500mg，1.72mmol)和1,4-二氯酞嗪1f(344mg，1.72mmol，梯希爱(上海)化成工业发展有限公司)溶于四氢呋喃(10mL)中，于0℃加入叔丁醇钾(582mg，5.19mmol)，搅拌反应5分钟。向反应液中加入水(10mL)淬灭反应，用乙酸乙酯萃取(40mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得固体用乙酸乙酯(5mL)打浆，过滤，真空干燥，得到标题化合物1g(550mg)，产率：70.5％。
MS m/z(ESI):452.8[M+1]。
第五步
4-(4-氨基-2,6-二溴苄基)酞嗪-1(2H)-酮1h
将化合物1g(550mg，1.21mmol)置于反应瓶中，依次加入浓盐酸(8mL)、水(2mL)和乙酸(2mL)，反应加热至120℃，搅拌16小时。减压浓缩至干，向所得残余物中加入饱和碳酸氢钠溶液(10mL)，有固体析出，过滤，真空干燥，得到标题化合物1h(400mg)，产率：80.5％。
MS m/z(ESI):409.9[M+1]。
第六步
(Z)-(2-氰基-2-(2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯1j
将化合物1h(80mg，0.20mmol)溶于乙醇(6mL)，再加入浓盐酸(0.3mL)，反应冷却至6～10℃。将亚硝酸钠(20mg，0.29mmol)溶于水(0.4mL)中，加入到上述体系中，搅拌反应0.5小时。依次加入乙酸钠(81mg，0.99mmol)和(2-氰基乙酰基) 氨基甲酸乙酯1i(31mg，0.20mmol，上海毕得医药科技有限公司)，反应体系在6～10℃搅拌0.5小时，恢复至室温后继续搅拌0.5小时。向反应液中加入水至有固体析出，过滤，真空干燥，得到标题化合物1j(100mg)，产率：88.7％。
MS m/z(ESI):576.7[M+1]。
第七步
2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈1
将化合物1j(100mg，0.17mmol)和乙酸钠(300mg，3.66mmol)分散于乙酸(6.0mL)中，加热至140℃，搅拌2小时。冷却至室温，减压浓缩，所得残余物用高效液相制备色谱法((Waters 2545，洗脱体系：0.1％三氟醋酸，水，29％-47％乙腈)纯化，)纯化，得到标题化合物1(50mg)，产率：54.3％。
MS m/z(ESI):530.7[M+1]。
1H NMR(400MHz,DMSO-d 6)δ13.24(brs,1H),12.44(s,1H),8.31-8.27(m,2H),8.02(t,1H),7.93(t,1H),7.85(s,2H),4.74(s,2H)。
实施例2
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-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
Figure PCTCN2020136431-appb-000040
Figure PCTCN2020136431-appb-000041
第一步
2-氰基-2-(2,6-二氯-4-硝基苯基)乙酸叔丁酯2b
将化合物1b(10.5g，74.3mmol)溶于N,N-二甲基甲酰胺(50mL)中，再将无水碳酸钾(13.7g，99.1mmol)和1,3-二氯-2-氟-5-硝基苯2a(10.4g，49.5mmol，韶远化学科技(上海)有限公司)加入上述反应体系，油浴加热至50℃，搅拌反应18小时。冷却至室温，加入乙酸乙酯(50mL)稀释反应液，用饱和氯化钠溶液洗涤(20mL×2)，有机相减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化，得到标题化合物2b(16.4g)，产率：99.9％。
MS m/z(ESI):329.0[M-1]。
第二步
2-(2,6-二氯-4-硝基苯基)乙腈2c
将化合物2b(16.4g，49.5mmol)置于反应瓶中，依次加入浓硫酸(5mL)、水(50mL)和乙酸(50mL)，反应加热至125℃搅拌1小时。冷却至室温，向反应液中加入水，有固体析出，过滤，真空干燥，得到标题化合物2c(11.3g)，产率：98.8％。
第三步
2-(4-氨基-2,6-二氯苯基)乙腈2d
将化合物2c(2.04g，8.83mmol)分散于60mL乙醇和水(V/V＝2/1)的混合溶剂中，再将铁粉(2.5g，44.8mmol)和氯化铵(2.5g，46.7mmol)加入上述反应体系， 油浴加热至75℃，搅拌反应3小时。过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法以洗脱剂体系B，纯化得到标题化合物2d(1.63g)，产率：91.8％。
MS m/z(ESI):201.0[M+1]。
第四步
2-(4-氨基-2,6-二氯苯基)-2-(4-氯酞嗪-1-基)乙腈2e
将化合物2d(1.63g，8.1mmol)和化合物1f(1.7g，8.5mmol)溶于四氢呋喃(25mL)中，于0℃加入叔丁醇钾(2.8g，24.95mmol)，搅拌5分钟。向反应液中加入水(10mL)淬灭反应，再用乙酸乙酯萃取(40mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得固体用乙酸乙酯(5mL)打浆，过滤，真空干燥，得到标题化合物2e(2.38g)，产率：80.7％。
MS m/z(ESI):362.9[M+1]。
第五步
4-(4-氨基-2,6-二氯苄基)酞嗪-1(2H)-酮2f
将化合物2e(1.15g，3.16mmol)置于反应瓶中，依次加入浓盐酸(40mL)、水(10mL)和乙酸(20mL)，反应液加热至130℃搅拌16小时。减压浓缩至干，得到标题化合物2f(1.00g)，产率：98.76％。
MS m/z(ESI):320.0[M+1]。
第六步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯基)腙基)乙酰基)氨基甲酸乙酯2g
将化合物2f(120mg，0.38mmol)溶于乙醇(6mL)中，再加入浓盐酸(0.3mL)，反应体系冷却至6～10℃。将亚硝酸钠(40mg，0.58mmol)溶于水(0.4mL)中，加入到上述体系中，继续反应0.5小时。依次加入乙酸钠(155mg，1.89mmol)和化合物1i(60mg，0.38mmol)，反应液在6～10℃搅拌0.5小时，恢复至室温后继续搅拌0.5小时。向反应液中加入水至有固体析出，过滤，真空干燥，得到标题化合物2g(160mg)，产率：87.6％。
MS m/z(ESI):486.8[M+1]。
第七步
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-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
将化合物2g(160mg，0.33mmol)和乙酸钠(538mg，6.56mmol)分散于乙酸(6.0mL)中，反应加热至140℃搅拌2小时，冷却至室温，减压浓缩，所得残余物用高效液相制备色谱法(Waters 2545，洗脱体系：0.1％三氟醋酸，水，43％-53％乙腈)纯化，得到标题化合物2(35mg)，产率：24.2％。
MS m/z(ESI):440.9[M+1]。
1H NMR(400MHz,DMSO-d 6)δ13.27(brs,1H),12.43(s,1H),8.31-8.26(m, 2H),8.03(t,1H),7.93(t,1H),7.68(s,2H),4.67(s,2H)。
实施例3
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈3
Figure PCTCN2020136431-appb-000042
第一步
3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺3b
将4-氨基-2,6-二氯苯酚3a(393.5mg，2.2mmol，韶远化学科技(上海)有限公司)溶于N,N-二甲基甲酰胺(10mL)，加入化合物1f(400mg，2.0mmol)和碳酸钾(700mg，5.0mmol)，加热至120℃，微波反应1小时。减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化，得到标题化合物3b(450mg)，产率：65.7％。
MS m/z(ESI):339.8[M+1]。
第二步
N-(3,5-二氯-4-((4-氧代-3,4--二氢酞嗪-1-基)氧基)苯基)乙酰胺3c
将化合物3b(900mg，2.64mmol)溶于冰乙酸(20mL)中，加入乙酸钠(2.16g，26.4mmol)，反应体系在130℃搅拌16小时。减压浓缩，得到标题化合物3c(962mg)，产率：99.9％。
MS m/z(ESI):363.8[M+1]。
第三步
4-(4-氨基-2,6-二氯苯氧基)酞嗪-1(2H)-酮3d
将化合物3c(962mg，2.64mmol)溶于乙醇(30mL)和水(15mL)，加入氢氧化钠(11.1g，277mmol)，反应体系在110℃搅拌18小时。减压浓缩，用硅胶柱层析色谱法以洗脱剂体系B纯化，得到标题化合物3d(500mg)，产率：58.7％。
MS m/z(ESI):322.0[M+1]。
第四步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)腙基)乙酰基)氨基甲酸乙酯3e
将化合物3d(350mg，1.0mmol)悬于水(30mL)中，加入浓盐酸(15mL)，反应液冷却至0℃，加入亚硝酸钠(224.8mg，3.26mmol)的水溶液(1mL)，加毕，0℃搅拌1小时，得黄色透明溶液A。在另一个反应瓶中加入化合物1i(186.6mg，1.20mmol)，加入水(10mL)和吡啶(15mL)，冷却至0℃，搅拌得溶液B。于0℃，将溶液A慢慢加入到溶液B中，析出橙色固体，反应在0～5℃搅拌1小时。过滤，滤饼依次用水(10mL×2)、正己烷洗涤(10mL×2)，真空干燥，得到标题化合物3e(500mg)，产率：94％。
MS m/z(ESI):489.0[M+1]
第五步
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈3
将化合物3e(500mg，1.0mmol)溶于冰乙酸(25mL)中，加入乙酸钠(838mg，10.22mmol)，反应体系在130℃搅拌3小时。减压浓缩，用高效液相制备色谱法(Waters 2545，洗脱体系：0.1％三氟醋酸，水，40％-54％乙腈)纯化，得标题化合物3(340mg)，产率：75％。
MS m/z(ESI):442.9[M+1]。
1H NMR(400MHz,DMSO-d 6)δ13.35(brs,1H),12.05(s,1H),8.33(d,1H),8.27(d,1H),8.11(t,1H),8.04(t,1H),7.84(s,2H)。
实施例4
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮4
Figure PCTCN2020136431-appb-000043
Figure PCTCN2020136431-appb-000044
第一步
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸4a
将化合物3(50mg，0.11mmol)溶于乙酸(2.2mL)和浓盐酸(0.25mL)中，反应体系在120℃搅拌2小时。原料未反应完全，补加乙酸(5mL)和浓盐酸(1mL)，继续搅拌2小时。减压浓缩，所得残余物用30mL乙酸乙酯和正己烷(V/V＝1/5)打浆，过滤，真空干燥，得到标题化合物4a(44mg)，产率：84％。
MS m/z(ESI):462.0[M+1]。
1H NMR(400MHz,DMSO-d 6):δ12.76-12.88(brs,1H),12.62-12.75(brs,1H),12.01(s,1H),8.32(d,1H),8.27(d,1H),8.09(t,1H),8.03(t,1H),7.84(s,2H)。
第二步
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮4
将化合物4a(44mg，0.10mmol)溶于巯基乙酸(5mL)，反应体系在170℃搅拌1小时。反应液降至室温后加水(30mL)稀释，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和碳酸氢钠洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以展开剂体系B纯化，得到标题化合物4(15mg)，产率：38％。
MS m/z(ESI):418.0[M+1]。
1H NMR(400MHz,DMSO-d 6):δ12.44-12.62(brs,1H),12.03(s,1H),8.31(d,1H),8.26(d,1H),8.09(t,1H),8.03(t,1H),7.84(s,2H),7.71(s,1H)。
实施例5
2-(3,5-二溴-4-((1-氧代-1,2-二氢异喹啉-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈5
Figure PCTCN2020136431-appb-000045
Figure PCTCN2020136431-appb-000046
第一步
1-氯-4-(2,6-二溴-4-硝基苯氧基)异喹啉5b
将1-氯异喹啉-4-酚5a(500mg，2.78mmol，药明览博(武汉)化学科技有限公司)溶于N,N-二甲基甲酰胺(20mL)，依次加入化合物1a(999mg，3.34mmol)、碳酸钾(1.15g，8.32mmol)，搅拌反应18小时。加入二氯甲烷(50mL)稀释，用饱和氯化钠溶液洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以展开剂体系B纯化，得到标题化合物5b(1.0g)，产率：78％。
MS m/z(ESI):458.8[M+1]。
1H NMR(400MHz,DMSO-d 6):δ8.72(s,2H),8.46(d,1H),8.35(d,1H),8.09(t,1H),8.00(t,1H),7.57(s,1H)。
第二步
3,5-二溴-4-((1-氯异喹啉-4-基)氧基)苯胺5c
将化合物5b(1.0g，2.18mmol)溶于乙醇(20mL)和水(10mL)，依次加入铁粉(609mg，10.90mmol)、氯化铵(583mg，10.90mmol)，反应体系在80℃搅拌2小时，过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以展开剂体系B纯化，得到标题化合物5c(450mg)，产率：48％。
MS m/z(ESI):428.9[M+1]。
第三步
N-(3,5-二溴-4-((1-氧代-1,2-二氢异喹啉-4-基)氧基)苯基)乙酰胺5d
将化合物5c(432mg，1.01mmol)溶于乙酸(15mL)，加入乙酸钠(1.24g，15.12mmol)，油浴加热至134℃，搅拌反应18小时。反应降至室温后减压浓缩，加水(40mL)稀释，冰水浴降温至0～5℃，滴加1M氢氧化钠溶液至反应液pH为13～14，用 乙酸乙酯萃取(50mL×3)，合并有机相，饱和氯化钠溶液洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物5d(450mg)，产率：98％。
MS m/z(ESI):452.9[M+1]。
第四步
4-(4-氨基-2,6-二溴苯氧基)异喹啉-1(2H)-酮5e
在反应瓶中依次加入化合物5d(450mg，1.00mmol)、氢氧化钠(398mg，9.95mmol)、水(5mL)，反应体系在110℃搅拌2小时。原料未反应完全，补加氢氧化钠(1.19g，29.75mmol)，反应体系在115℃继续搅拌2小时。降温后加水(40mL)稀释，用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以展开剂体系A纯化，得到标题化合物5e(230mg)，产率：56％。
MS m/z(ESI):410.9[M+1]。
1H NMR(400MHz,DMSO-d 6):δ10.73-11.01(brs,1H),8.23(d,1H),8.04(d,1H),7.86(t,1H),7.63(t,1H),6.91(s,2H),6.07(s,1H),5.42-5.87(brs,2H)。
第五步
(Z)-(2-氰基-2-(2-(3,5-二溴-4-((1-氧代-1,2-二氢异喹啉-4-基)氧基)苯基)腙基)乙酰基)氨基甲酸乙酯5f
将化合物5e(222mg，0.54mmol)悬浮于水(6mL)，加入浓盐酸(3mL)，冷却至0℃，加入亚硝酸钠(56mg，0.81mmol)的水溶液(1mL)，加毕，反应在0℃搅拌1小时，得橘红色的溶液A。在另一个反应瓶中加入化合物1i(93mg，0.59mmol)、水(6mL)和吡啶(3mL)，冷却至0℃，搅拌得溶液B。在0℃，将溶液A慢慢加入到溶液B中，析出橘红色固体，反应在0～5℃搅拌1小时。过滤，滤饼依次用水(5mL×2)、正己烷洗涤(5mL×2)，真空干燥，得到标题化合物5f(220mg)，产率：70％。
第六步
2-(3,5-二溴-4-((1-氧代-1,2-二氢异喹啉-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈5
将化合物5f(220mg，0.38mmol)溶于乙酸(10mL)，加入乙酸钠(156mg，1.90mmol)，反应体系在130℃搅拌2小时。降温后减压浓缩，用高效液相制备色谱法(Waters 2545，洗脱体系：0.1％三氟醋酸，水，40％-60％乙腈)纯化，得到标题化合物5(75mg)，产率：37％。
MS m/z(ESI):531.9[M+1]。
1H NMR(400MHz,DMSO-d 6):δ13.06-13.44(brs,1H),10.84-11.07(brs,1H),8.26(d,1H),8.08(d,1H),7.96(s,2H),7.90(t,1H),7.67(t,1H),6.27(d,1H)。
实施例6
2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢 -1,2,4-三嗪-6-甲腈6
Figure PCTCN2020136431-appb-000047
第一步
3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺6b
采用实施例3的合成路线，将第一步原料3a替换为原料4-氨基-2,6-二溴苯酚6a(上海阿拉丁生化科技股份有限公司)，制得标题化合物6b(470mg)，产率：58.8％。
MS m/z(ESI):429.9[M+1]。
第二步
N-(3,5-二溴-4-((4-氧代-3,4--二氢酞嗪-1-基)氧基)苯基)乙酰胺6c
采用实施例3的合成路线，将第二步化合物3b替换为化合物6b，制得标题化合物6c(490mg)，产率：98.8％。
MS m/z(ESI):453.9[M+1]。
第三步
4-(4-氨基-2,6-二溴苯氧基)酞嗪-1(2H)-酮6d
采用实施例3的合成路线，将第三步化合物3c替换为化合物6c，制得标题化合物6d(240mg)，产率：66.1％。
MS m/z(ESI):411.8[M+1]。
第四步
(Z)-(2-氰基-2-(2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)腙基)乙酰基)氨基甲酸乙酯6e
采用实施例3的合成路线，将第四步化合物3d替换为化合物6d，制得标题化合物6e(240mg)，产率：71.1％。
MS m/z(ESI):578.7[M+1]。
第五步
2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈6
采用实施例3的合成路线，将第五步化合物3e替换为化合物6e，制得标题化合物6(110mg)，产率：49.8％。
MS m/z(ESI):532.6[M+1]。
1H NMR(400MHz,d 6-DMSO)δ13.15(brs,1H),12.05(s,1H),8.33(d,1H),8.27(d,1H),8.11(t,1H),8.04(t,1H),7.96(s,2H)。
实施例7
2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈7
Figure PCTCN2020136431-appb-000048
第一步
2,6-二溴-4-硝基苯硫酚7c
将化合物1,3-二溴-2-氟-5-硝基苯7a(2g，6.69mmol，上海乐研实业发展有限公司)溶于10mL N,N-二甲基甲酰胺，再将硫化钠7b(0.64g，7.38mmol，百灵威科技有限公司)缓慢加入到上述体系中。在氮气氛下，搅拌反应2.5小时。向反应液中加入30mL水，用NaOH溶液(1N)调节反应液pH为11，用二氯甲烷萃取(15mL×2)，水相用浓盐酸调节pH至2～3，有固体析出，抽滤，滤饼减压干燥，得到标题化合物7c(1.6g，产率：76.4％)。
MS m/z(ESI):311.7[M-1]。
第二步
1-氯-4-((2,6-二溴-4-硝基苯基)硫基)酞嗪7d
将化合物7c(650mg，2.0769mmol)和化合物1f(413mg，2.0750mmol)分散于15mL乙腈中，搅拌反应1小时，减压浓缩，得到标题化合物7d(0.9g，产率：91.13％)。
MS m/z(ESI):475.6[M+1]。
第三步
3,5-二溴-4-((4-氯酞嗪-1-基)硫基)苯胺7e
将化合物7d(0.9g，1.89mmol)分散于30mL乙醇和水(V/V＝2/1)的混合溶剂中，再将铁粉(0.53g，9.49mmol)和氯化铵(0.53g，9.91mmol)加入上述反应体系，油浴加热至75℃，搅拌反应3小时。减压浓缩除去溶剂，所得残余物用硅胶柱层析色谱法以洗脱剂体系B纯化，得到标题化合物7e(0.2g，产率：23.7％)。
MS m/z(ESI):445.7[M+1]。
第四步
4-((4-氨基-2,6-二溴苯基)硫基)酞嗪-1(2H)-酮7f
向化合物7e(0.18g，0.40mmol)中依次加入4mL浓盐酸、2mL水和4mL乙酸，反应体系加热至130℃搅拌2.5小时。减压浓缩至干，向所得残余物中加入10mL饱和碳酸氢钠溶液，有固体析出，过滤，干燥，得到标题化合物7f(0.17g，产率：98.5％)。
MS m/z(ESI):427.8[M+1]。
第五步
(Z)-(2-氰基-2-(2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)腙基)乙酰基)氨基甲酸乙酯7g
将化合物7f(170mg，0.40mmol)分散于3mL浓盐酸中，再加入6mL水，冷却至0℃，将亚硝酸钠(42mg，0.61mmol)溶于1mL水中，加入到上述体系中，继续搅拌1小时，所得重氮液备用。将化合物1i(63mg，0.40mmol)溶于3mL吡啶中，加入4mL水，冷却至0℃，将已制备好的重氮液倾倒入反应体系中，在0～5℃继续搅拌1小时，过滤，干燥，得到标题化合物7g(140mg，产率：59.2％)。
MS m/z(ESI):594.3[M+1]。
第六步
2-(3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈7
将化合物7g(140mg，0.26mmol)溶于10mL N,N-二甲基乙酰胺中，加入乙酸钾(47mg，0.48mmol)，加热至120℃，搅拌反应2小时。冷却至室温，减压浓缩，所得残余物用高效液相制备色谱法(Waters 2767-SQ Detecor2，洗脱体系：0.1％三氟醋酸，水，45％-58％乙腈)纯化，得到标题化合物7(41mg，产率：31.8％)。
MS m/z(ESI):548.3[M+1]。
1H NMR(500MHz,DMSO-d 6):13.33-12.94(brs,1H),12.7(s,1H),8.32(d,1H),8.10-8.04(m,2H),8.01(s,2H),7.98(t,1H)。
实施例8
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈8
Figure PCTCN2020136431-appb-000049
第一步
2,6-二氯-4-硝基苯硫酚8b
采用实施例7中化合物7c的合成方法，将化合物7a替换为化合物1,3-二氯-2-氟-5-硝基苯8a，制得标题化合物8b(8.36g，收率：78％)。
MS m/z(ESI):222.2[M-1]。
1H NMR(500MHz,DMSO-d 6):8.10(s,2H)。
第二步
1-氯-4-((2,6-二氯-4-硝基苯基)硫基)酞嗪8c
将化合物8b(799mg，3.56mmol)、化合物1f(710mg，3.56mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸钾(986mg，7.13mol)，搅拌反应2小时。加入水(30mL)，用二氯甲烷萃取(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法以展开剂体系B(正己烷:乙酸乙酯＝9:1)纯化，得到标题化合物8c(462mg，产率：33％)。
MS m/z(ESI):387.5[M+1]。
第三步
3,5-二氯-4-((4-氯酞嗪-1-基)硫基)苯胺8d
采用实施例7中化合物7e的合成方法，将化合物7d替换为化合物8c，制得标题化合物8d(130mg，收率：31％)。
MS m/z(ESI):357.9[M+1]。
1H NMR(500MHz,DMSO-d 6):8.40-8.35(m,1H),8.34-8.28(m,1H),8.24-8.17(m,2H),6.83(s,2H),6.26(brs,2H)。
第四步
4-((4-氨基-2,6-二氯苯基)硫基)酞嗪-1(2H)-酮8e
采用实施例7中化合物7f的合成方法，将化合物7e替换为化合物8d，制得标题化合物8e(113mg，收率：99％)。
MS m/z(ESI):338.0[M+1]。
第五步
(Z)-(2-氰基-2-(2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)腙基)乙酰基)氨基甲酸乙酯8f
采用实施例7中化合物7g的合成方法，将化合物7f替换为化合物8e，制得标题化合物8f(87mg，收率：52％)。
MS m/z(ESI):505.0[M+1]
第六步
2-(3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)硫基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈8
采用实施例7中化合物7的合成路线，将化合物7g替换为化合物8f，制得标题化合物8(33mg，收率：43％)。
MS m/z(ESI):458.9[M+1]。
1H NMR(500MHz,DMSO-d 6):13.51-13.12(brs,1H),12.67(s,1H),8.30(d,1H),8.12-8.00(m,2H),7.96(t,1H),7.85(s,2H)。
测试例：
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本公开化合物对THRα(甲状腺激素受体α)以及THRβ(甲状腺激素受体β)的激动作用。根据EC 50以及Emax(最大效应)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(ATCC，货号CCL-61)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95ul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)上检测化学发光。
本公开化合物对THRα和THRβ的激动作用的EC 50值见表1。
表1本公开化合物对THRα和THRβ的激动作用的EC 50值。
Figure PCTCN2020136431-appb-000050
备注：Emax＝受试化合物组最大读值-T3组最小读值)/(T3组最大读值-T3组最小读值)*100；T3组指添加T3的对照组。
结论：本公开化合物对THRβ具有高选择性。

Claims (19)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
    Figure PCTCN2020136431-appb-100001
    其中：
    G为CR 5或N原子；
    环A选自芳基和杂芳基；
    L选自亚烷基、O原子和S原子；其中所述的亚烷基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、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；
    R 1相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
    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、氨基、硝基、羟基、羟烷基、-COOR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、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、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；
    R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
    R 4选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基任选被选自羟基、-OC(O)R 7、-OP(O)(OR 8) 2中的 一个或多个取代基所取代；
    R 5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、氨基、硝基、羟基、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、烷氧基、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、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；
    R 6选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 7选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 8选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3或4；和
    s为0、1、2、3或4。
  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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中环A为苯基或噻吩基。
  3. 根据权利要求1或2中所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
    Figure PCTCN2020136431-appb-100002
    其中
    R 1～R 4、G、L和s如权利要求1中所定义。
  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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中L选自CH 2、O原子和S原子，优选地，L为S原子。
  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、 内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中G为CH或N原子。
  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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
    Figure PCTCN2020136431-appb-100003
    其中：
    R 1～R 4和s如权利要求1中所定义。
  7. 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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其为通式(IV)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
    Figure PCTCN2020136431-appb-100004
    其中：
    R 1～R 4和s如权利要求1中所定义。
  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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 1相同或不同，且各自独立地为氢原子或卤素。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 2选自氢原子、卤素、氰基和烷基，优选地，R 2为 氰基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 3选自氢原子、卤素、烷基和环烷基；优选地，R 3为氢原子。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中R 4为氢原子或烷基；优选地R 4为氢原子。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2020136431-appb-100005
  13. 一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐：
    Figure PCTCN2020136431-appb-100006
    其中：
    R m为烷基；
    G为CR 5或N原子；
    环A选自芳基和杂芳基；
    L选自亚烷基、O原子和S原子；其中所述的亚烷基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、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；
    R 1相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
    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、氨基、硝基、羟基、羟烷基、-COOR 6、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、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、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；
    R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、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、烷氧基、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、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；
    R 4选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基任选被选自羟基、-OC(O)R 7、-OP(O)(OR 8) 2中的一个或多个取代基所取代；
    R 5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、氨基、硝基、羟基、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、烷氧基、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、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；
    R 6选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 7选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    R 8选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3或4；和
    s为0、1、2、3或4。
  14. 根据权利要求13中所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2020136431-appb-100007
  15. 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、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐，其包括以下步骤：
    Figure PCTCN2020136431-appb-100008
    通式(IA)的化合物或其可药用的盐发生分子内反应，得到通式(I)所示的化合物，
    其中：
    R m为烷基；
    环A、G、L、R 1～R 4、n和s如权利要求1中所定义。
  16. 一种药物组合物，其含有根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、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。
  17. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐或根据权利要求16所述的药物组合物在制备THRβ激动剂中的用途。
  18. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐、或根据权利要求16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。
  19. 根据权利要求1～12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、前药、水合物、或其混合物形式、或其可药用的盐、或根据权利要求16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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