WO2022242743A1 - 一种杂环化合物及其应用 - Google Patents

一种杂环化合物及其应用 Download PDF

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WO2022242743A1
WO2022242743A1 PCT/CN2022/094094 CN2022094094W WO2022242743A1 WO 2022242743 A1 WO2022242743 A1 WO 2022242743A1 CN 2022094094 W CN2022094094 W CN 2022094094W WO 2022242743 A1 WO2022242743 A1 WO 2022242743A1
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alkyl
unsubstituted
oxy
cycloalkyl
substituted
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PCT/CN2022/094094
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English (en)
French (fr)
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邓舟
周游
山松
叶志勇
张堃
潘德思
李志斌
鲁先平
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深圳微芯生物科技股份有限公司
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Priority to CN202280032814.6A priority Critical patent/CN117279911A/zh
Publication of WO2022242743A1 publication Critical patent/WO2022242743A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a heterocyclic compound and its application.
  • Thyroid hormone plays a key role in normal growth and development and maintenance of metabolic balance (Paul M Yen, Physiological Reviews, Vol. 81(3): pp. 1097-1126 (2001)).
  • TH can promote the hydrolysis of lipids, increase the utilization of fatty acids, thereby providing energy for the body, and finally lead to the reduction of lipids and weight loss.
  • Studies have shown that the TH level of obese patients has a great change compared with that of normal people.
  • T4 is the predominant form secreted by the thyroid
  • T3 is the more physiologically active form.
  • T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues but mainly in the liver and kidney.
  • tissue-specific deiodinases which are present in all tissues but mainly in the liver and kidney.
  • Relevant studies have shown that T3 or T3 analogues can effectively treat obesity, especially when intervened with low-calorie food at the same time, the weight loss effect is more obvious. Therefore, controlling the level of TH can effectively regulate the energy balance.
  • hypothyroidism hypothyroidism
  • LDL-C low-density lipoprotein-cholesterol
  • tachycardia, arrhythmias, and heart failure have been observed in hyperthyroidism, as well as feelings of fatigue, shortness of breath, and skeletal sarcopenia and osteoporosis (Physiology Review, 81 Volume: 1097 pages (2001)).
  • beneficial phenomena for the treatment of metabolic diseases such as reduction of blood cholesterol and increase of basal metabolism have also been observed.
  • hypothyroidism hypothyroidism
  • a decrease in heart rate, an increase in blood cholesterol, and an increase in body weight are observed. This is why the cardiotoxicity of naturally occurring thyroid hormones limits their therapeutic use.
  • TRs nuclear receptors - thyroid hormone receptors
  • TRs nuclear receptors - thyroid hormone receptors
  • TRs form heterodimers with retinoid receptors that act as ligand-induced transcription factors.
  • TRs possess a ligand-binding domain, a DNA-binding domain, and an amino-terminal domain, and regulate gene expression through interactions with NDA-corresponding elements and with various nuclear co-activators and co-repressors.
  • TRs are encoded by different genes ⁇ and ⁇ located on human chromosomes 17 and 3, respectively, and different protein isoforms are produced by alternative splicing of primary transcripts, and each gene produces two isoforms: ⁇ 1, ⁇ 2 , ⁇ 1 and ⁇ 2.
  • TR ⁇ 1, TR ⁇ 1 and TR ⁇ 2 can combine with T3, TR ⁇ 2 can not combine with TH.
  • thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses.
  • TR ⁇ 1 is present in most tissues, especially the liver.
  • the distribution of TR ⁇ 1 is also relatively wide, and TH has similar activity when binding TR ⁇ 1 and TR ⁇ 1, but its distribution range is smaller than that of TR ⁇ 1.
  • Studies have shown that most of the effects of TH on the heart, especially heart rhythm and heart rate, are mainly achieved through the TR ⁇ 1 subtype .
  • TH mainly regulates gene expression on target organs (liver) through receptors to maintain metabolic balance, including maintaining lipid balance in liver and adipose tissue. Therefore, specifically exerting the beneficial aspects of TH and its analogues such as lowering of cholesterol or increasing of basal metabolism while avoiding the harmful events mentioned above, and their specific accumulation in the liver is of clinical significance and will open new avenues for the treatment of patients with metabolic diseases
  • metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other diseases such as hepatic steatosis and nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, etc. Therefore, it is of great significance to provide thyroid hormone beta receptor agonists for the treatment and/or prevention of diseases regulated by thyroid hormone.
  • the applicant's previous Chinese patent application CN112300133A has disclosed the structure of a heterocyclic compound with agonistic activity on thyroid hormone receptor ⁇ . On this basis, the applicant further optimized and modified the series of TR ⁇ agonists in order to obtain pharmaceutically acceptable compounds with higher selectivity to TR ⁇ and stronger agonistic activity.
  • the technical problem to be solved by the present invention is to provide a heterocyclic compound.
  • the heterocyclic compound provided by the present invention has better TR ⁇ agonistic activity and TR ⁇ selectivity.
  • X is selected from N or CH
  • R 1 and R 2 are independently selected from F, Cl, Br, I or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 and R 2 are independently selected from Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 1 and R 2 are independently selected from Cl or Br;
  • R 1 and R 2 are the same group
  • R 3 is selected from C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl; wherein, when R 1 and R 2 are both Cl and X is CH, R 3 is not methyl;
  • R 3 is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; preferably, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl is unsubstituted or independently Substituted by one or more of the following substituents: F, Cl or Br;
  • R is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, preferably, methyl, ethyl, propyl, isopropyl, cyclo
  • the substituents of propyl or cyclobutyl are independently selected from one or more of the following groups: F, Cl or Br.
  • R and R are both Cl.
  • R and R are both Br.
  • X is CH
  • R 1 and R 2 are both Br
  • R 3 is selected from C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 3 is selected from C 1 -C 6 alkyl groups that are unsubstituted or independently substituted by one or more of the following groups: D, F, Cl , Br or substituted or Unsubstituted C 1 ⁇ C 3 alkyl;
  • R 3 is selected from C 1 -C 4 alkyl
  • R3 is selected from methyl, ethyl, propyl and isopropyl.
  • X is CH
  • R 1 and R 2 are Cl
  • R 3 is selected from C 2 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 2 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 3 is selected from C 2 -C 4 alkyl or C 3 -C 6 cycloalkyl, and said C 2 -C 4 alkyl or C 3 -C 6 cycloalkyl is unsubstituted or independently replaced by one or more of the following substituents: F, Cl or Br;
  • R is selected from ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl being unsubstituted Or independently substituted by one or more of the following substituents: F, Cl or Br;
  • R is selected from ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and cyclobutyl;
  • R3 is selected from ethyl, isopropyl and cyclobutyl.
  • X is N
  • R 1 and R 2 are independently selected from F, Cl, Br, I or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 3 is selected from C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl.
  • X is N
  • R 1 and R 2 are Cl
  • R 3 is selected from C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 3 is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, and said C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl is unsubstituted or independently replaced by one or more of the following substituents: F, Cl or Br;
  • R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl or Br;
  • R3 is selected from methyl, isopropyl and cyclopropyl.
  • X is selected from N or CH;
  • R 1 and R 2 are Cl
  • R 3 is selected from C 2 -C 6 alkyl or C 3 -C 8 cycloalkyl, said C 2 -C 6 alkyl or C 3 -C 8 cycloalkyl is unsubstituted or independently replaced by one or more The following groups are substituted: D, F, Cl, Br or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 3 is selected from C 2 -C 4 alkyl or C 3 -C 6 cycloalkyl, and said C 2 -C 4 alkyl or C 3 -C 6 cycloalkyl is unsubstituted or independently replaced by one or more of the following substituents: F, Cl or Br;
  • R is selected from ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, said ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl being unsubstituted or independently Substituted by one or more of the following substituents: F, Cl or Br;
  • R3 is selected from ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropyl or cyclobutyl.
  • heterocyclic compound is selected from the specific compounds shown below:
  • the present invention also provides methods for preparing the compounds.
  • the preparation of the compound described in the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way.
  • the compounds described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and methods described in the present invention can be used.
  • the products obtained in each reaction step are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, and the like.
  • the starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.
  • the compound described in the general formula (I) of the present invention can be synthesized according to the route described in the following method: 1) After the starting material A is alkalized in a low-temperature organic solvent, it is condensed with the haloalkane (compound 1) of R3 under normal temperature conditions 2) Substitution reaction of intermediate A1 with p-aminophenol (compound 2) containing R 1 and R 2 substituents (compound 2) to obtain intermediate A2; Substitution reaction of acetylurethane (compound 3) produces intermediate A3; 4) intramolecular degreasing condensation of intermediate A3 to obtain the target compound formula I.
  • R 1 , R 2 , and R 3 are as described above.
  • the pharmaceutical composition includes a therapeutically and/or preventively effective amount of the heterocyclic compound represented by the above-mentioned formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally a pharmaceutically acceptable drug Carriers and/or excipients and/or diluents.
  • the present invention also provides the application of the compound or its pharmaceutically acceptable salt/stereoisomer, or the pharmaceutical composition in the preparation of an agonist that stimulates thyroid hormone.
  • the present invention also provides the compound or its pharmaceutically acceptable salt/stereoisomer, or the use of the pharmaceutical composition in the preparation of drugs for the treatment and/or prevention of thyroid hormone-related diseases application.
  • the present invention also provides the application of the compound or its pharmaceutically acceptable salt/stereoisomer, or the pharmaceutical composition, in the treatment and/or prevention of thyroid hormone-related diseases.
  • Another object of the present invention is to provide a method for treating and/or preventing thyroid hormone-related diseases, which includes administering to individuals in need a therapeutically and/or preventively effective amount of: the compound or its pharmaceutically acceptable Accepted salts/stereoisomers, or the pharmaceutical compositions described.
  • the present invention also provides the compound or its pharmaceutically acceptable salt/stereoisomer, or the pharmaceutical composition used in the preparation of thyroid hormone receptor agonists, especially thyroid hormone ⁇ receptor Use in body agonists (such as thyroid hormone ⁇ 1 receptor agonists).
  • the present invention also provides the compound or its pharmaceutically acceptable salt/stereoisomer, or the use of the pharmaceutical composition in the preparation of drugs for the treatment and/or prevention of thyroid hormone-related diseases use.
  • the present invention also provides the compound or its pharmaceutically acceptable salt/stereoisomer, or the pharmaceutical composition, which is used for treating and/or preventing thyroid hormone-related diseases.
  • the present invention also provides a method for treating and/or preventing thyroid hormone-related diseases, comprising administering a therapeutically and/or preventively effective amount of the compound or its pharmaceutically acceptable amount to an individual in need thereof salts/stereoisomers, or the pharmaceutical composition.
  • the thyroid hormone-related disease is a metabolic disease, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiac Blood vessel disease, hypothyroidism, or thyroid cancer.
  • a metabolic disease such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiac Blood vessel disease, hypothyroidism, or thyroid cancer.
  • treatment generally refers to obtaining desired pharmacological and/or physiological effects, and covers any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, that is, preventing its development; or (b) alleviating Symptoms of disease, ie, cause disease or regression of symptoms.
  • a vertebrate refers to a vertebrate.
  • a vertebrate is a mammal.
  • Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats.
  • a mammal is a human.
  • an effective amount refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dose and time.
  • a “therapeutically effective amount” of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual.
  • a therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance/molecule outweigh any toxic or detrimental consequences.
  • a “prophylactically effective amount” refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect.
  • the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease.
  • the therapeutically effective amount of the drug reduces the number of cancer cells; reduces tumor volume; inhibits (i.e. slows down to some extent, preferably stops) the infiltration of cancer cells into surrounding organs; inhibits (i.e. slows down to some extent, preferably stops) ) tumor metastasis; inhibition of tumor growth to a certain extent; and/or alleviation of one or more symptoms associated with cancer to a certain extent.
  • examples of the term "pharmaceutically acceptable salts of compounds represented by formula (I)" are organic acid addition salts formed from organic acids that form pharmaceutically acceptable anions, including but not limited to formazan salt, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, alpha-ketoglutarate, alpha- Glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkylsulfonate is methylsulfonate or ethylsulfonate; the arylsulfonate is benzenesulfonic acid salt or p-toluenesulfonate.
  • Suitable inorganic salts may also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, and carbonate, sulfate or phosphate salts, and the like.
  • Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid to furnish a pharmaceutically acceptable anion.
  • C 1-6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl, or independently disclosed "C 2- 6 alkyl", or independently disclosed "C 1-4 alkyl", or independently disclosed "C 1-3 alkyl”.
  • alkyl means a straight chain or branched saturated hydrocarbon group.
  • alkyl specifically methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert-butyl) and the like.
  • alkenyl refers to a hydrocarbon chain including straight or branched configurations and having one or more carbon-carbon double bonds which may exist at any stable point along the chain.
  • C 2-6 alkenyl includes C 2 , C 3 , C 4 , C 5 and C 6 alkenyl.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl , 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.
  • alkynyl refers to hydrocarbon groups including straight or branched chain configurations and having one or more carbon-carbon triple bonds which may exist at any stable point along the chain.
  • C 2-6 alkynyl includes C 2 , C 3 , C 4 , C 5 and C 6 alkynyl.
  • alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkyl and cycloalkyl groups can be substituted or unsubstituted. In the case of substitution, there are typically, for example, 1 to 4 substituents, preferably 2-3 substituents.
  • Substituents may include, for example: carbon-containing groups such as alkyl groups, aryl groups, aralkyl groups (such as substituted and unsubstituted phenyl groups, substituted and unsubstituted benzyl groups); halogen atoms and halogen-containing groups such as haloalkyl groups; groups (such as trifluoromethyl); oxygen-containing groups such as alcohols (hydroxyl, hydroxyalkyl, aryl (hydroxy)alkyl), ethers (such as alkoxy, aryloxy, alkoxyalkyl, aryloxy alkyl), aldehydes (such as formaldehyde), ketones (such as alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,
  • substituted means that any one or more hydrogens on the designated atom or group are replaced by the selection of the designated group, provided that the designated atom's normal valence is not exceeded.
  • cycloalkyl refers to cyclized alkyl groups, including monocyclic, bicyclic or polycyclic ring systems.
  • C 3-7 cycloalkyl refers to C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl, such as C 3-6 cycloalkyl.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to an aromatic hydrocarbon group having a single ring or condensed rings, such as a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 ring-forming carbon atoms, such as phenyl and naphthyl.
  • heterocycle used interchangeably and include 3-membered to 7-membered monocyclic groups, 7-membered to 11-membered bicyclic groups, Cyclic groups and 10-membered to 15-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S or N), the heteroatom-containing ring preferably has 1, 2 or 3 selected from O, S and N heteroatoms.
  • Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, And with the further proviso that the ring contains at least one carbon atom.
  • the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atoms can be optionally quaternized.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated.
  • a heterocyclic group can be attached at any available nitrogen or carbon atom.
  • the present invention provides a heterocyclic compound with a structure shown in formula (I): by selecting a specific modification group, the experimental results show that the heterocyclic compound provided by the present invention acts as a thyroid hormone ⁇ receptor Compared with the prior art, the body agonist has better activity and/or selectivity, and can be used to treat and/or prevent diseases caused by thyroid hormone regulation.
  • the present invention provides a heterocyclic compound and its application.
  • Those skilled in the art can refer to the content of this article to appropriately improve the structure and group realization.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they all belong to the protection scope of the present invention.
  • the method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method and application herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention Invent technology.
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy) ) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 4 Preparation of 2-(3,5-dibromo-4-((7-methyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5- Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy) ) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 4 Preparation of 2-(3,5-dichloro-4-((7-ethyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5- Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • the target 3,5-dichloro-4-((7-isopropyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)aniline (223 mg, 66.0% yield), LC-MS (m/z) 338.2 (M+1).
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy Base) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 4 Preparation of 2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5 -Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Step 2 Preparation of (2-cyano-2-(2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy Base) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 3 Preparation of 2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5 -Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • the target 3,5-dichloro-4-((7-cyclobutyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)aniline (219 mg, 61.7% yield), LC-MS (m/z) 350.2 (M+1).
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy Base) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 4 Preparation of 2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5 -Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • Step 2 Preparation of (2-cyano-2-(2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy) ) phenyl) hydrazono) acetyl) ethyl carbamate
  • Step 3 Preparation of 2-(3,5-dibromo-4-((7-ethyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5- Dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Step 3 Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrole[2,3-d ]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate)
  • Step 4 Preparation of 2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy) Phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Step 3 Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrole[2,3 -d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate)
  • Step 4 Preparation of 2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy Base) phenyl) -3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Step 2 Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)hydrazono ) acetyl) urethane)
  • 3,5-Dichloro-4-((9-methyl-9H-purin-6-yl)oxy)aniline (388mg, 1.25mmol) was dissolved in a solution of hydrochloric acid (4ml) and water (5ml), After cooling down to 0-5°C, an aqueous solution of sodium nitrite (104mg, 1.5mmol) was added dropwise, and the mixture was incubated for 30 minutes to prepare a reaction mother liquor.
  • Step 3 Preparation of 2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3, 4,5-Tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Step 2 Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)hydrazine base) acetyl) urethane)
  • 3,5-Dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)aniline (431mg, 1.27mmol) was dissolved in a solution of hydrochloric acid (4ml) and water (5ml) , cooled to 0-5° C., and then added dropwise with an aqueous solution of sodium nitrite (104 mg, 1.5 mmol), and kept for 30 minutes to prepare a reaction mother liquor.
  • Step 3 Preparation of 2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3 ,4,5-Tetrahydro-[1,2,4]triazine-6-carbonitrile
  • reaction system is protected by nitrogen replacement, heating and stirring to raise the temperature to 120°C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and reduce pressure
  • the target 3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)aniline (342 mg, 67.8% yield), LC-MS (m/z) 337.2 (M +1).
  • Step 2 Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)hydrazine base) acetyl) urethane)
  • 3,5-Dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)aniline (340 mg, 1 mmol) was dissolved in a solution of hydrochloric acid (4 ml) and water (5 ml), After cooling down to 0-5°C, an aqueous solution of sodium nitrite (83mg, 1.2mmol) was added dropwise, and the mixture was incubated for 30 minutes to obtain a reaction mother liquor.
  • Step 3 Preparation of 2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3 ,4,5-Tetrahydro-[1,2,4]triazine-6-carbonitrile
  • Example 1 of CN112300133A For its structure and preparation method, refer to Example 1 of CN112300133A.
  • Example 4 For its structure and preparation method, refer to Example 4 of CN112300133A.
  • the pcDNA3.1 vector (manufactured by Invitrogen) of TR ⁇ 1 or TR ⁇ 1 cloned from human liver cells and the firefly luciferase vector pTA-TRE- Luc (manufactured by Promega) was transfected into CV-1 cells cultured in Dulbecco's modified Eagle medium (DMEM). 16 hours after transfection, compounds diluted with dimethyl sulfoxide solution were added, and luciferase activity was measured 24 hours later.
  • DMEM Dulbecco's modified Eagle medium
  • T 3 3,3',5-Triiodo-L-thyroxine
  • T 3 3,3',5-Triiodo-L-thyroxine
  • the respective EC 50 values and maximum luciferase activity values in % show the EC 50 and selectivity of the compounds of the present invention, near 50% active doses and maximum agonistic activity and their concentrations are shown in Tables 1-3 below. Among them, the selectivity ( ⁇ / ⁇ ) is TR ⁇ EC 50 /TR ⁇ 1EC 50 .
  • Nearly 50% active dose refers to the concentration of the compound when the activity of agonizing ⁇ subtype and ⁇ subtype respectively reaches 50% of T3 agonism as 100%. This data can show the agonistic activity of the compound on TR[alpha] and TR[beta].
  • Comparative Example 1 reached 50% of TR ⁇ agonistic activity at 10 ⁇ m, while Examples 1-3 did not measure near 50% agonistic activity (measured value) even at 30 ⁇ m.
  • the agonistic activity of Example 1 to ⁇ is stronger than that of Comparative Example 1, and Example 2 and Example 3 can reach nearly 50% at 0.3 ⁇ m. This effect is unpredictable.
  • Example max%( ⁇ ) Cmax( ⁇ ) max%( ⁇ ) Cmax( ⁇ ) Comparative example 1 49.36 10 57.35 3
  • Example 1 33.91 10 59.25 1
  • Example 2 39.29 10 70.80 3
  • Example 3 39.58 3 73.84 1
  • max% is the maximum agonistic activity of the compound (taking T3 as 100%), and Cmax refers to the concentration of the compound corresponding to max%.
  • the heterocyclic compound of the present invention has good thyroid hormone beta receptor agonizing activity and can be used as a drug for treating or preventing diseases related to the action.

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Abstract

提供了一种具有式(I)所示结构的杂环化合物。实验结果表明，通过选择特定的修饰基团，所述杂环化合物作为TRβ激动剂相比于现有技术活性具有显著的提高并具有更高的TRβ选择性，可用于治疗和/或预防由甲状腺激素调节引起的疾病，并具有更低的副作用。

Description

一种杂环化合物及其应用
本申请是以CN申请号为202110557323.0，申请日为2021年5月21日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本发明涉及药物化学技术领域，具体涉及一种杂环化合物及其应用。
背景技术
甲状腺激素(TH)对于正常生长和发育以及维持代谢平衡具有关键作用(Paul M Yen，生理学评论(physiological reviews))，81(3)卷：1097-1126页(2001))。TH可促进脂质水解，增加脂肪酸的利用度，从而为机体提供能量，最后导致脂质的减少，降低体重。研究显示，肥胖症患者的TH水平与正常人的相比，发生很大变化。TH主要有两种形式：3,5,3’,5’-四碘-L-甲状腺原氨酸(T4)和3,5,3’,-四碘-L-甲状腺原氨酸(T3)。尽管T4是有甲状腺分泌的主要形式，但T3是生理上更为活跃的形式。T4通过组织特异性脱碘酶被转化为T3，组织特异性脱碘酶存在于所有组织中，但是主要在肝脏和肾脏中。相关研究表明T3或者T3类似物能够对肥胖进行有效治疗，尤其在与低热量的食物同时干预后减肥效果更为明显。因此，控制TH的水平可以有效调节能量平衡。临床上已经观察到，甲状腺功能减退症(甲减)可降低胆固醇的排泄、减少肝脏表面低密度脂蛋白-胆固醇(LDL-C)受体数量，从而使LDL-C分解减少，因此患者常出现总胆固醇和LDL-C水平升高，导致高脂血症、动脉粥样硬化、胰岛素抵抗、非酒精性脂肪性肝病(NAFLD)等代谢综合征。
从病理生理学角度看，在甲状腺机能亢进症中观察到心动过速、心律不齐、心脏衰竭，以及疲劳感、呼吸急促和骨骼肌减少、骨质疏松等现象(生理学评论(Physiology Review),81卷：1097页(2001))。相对地，还观察到对于代谢性疾病如血液中的胆固醇降低和基础代谢增加等治疗有益的现象。反之，在通过垂体障碍和先天性功能障碍等引起的甲状腺功能减退(甲减)中观察到心率下降、血液中胆固醇增加和体重增加。这也是天然存在的甲状腺激素存在心脏毒性使其治疗用途受到限制的原因。
从分子生物学角度看，TH的生物活性由核受体——甲状腺激素受体(TRs)介导的(M.A.Lazar，内分泌评论(Endocrine Reviews),14卷:348-399页(1993))。TRs与担当配体-诱导的转录因子的类维生素A受体形成异二聚体。TRs具有配体结合结构域，DNA结合结构域和氨基末端结构域，并通过与NDA相应要素以及与各种核共-活化剂和共-阻遏剂的相互作用而调节基因表达。TRs分别由位于人类染色体17和3上的不同基因α和β 编码而来，通过对初级转录物进行选择性剪切后产生不同的蛋白亚型，每个基因产生两个亚型：α1、α2、β1和β2。TRα1、TRβ1和TRβ2可与T3结合，TRα2不与TH结合。研究显示，甲状腺激素受体亚型在他们对于特殊生理响应的贡献方面可以不同。TRβ1存在于大部分组织中，特别是肝脏。TRα1的分布也比较广泛，并且TH在结合TRα1和TRβ1时活性类似，但是它的分布范围小于TRβ1，研究显示大多数TH对心脏的影响，特别是心律和心率，主要是通过TRα1亚型实现的。
由于TH主要通过受体调控靶器官(肝脏)上的基因表达来维持代谢平衡，包括维持肝脏和脂肪组织的脂质平衡。因此，在避免上述有害事件的同时特别地发挥TH及其类似物的有益方面如胆固醇降低或基础代谢增加，以及在肝脏的特别积累具有临床意义，将打开治疗以下疾病患者的新途径：代谢疾病如肥胖、高脂血症、高胆固醇血症、糖尿病和其他疾病如肝脂肪变性和非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退、甲状腺癌等。因此，提供甲状腺激素β受体激动剂用于治疗和/或预防由甲状腺激素调节的疾病具有重要意义。
申请人的在先中国专利申请CN112300133A已经公开了一种对甲状腺激素受体β的激动活性的杂环化合物结构。在此基础上，申请人对该系列TRβ激动剂进一步有优化和修饰，以求获得对TRβ选择性更高、激动活性更强的可药用化合物。
发明内容
本发明要解决的技术问题在于提供一种杂环化合物，本发明提供的杂环化合物相比于现有技术，具有更优异的TRβ激动活性和TRβ选择性。
为了实现上述发明目的，本发明提供了以下技术方案：
一种具有式(I)所示结构的杂环化合物，或其药学上可接受的盐或其立体异构体：
Figure PCTCN2022094094-appb-000001
其中：
X选自N或CH；
R 1和R 2独立地选自F、Cl、Br、I或取代或未取代的C 1～C 6烷基；
优选的，R 1和R 2独立地选自Cl、Br或取代或未取代的C 1～C 3烷基；
优选的，R 1和R 2独立地选自Cl或Br；
优选的，R 1和R 2为相同的基团；
R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；其中，R 1和R 2同时为Cl且X为CH时，R 3不为甲基；
优选的，R 3选自C 1～C 4烷基或C 3～C 6环烷基；优选的，C 1-C 4烷基或C 3-C 6环烷基为未取代或独立的被一个或多个以下取代基取代：F、Cl或Br；
优选的，R 3选自取代或未取代的甲基、乙基、丙基、异丙基、环丙基或环丁基，优选的，甲基、乙基、丙基、异丙基、环丙基或环丁基的取代基独立的选自一个或多个以下基团：F、Cl或Br。
在一些实施方案中，R 1和R 2均为Cl。
在一些实施方案中，R 1和R 2均为Br。
在一些实施方案中，X为CH；
R 1和R 2均为Br；
R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
优选地，R 3选自C 1-C 6烷基，所述C 1-C 6烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
优选地，R 3选自C 1～C 4烷基；
优选地，R 3选自甲基、乙基、丙基和异丙基。
在一些实施方案中，X为CH；
R 1和R 2均为Cl；
R 3选自C 2-C 6烷基或C 3-C 8环烷基，所述C 2-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
优选地，R 3选自C 2～C 4烷基或C 3～C 6环烷基，所述C 2-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自乙基、丙基、异丙基、环丙基或环丁基，所述甲基、乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自乙基、异丙基、2,2-二氟乙基、2,2,2-三氟乙基和环丁基；
优选地，R 3选自乙基、异丙基和环丁基。
在一些实施方案中，X为N；
R 1和R 2独立地选自F、Cl、Br、I或取代或未取代的C 1～C 6烷基；
R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基。
在一些实施方案中，X为N；
R 1和R 2均为Cl；
R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
优选地，R 3选自C 1～C 4烷基或C 3～C 6环烷基，所述C 1-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自甲基、乙基、丙基、异丙基、环丙基或环丁基，所述甲基、乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自甲基、异丙基和环丙基。
在一些实施方案中，X选自N或CH；
R 1和R 2均为Cl；
R 3选自C 2-C 6烷基或C 3-C 8环烷基，所述C 2-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
优选地，R 3选自C 2～C 4烷基或C 3～C 6环烷基，所述C 2-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自乙基、丙基、异丙基、环丙基或环丁基，所述乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
优选地，R 3选自乙基、异丙基、2,2-二氟乙基、2,2,2-三氟乙基、环丙基或环丁基。
在一些实施方案中，所述杂环化合物为选自如下所示的具体化合物：
Figure PCTCN2022094094-appb-000002
Figure PCTCN2022094094-appb-000003
Figure PCTCN2022094094-appb-000004
制备方法：
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知的合成方法和本发明所述方法。每步反应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需的起始原料和化学试剂可以根据文献常规合成(如Scifinder提供的)或购买。
本发明通式(I)所述化合物可按照以下方法所述路线合成：1)起始物料A在低温有机溶剂中碱化处理后，与R 3的卤代烷(化合物1)在常温条件下发生缩合反应得中间体A1；2)中间体A1与含R 1、R 2取代基的对氨基苯酚(化合物2)发生取代反应得中间体A2；3)中间体A2重氮盐化后与N-氰基乙酰尿烷(化合物3)发生取代反应生成中间体A3；4)中间体A3分子内脱脂缩合得到目标化合物式I。
Figure PCTCN2022094094-appb-000005
其中，R 1、R 2、R 3的定义如前所述。
药物组合物：
本发明的另一发明目的还在于提供一种药物组合物。所述药物组合物包括治疗和/或预防有效量的如上所述式(I)所示的杂环化合物或其药学上可接受的盐或立体异构体，以及任选药学上可接受的药用载体和/或赋型剂和/或稀释剂。
制备各种含有一定量的活性成分的药物组合物的方法是已知的，或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述，制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等。
医药用途：
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者 所述的药物组合物在制备激动甲状腺激素的激动剂中的应用。
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物在制备治疗和/或预防甲状腺激素相关疾病的药物中的应用。
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物，在治疗和/或预防甲状腺激素相关疾病中的应用。
本发明的另一发明目的还在于，提供一种治疗和/或预防甲状腺激素相关疾病的方法，其包括给予有需要的个体治疗和/或预防有效量的：所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物。
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物在制备甲状腺激素受体激动剂，尤其是甲状腺激素β受体激动剂(例如甲状腺激素β1受体激动剂)中的用途。
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物在制备治疗和/或预防甲状腺激素相关疾病的药物中的用途。
在另一方面，本发明还提供了所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物，其用于治疗和/或预防甲状腺激素相关疾病。
在另一方面，本发明还提供了一种治疗和/或预防甲状腺激素相关疾病的方法，包括向有此需要的个体施用治疗和/或预防有效量的所述的化合物或其药学上可接受的盐/立体异构体，或者所述的药物组合物。
在一些实施方案中，所述甲状腺激素相关疾病为代谢疾病，例如肥胖、高脂血症、高胆固醇血症、糖尿病、肝脂肪变性、非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退或甲状腺癌。
在本发明中，“治疗”一般是指获得需要的药理和/或生理效应，涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
在本发明中，“个体”指脊椎动物。在某些实施方案中，脊椎动物指哺乳动物。哺乳动物包括，但不限于，牲畜(诸如牛)、宠物(诸如猫、犬、和马)、灵长类动物、小鼠和大鼠。在某些实施方案中，哺乳动物指人。
在本发明中，“有效量”指在必需的剂量和时间上有效实现期望的治疗或预防效果的量。本发明的物质/分子的“治疗有效量”可根据诸如个体的疾病状态、年龄、性别和体重及该物质/分子在个体中引发期望应答的能力等因素而变化。治疗有效量还涵盖该物质/分子 的治疗有益效果胜过任何有毒或有害后果的量。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然，由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的，因此预防有效量会低于治疗有效量。在癌症的情况中，药物的治疗有效量可减少癌细胞数；缩小肿瘤体积；抑制(即一定程度的减缓，优选停止)癌细胞浸润到周围器官中；抑制(即一定程度的减缓，优选停止)肿瘤转移；一定程度的抑制肿瘤生长；和/或一定程度的减轻与癌症有关的一种或多种症状。
术语及定义：
应该理解，此处采用的术语目的在于描述具体的实施方案，并非意在限制。此外，尽管类似或者等价于此处描述的任何方法、装置和材料均可用于实施或者测试本发明，但是现在描述的是优选的方法、装置和材料。
如本文所使用，术语“式(I)所示的化合物的药学上可接受的盐”的例子是由形成药学上可以接受的阴离子的有机酸形成的有机酸加合盐，包括但不限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐；优选地，所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐；所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。也可形成合适的无机盐，包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐等。药学上可以接受的盐可使用本领域熟知的标准程序获得，例如，通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基，或者独立公开的“C 2-6烷基”，或者独立公开的“C 1-4烷基”，或者独立公开的“C 1-3烷基”。
术语“烷基”表示直链或支链饱和烃基。例如C 1至C 6烷基，具体如甲基、乙基、丙基(正丙基或异丙基)、丁基(正丁基、异丁基或叔丁基)等。
术语“烯基”是指包括直链或支链构型并具有一或多个可存在于沿该链的任一稳定点处的碳-碳双键的烃链。例如，“C 2-6烯基”包括C 2、C 3、C 4、C 5和C 6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基等。
术语“炔基”是指包括直链或支链构型并具有一或多个可存在于沿该链的任一稳定点处的碳-碳三键的烃基。例如“C 2-6炔基”包括C 2、C 3、C 4、C 5和C 6炔基。炔基的实例包括 但不限于乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
烷基和环烷基可以是取代的或未取代的。在取代的情况下，通常存在例如1到4个取代基，优选2-3个取代基。取代基可以包括，例如：含碳基团如烷基、芳基、芳烷基(例如取代和未取代的苯基、取代和未取代的苄基)；卤素原子和含卤素的基团如卤代烷基(如三氟甲基)；含氧基团如醇(羟基、羟烷基、芳基(羟基)烷基)、醚(如烷氧基、芳氧基、烷氧基烷基、芳氧基烷基)、醛(如甲醛)、酮(如烷基羰基、烷基羰基烷基、芳基羰基、芳基烷基羰基)、酸(如羧酸、羧基烷基)、酸衍生物如酯(如烷氧基羰基、烷氧基羰基烷基、烷基羰基氧基烷基)、酰胺(如氨基羰基、单-或二-烷基氨基羰基、氨基羰基烷基、单-或二-烷基氨基羰基烷基、芳基氨基羰基)、氨基甲酸酯(如烷氧基羰基氨基、芳氧基羰基氨基、氨基羰基氧基、单-或二-烷基氨基羰基氨基或芳基氨基羰基氨基)；含氮基团如胺(氨基、单-或二-烷基氨基、氨基烷基、单-或二-烷基氨基烷基)、叠氮化物、腈(如氰基、氰基烷基)、硝基；含硫基团如硫醇、硫醚、亚砜和砜(如烷硫基、烷基亚磺酰基、烷基磺酰基、烷硫基烷基、烷基亚磺酰基烷基、烷基磺酰基烷基、芳硫基、芳基亚磺酰基、芳基磺酰基、芳硫基烷基、芳基亚磺酰烷基、芳基磺酰基烷基)。
本文所用术语“被取代的”是指指定原子或基团上的任一或多个氢被指定基团的选择替代，条件为不超过指定原子的正常价态。
术语“环烷基”是指环化的烷基，包括单环、双环或多环体系。C 3-7环烷基是指包括C 3、C 4、C 5、C 6和C 7环烷基，例如C 3-6环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳基”是指具有单环或稠合环的芳香族烃基，例如具有6至12个成环碳原子的单环或二环芳香族烃基，例如苯基和萘基。
术语“杂环”、“杂环烷基”、“杂环的”或“杂环基”可互换使用，包括3-元至7-元单环基团、7-元至11-元二环基团和10-元至15-元三环基团，其中至少一个环具有至少一个杂原子(O、S或N)，该含杂原子环优选具有1个、2个或3个选自O、S和N的杂原子。该基团中的每一含有杂原子的环皆可含有1或2个氧或硫原子和/或1至4个氮原子，限制条件为每一环中的杂原子总数是4或更小，并且进一步的限制条件为该环含有至少一个碳原子。氮和硫原子可任选被氧化且氮原子可任选被季铵化。完成二环和三环基团的稠环可仅含有碳原子且可为饱和、部分饱和或完全不饱和。杂环基团可在任何可用氮或碳原子上连接。
有益效果
与现有技术相比，本发明提供了一种具有式(I)所示结构的杂环化合物：通过选择特定的修饰基团，实验结果表明，本发明提供的杂环化合物作为甲状腺激素β受体激动剂相比于现有技术具有更好的活性和/或选择性，可用于治疗和/或预防由甲状腺激素调节引起的疾病。
具体实施方式
本发明提供了一种杂环化合物及其应用，本领域技术人员可以借鉴本文内容，适当改进结构和基团实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都属于本发明保护的范围。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步说明本发明，以下结合实施例对本发明提供的一种杂环化合物及其应用进行详细描述。
实施例1
2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000006
步骤1：制备4-氯-7-甲基-7H-吡咯[2,3-d]嘧啶
将4-氯-7H-吡咯[2,3-d]嘧啶(307mg，2mmol)溶于四氢呋喃(5ml)中，氮气保护，冷却降温至0～5℃，再分批加入氢化钠(144mg，6mmol)，加料完毕，保温反应30分钟，再加入碘甲烷(570mg，4mmol)，升至室温，继续搅拌反应2小时。反应完毕，缓慢滴加水(20ml)，再加入乙酸乙酯萃取，饱和盐水洗涤有机相，有机相干燥，过滤，减压蒸馏得到残留物，最后加入石油醚搅拌析晶，过滤，烘干滤渣，得到目标4-氯-7-甲基-7H-吡咯[2,3-d]嘧啶(310mg，92.5％yield)，LC-MS(m/z)168.6(M+1)。
步骤2：制备3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二溴-4氨基苯酚(320mg，1.2mmol)和4-氯-7-甲基-7H-吡咯[2,3-d]嘧啶(168mg，1mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(815mg，2.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系 中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得到目标3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(63mg，15.8％yield)，LC-MS(m/z)399.2(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(63mg，0.16mmol)溶于盐酸(2ml)和水(2ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(14mg，0.19mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(27mg，0.17mmol)溶于吡啶(2ml)和水(2ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成浅褐色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(74mg，82.8％yield)，LC-MS(m/z)566.2(M+1)。
步骤4：制备2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(74mg，0.13mmol)溶于5ml乙酸中，再加入醋酸钠(54mg，0.65mmol)，升温至100℃搅拌反应5小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得目标化合物2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(51mg，74.7％yield)，LC-MS(m/z)520.1(M+1)。1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.95(s,3H),7.62(d,J＝3.5Hz,1H),6.74(d,J＝3.5Hz,1H),3.86(s,4H)。
实施例2 2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000007
步骤1：制备4-氯-7-乙基-7H-吡咯[2,3-d]嘧啶
将4-氯-7H-吡咯[2,3-d]嘧啶(922mg，6mmol)溶于N,N-二甲基甲酰胺(10ml)中，氮气保护，室温下加入氢氧化钾(672mg，12mmol)，冰水浴下降温，剧烈搅拌，再加入溴乙烷(785mg，7.2mmol)，升至室温继续搅拌反应1小时。反应完毕，滴加水(20ml)，再加入乙酸乙酯萃取，饱和盐水洗涤有机相，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/5)。得到目标4-氯-7-乙基-7H-吡咯[2,3-d]嘧啶(955mg，87.7％yield)，LC-MS(m/z)182.6(M+1)。
步骤2：制备3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二氯-4氨基苯酚(214mg，1.2mmol)和4-氯-7-乙基-7H-吡咯[2,3-d]嘧啶(182mg，1mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(815mg，2.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得到目标3,5-二氯-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(225mg，69.5％yield)，LC-MS(m/z)324.2(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二氯-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(225mg，0.7mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(58mg，0.85mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(116mg，0.74mmol)溶于吡啶(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(248mg，72.7％yield)，LC-MS(m/z)491.3(M+1)。
步骤4：制备2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(248mg，0.5mmol)溶于5ml乙酸中，再加入醋酸钠(205mg，2.5mmol)，升温至100℃搅拌反应5小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)， 得目标化合物2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(152mg，68.5％yield)，LC-MS(m/z)445.2(M+1)。1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.81(s,2H),7.69(d,J＝3.5Hz,1H),6.75(d,J＝3.5Hz,1H),4.32(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).
实施例3 2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000008
步骤1：制备4-氯-7-异丙基-7H-吡咯[2,3-d]嘧啶
将4-氯-7H-吡咯[2,3-d]嘧啶(922mg，6mmol)溶于N,N-二甲基甲酰胺(10ml)中，氮气保护，室温下加入氢氧化钾(672mg，12mmol)，剧烈搅拌，再加入碘代异丙烷(1.23g，7.2mmol)，继续室温搅拌反应8小时。反应完毕，滴加水(20ml)，再加入乙酸乙酯萃取，饱和盐水洗涤有机相，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/6)。得到目标制备4-氯-7-异丙基-7H-吡咯[2,3-d]嘧啶(905mg，77.1％yield)，LC-MS(m/z)196.6(M+1)。
步骤2：制备3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二氯-4氨基苯酚(214mg，1.2mmol)和4-氯-7-异丙基-7H-吡咯[2,3-d]嘧啶(196mg，1mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(815mg，2.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得到目标3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(223mg，66.0％yield)，LC-MS(m/z)338.2(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(222mg，0.65mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(54mg，0.78mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(106mg，0.68mmol) 溶于吡啶(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(239mg，71.8％yield)，LC-MS(m/z)505.3(M+1)。
步骤4：制备2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(239mg，0.47mmol)溶于5ml乙酸中，再加入醋酸钠(189mg，2.3mmol)，升温至100℃搅拌反应5小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得目标化合物2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(101mg，46.6％yield)。LC-MS(m/z)459.3(M+1)。1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.87–7.71(m,3H),6.76(d,J＝3.6Hz,1H),5.05(p,J＝6.8Hz,1H),1.51(d,J＝6.8Hz,6H)。
实施例4 2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000009
步骤1：制备3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二溴-4氨基苯酚(615mg，2.4mmol)和4-氯-7-异丙基-7H-吡咯[2,3-d]嘧啶(392mg，2mmol)溶于N,N-二甲基甲酰胺(15ml)中，再加入碳酸铯(1.6g，5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/2)。得到目标3,5-二溴-4-((7-异 丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(123mg，14.5％yield)，LC-MS(m/z)427.1(M+1)。
步骤2：制备(2-氰基-2-(2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(123mg，0.29mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(24mg，0.35mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(48mg，0.31mmol)溶于吡啶(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成褐色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(126mg，86.5％yield)，LC-MS(m/z)505.3(M+1)。
步骤3：制备2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(126mg，0.25mmol)溶于5ml乙酸中，再加入醋酸钠(103mg，1.25mmol)，升温至100℃搅拌反应4小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得目标化合物2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(53mg，46.3％yield)。LC-MS(m/z)459.3(M+1)。1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.94(d,J＝0.8Hz,2H),7.79(d,J＝3.6Hz,1H),6.77(d,J＝3.6Hz,1H),5.04(q,J＝6.7Hz,1H),1.51(d,J＝6.7Hz,8H).
实施例5 2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000010
步骤1：制备4-氯-7-环丁基-7H-吡咯[2,3-d]嘧啶
将4-氯-7H-吡咯[2,3-d]嘧啶(922mg，6mmol)溶于N,N-二甲基甲酰胺(10ml)中，氮气保护，室温下加入氢氧化钾(672mg，12mmol)，剧烈搅拌，再加入环丁基溴(972mg，7.2mmol)，继续室温搅拌反应48小时。反应不完全，滴加水(20ml)，再加入乙酸乙酯萃取，饱和盐水洗涤有机相，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/6)。得到目标4-氯-7-环丁基-7H-吡咯[2,3-d]嘧啶(211mg，16.9％yield)，LC-MS(m/z)208.7(M+1)。
步骤2：制备3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二氯-4氨基苯酚(215mg，1.2mmol)和4-氯-7-环丁基-7H-吡咯[2,3-d]嘧啶(211mg，1mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(815mg，2.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得到目标3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(219mg，61.7％yield)，LC-MS(m/z)350.2(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(219mg，0.63mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(53mg，0.76mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(103mg，0.66mmol)溶于吡啶(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成橙红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(237mg，73.2％yield)，LC-MS(m/z)517.3(M+1)。
步骤4：制备2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(237mg，0.46mmol)溶于5ml乙酸中，再加入醋酸钠(188mg，2.3mmol)，升温至100℃搅拌反应4小时，停止加热。冷却至室温，加入冰水，析出固体， 过滤，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得目标化合物2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(99mg，45.8％yield)，LC-MS(m/z)471.3(M+1)。1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.93(d,J＝3.7Hz,1H),7.82(s,2H),6.80(d,J＝3.6Hz,1H),5.26(q,J＝8.7Hz,1H),2.61(p,J＝10.3,9.9Hz,2H),2.49–2.38(m,4H),1.88(dt,J＝13.3,6.5Hz,2H).
实施例6 2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000011
步骤1：制备3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二溴-4氨基苯酚(615mg，2.4mmol)和4-氯-7-乙基-7H-吡咯[2,3-d]嘧啶(364mg，2mmol)溶于N,N-二甲基甲酰胺(15ml)中，再加入碳酸铯(1.6g，5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/2)。得到目标3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(114mg，13.4％yield)，LC-MS(m/z)413.1(M+1)。
步骤2：制备(2-氰基-2-(2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯
将3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(114mg，0.27mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(23mg，0.33mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(44mg，0.28mmol)溶于吡啶(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成褐色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(135mg， 84.4％yield)，LC-MS(m/z)580.3(M+1)。
步骤3：制备2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(135mg，0.23mmol)溶于5ml乙酸中，再加入醋酸钠(95mg，1.15mmol)，升温至100℃搅拌反应4小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入EA溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得目标化合物2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(47mg，37.8％yield)，LC-MS(m/z)534.1(M+1)。1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.94(d,J＝0.7Hz,2H),7.70(d,J＝3.6Hz,1H),6.76(d,J＝3.5Hz,1H),4.32(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).
实施例7 2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000012
步骤1：制备4-氯-7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶
将4-氯-7H-吡咯[2,3-d]嘧啶(615mg，4mmol)溶于N,N-二甲基甲酰胺(10ml)中，氮气保护，室温下加入氢氧化钾(448mg，8mmol)，剧烈搅拌，再加入1,1-二氟-2-碘代乙烷(922mg，4.8mmol)，继续室温搅拌反应16小时。反应完毕，过滤，滤饼再加入乙酸乙酯搅洗，饱和盐水洗涤萃取有机相，有机相无水硫酸钠干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/4)。得到目标4-氯-7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶(279mg，32.1％yield)，LC-MS(m/z)218.6(M+1)。
步骤2：制备3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺
将2,6-二氯-4-氨基苯酚(215mg，1.2mmol)和4-氯-7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶(218mg，1mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(815mg，2.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，向反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相无水硫酸钠干燥，过滤，减压蒸馏得到残留物，进行柱层析分离(乙酸乙酯/石油醚＝1/2)。得到目标3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(259mg，72.1％yield)， LC-MS(m/z)360.2(M+1)。
步骤3：制备((2-氰基-2-(2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯)
将3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(259mg，0.72mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(60mg，0.87mmol)的水溶液，0～5℃保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(118mg，0.76mmol)溶于吡啶(3ml)和水(6ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成橙红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(279mg，73.6％yield)，LC-MS(m/z)527.2(M+1)。
步骤4：制备2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(263mg，0.5mmol)溶于10ml乙酸中，再加入醋酸钠(205mg，2.5mmol)，升温至100℃搅拌反应3小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入乙酸乙酯溶解，干燥浓缩得到橙色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得浅黄色固体2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(67mg，28.0％yield)，LC-MS(m/z)481.2(M+1)。 1H NMR(400MHz,DMSO-d 6)δ8.41(s,1H),7.83(s,2H),7.68(d,J＝3.7Hz,1H),6.87(d,J＝3.6Hz,1H),6.49(t,J＝54.6Hz,1H),4.92–4.71(m,2H).
实施例8 2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000013
步骤1：制备(4-氯-(7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶)
将4-氯-7H-吡咯[2,3-d]嘧啶(615mg，4mmol)溶于N,N-二甲基甲酰胺(10ml)中，室温下加入碳酸铯(3.25g，10mmol)，再加入2,2,2-三氟乙基三氟甲烷磺酸酯(1.11g，4.8mmol)，氮气置换保护，升温至60℃搅拌反应10小时。反应完毕，冷却反应，过滤，滤饼再加入乙酸乙酯搅洗，饱和盐水洗涤萃取有机相，有机相无水硫酸钠干燥，过滤，减 压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/4)。得到目标4-氯-(7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶(413mg，43.9％yield)，LC-MS(m/z)236.6(M+1)。
步骤2：制备(4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺)
将2,6-二氯-4-氨基苯酚(356mg，2.0mmol)和4-氯-(7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶(400mg，1.7mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(1.37g，4.2mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，向反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相无水硫酸钠干燥，过滤，减压蒸馏得到残留物，进行柱层析分离(乙酸乙酯/石油醚＝1/2)。得到目标4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(238mg，37.1％yield)，LC-MS(m/z)378.2(M+1)。
步骤3：制备((2-氰基-2-(2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯)
将4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(238mg，0.63mmol)溶于盐酸(3ml)和水(3ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(52mg，0.76mmol)的水溶液，0～5℃保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(103mg，0.66mmol)溶于吡啶(3ml)和水(6ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成橙红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(277mg，80.8％yield)，LC-MS(m/z)545.3(M+1)。
步骤4：制备2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(277mg，0.5mmol)溶于10ml乙酸中，再加入醋酸钠(205mg，2.5mmol)，升温至100℃搅拌反应3小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，再加入乙酸乙酯溶解，干燥浓缩得到橙色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/20)，得浅黄色固体2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(85mg，34.1％yield)，LC-MS(m/z)499.2(M+1)。 1H NMR(400MHz,DMSO-d 6)δ8.45(s,1H),7.84(s,2H),7.73(d,J＝3.7Hz,1H),6.93(d,J＝3.7Hz,1H),5.27(q,J＝9.2Hz,2H).
实施例9 2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢 -[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000014
步骤1：制备(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯胺)
将2,6-二氯-4-氨基苯酚(427mg，2.4mmol)和6-氯-9-甲基嘌呤(337mg，2mmol)溶于N,N-二甲基甲酰胺(15ml)中，再加入碳酸铯(1.63g，5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/1)。得到目标3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯胺(388mg，62.6％yield)，LC-MS(m/z)311.1(M+1)。
步骤2：制备((2-氰基-2-(2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯)
将3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯胺(388mg，1.25mmol)溶于盐酸(4ml)和水(5ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(104mg，1.5mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(205mg，1.3mmol)溶于吡啶(4ml)和水(8ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(414mg，69.4％yield)，LC-MS(m/z)478.3(M+1)。
步骤3：制备2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(414mg，0.87mmol)溶于5ml乙酸中，再加入醋酸钠(360mg，4.4mmol)，升温至100℃搅拌反应3小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，，再加入四氢呋喃溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/15)，得橙色固体2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(185mg，49.3％yield)，LC-MS(m/z)432.2(M+1)。 1H NMR(400MHz,DMSO-d 6)δ8.54(d,J＝21.8Hz,1H),7.84(s,1H),3.88(s,2H).
实施例10 2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000015
步骤1：制备(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯胺)
将2,6-二氯-4-氨基苯酚(427mg，2.4mmol)和6-氯-9-异丙基嘌呤(393mg，2mmol)溶于N,N-二甲基甲酰胺(15ml)中，再加入碳酸铯(1.63g，5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/1)。得到目标3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯胺(431mg，63.8％yield)，LC-MS(m/z)339.2(M+1)。
步骤2：制备((2-氰基-2-(2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯)
将3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯胺(431mg，1.27mmol)溶于盐酸(4ml)和水(5ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(104mg，1.5mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(205mg，1.3mmol)溶于吡啶(4ml)和水(8ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(472mg，73.6％yield)，LC-MS(m/z)506.3(M+1)。
步骤3：制备2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(472mg，0.93mmol)溶于10ml乙酸中，再加入醋酸钠(385mg，4.7mmol)，升温至100℃搅拌反应5小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，，再加入四氢呋喃溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/15)，得橙色固体2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(204mg，47.8％yield)，LC-MS(m/z)460.3(M+1)。 1H NMR(400MHz,DMSO-d 6) δ8.73(s,1H),8.50(s,1H),7.84(d,J＝0.8Hz,2H),5.03–4.80(m,1H),1.60(d,J＝6.8Hz,7H).
实施例11 2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈的制备
Figure PCTCN2022094094-appb-000016
步骤1：制备(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯胺)
将2,6-二氯-4-氨基苯酚(321mg，1.8mmol)和6-氯-9-环丙基嘌呤(292mg，1.5mmol)溶于N,N-二甲基甲酰胺(10ml)中，再加入碳酸铯(1.24g，3.8mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至120℃，反应1小时，停止加热，反应体系中加入乙酸乙酯搅拌过滤，向滤液中加入饱和盐水，萃取，有机相干燥，过滤，减压蒸馏得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/2)。得到目标3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯胺(342mg，67.8％yield)，LC-MS(m/z)337.2(M+1)。
步骤2：制备((2-氰基-2-(2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯)
将3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯胺(340mg，1mmol)溶于盐酸(4ml)和水(5ml)的溶液中，冷却降温至0～5℃，再滴加入亚硝酸钠(83mg，1.2mmol)的水溶液，保温反应30分钟，制得反应母液。将N-氰基乙酰尿烷(164mg，1.05mmol)溶于吡啶(4ml)和水(8ml)的溶液中，冷却降温至0～5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成红色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到目标(2-氰基-2-(2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(387mg，76.9％yield)，LC-MS(m/z)504.3(M+1)。
步骤3：制备2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(387mg，0.77mmol)溶于10ml乙酸中，再加入醋酸钠(316mg，3.85mmol)，升温至100℃搅拌反应3小时，停止加热。冷却至室温，加入冰水，析出固体，过滤，，再加入四氢呋喃溶解，干燥浓缩得到红色固体粗品。柱层析分离(甲醇/二氯甲烷＝1/15)，得 橙色固体2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈(138mg，39.2％yield)，LC-MS(m/z)458.3(M+1)。 1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.51(s,1H),7.83(s,2H),5.76(s,1H),1.16(dd,J＝30.9,5.4Hz,4H).
对比例：
对比例1：2-(3,5-二氯-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)-苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈)。
其结构及制备方法参见CN112300133A的实施例1。
Figure PCTCN2022094094-appb-000017
对比例2：
2-(3,5-二氯-4-((7H-吡咯[2,3-d]嘧啶-4-基)氧基)-苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
其结构及制备方法参见CN112300133A的实施例4。
Figure PCTCN2022094094-appb-000018
对比例3：
2-(3,5-二溴-4-((7H-吡咯[2,3-d]嘧啶-4-基)氧基)-苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈
其结构及制备方法参见CN112300133A的实施例6。
Figure PCTCN2022094094-appb-000019
实施例12人类甲状腺激素受体α1(TRα1)和β1(TRβ1)的转录活化实验
使用X-tremeGENE HP DNA Transfection Reagent(由Roche制造)将来自人体肝脏的细胞克隆的TRα1或TRβ1的pcDNA3.1载体(由Invitrogen制造)和具有甲状腺激素响应序列的萤火虫荧光素酶载体pTA-TRE-Luc(由Promega制造)转染至达尔伯克氏伊格尔培养基(Dulbecco’s modified Eagle medium，DMEM)中培养的CV-1细胞中。转染 16小时后，添加用二甲亚砜溶液稀释的化合物，并测量24小时后荧光素酶的活性。
使用3,3’,5-三碘代-L-甲状腺素(T 3)作为阳性对照，所述化合物在TRα1和TRβ1上的转录活化作用通过相对于T 3的最大荧光素酶活性值为100％的各EC 50值和最大荧光素酶的活性值示出，本发明化合物EC 50和选择性，近50％活性剂量以及最大激动活性及其浓度示于下表1-表3中。其中，选择性(α/β)为TRαEC 50/TRβ1EC 50。
表1本发明化合物EC 50和选择性
实施例 TRβ1EC 50(μM) 选择性(α/β) 实施例 TRβ1EC 50(μM) 选择性(α/β)
实施例1 0.8862 ＞11.28 实施例2 0.4615 ＞21.67
实施例3 0.2442 ＞40.95 实施例4 0.1373 ＞72.83
实施例5 0.08098 ＞123.49 实施例6 ＜0.3 ＞33.33
实施例7 0.763 58.23 实施例8 0.959 21.88
对比例1 2.717 3.31 对比例2 3.393 /
对比例3 3.602 /      
根据表1的转录活化实验结果表明，本发明实施例化合物能实现对甲状腺激素受体β的激动活性；且与对比例1、2、3相比，本发明各实施例化合物对TRβ的激动活性出乎意料的显著提高；同时本发明各实施例还表现出对TRβ1具有非常高的选择性，相比于对比例1的具有出乎意料的效果。
表2本发明化合物的近50％活性剂量
Figure PCTCN2022094094-appb-000020
近50％活性剂量，是指分别激动α亚型和β亚型的活性达到以T3激动时作为100％的50％时，化合物的浓度。该数据可显示化合物对TRα和TRβ的激动活性。
根据表2的上述数据可知，对比例1在10μm时对TRα激动活性达到50％，而实施例1-3即使在30μm时都没有测量到激动活性50％附近的值(实测值)。在均为1μm浓 度下，实施例1比对比例1对β的激动活性强，实施例2和实施例3在0.3μm就能达到近50％。该效果是难以预料的。
表3本发明化合物的最大激动活性及其浓度
实施例 max％(α) Cmax(α) max％(β) Cmax(β)
对比例1 49.36 10 57.35 3
实施例1 33.91 10 59.25 1
实施例2 39.29 10 70.80 3
实施例3 39.58 3 73.84 1
max％是化合物的最大激动活性(以T3激动时作为100％)，Cmax是指max％相应的化合物浓度。
根据表3的上述数据可知，对比例1对α亚型的max％明显比实施例1-3高，而对β亚型的max％明显比实施例1-3低，说明本发明的化合物与对比例1相比，对β亚型激动活性强，而对α亚型的激动活性弱，体现出更好的β激动活性的同时具有更好的选择性，该效果是难以预料的。
产业上的可应用性
本发明的杂环化合物具有良好的甲状腺激素β受体激动活性，可成为治疗或预防与该作用相关的疾病的药物。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (13)

  1. 一种具有式(I)所示结构的杂环化合物，或其药学上可接受的盐或立体异构体：
    Figure PCTCN2022094094-appb-100001
    其中：
    X选自N或CH；
    R 1和R 2独立地选自F、Cl、Br、I或取代或未取代的C 1～C 6烷基；
    R 3选自C 1-C 6烷基或C 3-C 8环烷基，C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    其中，R 1和R 2同时为Cl且X为CH时，R 3不为甲基。
  2. 根据权利要求1所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，R 1和R 2独立地选自Cl、Br或取代或未取代的C 1～C 3烷基；
    优选的，R 1和R 2独立地选自Cl或Br；
    优选的，R 1和R 2均为Cl；
    优选的，R 1和R 2均为Br。
  3. 根据权利要求1或2所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，R 3选自C 1～C 4烷基或C 3～C 6环烷基；优选的，C 1-C 4烷基或C 3-C 6环烷基为未取代或独立的被一个或多个以下取代基取代：F、Cl或Br；
    优选的，R 3选自取代或未取代的甲基、乙基、丙基、异丙基、环丙基或环丁基，优选的，甲基、乙基、丙基、异丙基、环丙基或环丁基的取代基独立的选自一个或多个以下基团：F、Cl或Br。
  4. 根据权利要求1-3任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，X为CH；
    R 1和R 2均为Br；
    R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    优选地，R 3选自C 1-C 6烷基，所述C 1-C 6烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    优选地，R 3选自C 1～C 4烷基；
    优选地，R 3选自甲基、乙基、丙基和异丙基。
  5. 根据权利要求1-3任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，X为CH；
    R 1和R 2均为Cl；
    R 3选自C 2-C 6烷基或C 3-C 8环烷基，所述C 2-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    优选地，R 3选自C 2～C 4烷基或C 3～C 6环烷基，所述C 2-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自乙基、丙基、异丙基、环丙基或环丁基，所述甲基、乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自乙基、异丙基、2,2-二氟乙基、2,2,2-三氟乙基和环丁基；
    优选地，R 3选自乙基、异丙基和环丁基。
  6. 根据权利要求1-3任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，X为N；
    R 1和R 2独立地选自F、Cl、Br、I或取代或未取代的C 1～C 6烷基；
    R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基。
  7. 根据权利要求1-3或6任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，X为N；
    R 1和R 2均为Cl；
    R 3选自C 1-C 6烷基或C 3-C 8环烷基，所述C 1-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    优选地，R 3选自C 1～C 4烷基或C 3～C 6环烷基，所述C 1-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自甲基、乙基、丙基、异丙基、环丙基或环丁基，所述甲基、乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自甲基、异丙基和环丙基。
  8. 根据权利要求1-7任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其中，X选自N或CH；
    R 1和R 2均为Cl；
    R 3选自C 2-C 6烷基或C 3-C 8环烷基，所述C 2-C 6烷基或C 3-C 8环烷基为未取代或独立的被一个或多个以下基团取代：D、F、Cl、Br或取代或未取代的C 1～C 3烷基；
    优选地，R 3选自C 2～C 4烷基或C 3～C 6环烷基，所述C 2-C 4烷基或C 3-C 6环烷基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自乙基、丙基、异丙基、环丙基或环丁基，所述乙基、丙基、异丙基、环丙基或环丁基为未取代或独立地被一个或多个以下取代基取代：F、Cl或Br；
    优选地，R 3选自乙基、异丙基、2,2-二氟乙基、2,2,2-三氟乙基、环丙基或环丁基。
  9. 根据权利要求1-8任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体，其特征在于：所述杂环化合物为选自如下所示的具体化合物：
    2-(3,5-二溴-4-((7-甲基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二溴-4-((7-异丙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((7-环丁基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二溴-4-((7-乙基-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((7-(2,2-二氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((7-(2,2,2-三氟乙基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((9-甲基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪 -6-腈；
    2-(3,5-二氯-4-((9-异丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈；
    2-(3,5-二氯-4-((9-环丙基-9H-嘌呤-6-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-[1,2,4]三嗪-6-腈。
  10. 一种药物组合物，包括治疗和/或预防有效量的如权利要求1-9任一项所述的杂环化合物或其药学上可接受的盐或立体异构体，以及任选药学上可接受的药用载体和/或赋型剂和/或稀释剂。
  11. 如权利要求1-9任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体或权利要求10所述的药物组合物在制备甲状腺激素受体激动剂，尤其是甲状腺激素β受体激动剂(例如甲状腺激素β1受体激动剂)，和/或，制备治疗和/或预防甲状腺激素相关疾病的药物中的用途；
    优选的，所述甲状腺激素相关疾病为代谢疾病，例如肥胖、高脂血症、高胆固醇血症、糖尿病、肝脂肪变性、非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退或甲状腺癌。
  12. 如权利要求1-9任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体或权利要求10所述的药物组合物，其用于治疗和/或预防甲状腺激素相关疾病；
    优选的，所述甲状腺激素相关疾病为代谢疾病，例如肥胖、高脂血症、高胆固醇血症、糖尿病、肝脂肪变性、非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退或甲状腺癌。
  13. 一种治疗和/或预防甲状腺激素β受体相关疾病的方法，包括向有此需要的个体施用治疗和/或预防有效量的如权利要求1-9任一项所述的杂环化合物，或其药学上可接受的盐或立体异构体或权利要求10所述的药物组合物；
    优选的，所述甲状腺激素相关疾病为代谢疾病，例如肥胖、高脂血症、高胆固醇血症、糖尿病、肝脂肪变性、非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退或甲状腺癌。
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Citations (4)

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WO2020169069A1 (en) * 2019-02-21 2020-08-27 Nanjing Ruijie Pharma Co., Ltd. Novel compounds and their uses as thyroid hormone receptor agonists
WO2020227549A1 (en) * 2019-05-08 2020-11-12 Aligos Therapeutics, Inc. MODULATORS OF THR-β AND METHODS OF USE THEREOF
CN112300133A (zh) * 2019-07-31 2021-02-02 深圳微芯生物科技股份有限公司 一种杂环化合物及其应用
WO2021041237A1 (en) * 2019-08-23 2021-03-04 Terns, Inc. Thyroid hormone receptor beta agonist compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020169069A1 (en) * 2019-02-21 2020-08-27 Nanjing Ruijie Pharma Co., Ltd. Novel compounds and their uses as thyroid hormone receptor agonists
WO2020227549A1 (en) * 2019-05-08 2020-11-12 Aligos Therapeutics, Inc. MODULATORS OF THR-β AND METHODS OF USE THEREOF
CN112300133A (zh) * 2019-07-31 2021-02-02 深圳微芯生物科技股份有限公司 一种杂环化合物及其应用
WO2021018226A1 (zh) * 2019-07-31 2021-02-04 深圳微芯生物科技股份有限公司 一种杂环化合物及其应用
WO2021041237A1 (en) * 2019-08-23 2021-03-04 Terns, Inc. Thyroid hormone receptor beta agonist compounds

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