WO2021032161A1 - 卤素取代的苯醚类化合物及其用途 - Google Patents

卤素取代的苯醚类化合物及其用途 Download PDF

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WO2021032161A1
WO2021032161A1 PCT/CN2020/110252 CN2020110252W WO2021032161A1 WO 2021032161 A1 WO2021032161 A1 WO 2021032161A1 CN 2020110252 W CN2020110252 W CN 2020110252W WO 2021032161 A1 WO2021032161 A1 WO 2021032161A1
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compound
independently selected
thr
aqueous
formula
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PCT/CN2020/110252
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English (en)
French (fr)
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杜武
李宇
李海波
陈元伟
张承智
李兴海
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成都海创药业有限公司
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Priority to US17/753,162 priority Critical patent/US11926618B2/en
Priority to AU2020334850A priority patent/AU2020334850A1/en
Priority to EP20854575.6A priority patent/EP4019510A4/en
Priority to CA3148658A priority patent/CA3148658A1/en
Priority to KR1020227008194A priority patent/KR20220045212A/ko
Priority to JP2022510891A priority patent/JP2022545428A/ja
Publication of WO2021032161A1 publication Critical patent/WO2021032161A1/zh

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    • 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
    • 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
    • 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
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • 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
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of medicine preparation, and specifically relates to a halogen-substituted phenyl ether compound and its use.
  • MGL-3196 is a phenyl ether compound substituted with chlorine atoms. It is a highly selective thyroid hormone receptor ⁇ (THR- ⁇ ) agonist with an EC50 value of 0.21 ⁇ M and its structural formula is A late-stage clinical trial is currently underway, showing the efficacy of dyslipidemia, hypercholesterolemia, and non-alcoholic steatohepatitis (NASH).
  • TRR- ⁇ thyroid hormone receptor ⁇
  • MGL-3196 has yet to be improved in its pharmacokinetic properties and agonistic activity. Therefore, the structural modification of MGL-3196 and the development of drugs with better properties have become one of the research hotspots.
  • Deuteration is a commonly used modification method.
  • Deuterated drugs refer to the replacement of part of the hydrogen atoms in drug molecules with deuterium. Since deuterium is close to hydrogen in shape and volume in drug molecules, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond is less likely to be broken during the chemical reaction of deuterated drugs, and its half-life may be prolonged.
  • the pharmacokinetic properties of drugs in organisms are affected by many factors, and they also exhibit corresponding complexity.
  • the changes in the pharmacokinetic properties of deuterated drugs show great chance and unpredictability.
  • Deuterium at certain sites can not extend the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406), deteriorating its pharmacokinetic properties;
  • the hydrogen at certain positions on the drug molecule is not easily deuterated due to steric hindrance and other reasons. Therefore, the deuteration of drugs is not arbitrary, and the sites that can be deuterated are also unpredictable.
  • the present invention expects to obtain a class of drugs with enhanced activity and improved pharmacokinetic properties through appropriate chemical modification.
  • the purpose of the present invention is to provide a class of drugs with high activity, good pharmacokinetic properties, small side effects and good metabolic stability.
  • the present invention provides a compound represented by formula (I) or its optical isomer, salt, prodrug, hydrate or non-aqueous solvate:
  • R 1 -R 7 , R 9 and R 10 are each independently selected from H and D;
  • a and B are each independently selected from N, CH, CD;
  • X, Y are each independently selected from F, Cl, Br, I;
  • R 1 -R 7 , R 9 and R 10 are each independently selected from H and D; A and B are each independently selected from N, CH, and CD.
  • R 1 -R 7 , R 9 and R 10 are each independently selected from H and D; A and B are each independently selected from N, CH, and CD. Further, the compound has a structure represented by formula (IV):
  • R 1 -R 7 , R 9 and R 10 are each independently selected from H and D;
  • A is selected from N, CH, CD;
  • R 7 , R 9 and R 10 are each independently selected from H; R 1 -R 6 are each independently selected from H and D; A is selected from CH and CD.
  • R 1 -R 7 , R 9 and R 10 are each independently selected from H and D;
  • A is selected from N, CH, CD;
  • R 7 , R 9 and R 10 are each independently selected from H; R 1 -R 6 are each independently selected from H and D; A is selected from CH and CD.
  • R 1 -R 7 , R 9 , and R 10 are each independently selected from H and D;
  • X, Y are each independently selected from F, Cl, Br, I, preferably, X, Y are each independently selected from Cl Or Br.
  • the compound is selected from one of the following compounds:
  • the present invention also provides the use of the above-mentioned compound or its optical isomer, salt, prodrug, hydrate or non-aqueous solvate in preparing THR- ⁇ agonist.
  • the THR- ⁇ agonist is a medicine for lowering cholesterol, treating dyslipidemia and non-alcoholic fatty liver disease.
  • the THR- ⁇ agonist is a medicine for treating familial hypercholesterolemia and non-alcoholic steatohepatitis.
  • the present invention also provides the use of the above compound or its optical isomers, salts, prodrugs, hydrates or non-aqueous solvates in the preparation of THR- ⁇ agonists.
  • the THR- ⁇ agonists are therapeutic Drugs for diffuse toxic goiter.
  • the present invention also provides a medicine for lowering cholesterol, treating dyslipidemia, and treating non-alcoholic fatty liver, which is based on the above-mentioned compound or its optical isomer, salt, prodrug, hydrate or non-aqueous solvate Active ingredients plus pharmaceutically acceptable excipients to prepare preparations.
  • deuterated refers to the replacement of one or more hydrogens in a compound or group with deuterium. Deuteration can be mono-, di-, poly, or fully-substituted.
  • the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably The content is greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%.
  • compound of the present invention refers to a compound represented by formula (I).
  • the term also includes various optical isomers, salts, prodrugs, hydrates or non-aqueous solvates of the compound of formula (I).
  • the active ingredient mentioned herein refers to any substance or mixture of substances used in the manufacture of medicines, which has pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, treatment or prevention of diseases or Can affect the function or structure of the body.
  • the pharmaceutically acceptable excipient has certain physiological activity, but the addition of the component will not change the dominant position of the above-mentioned pharmaceutical composition in the course of disease treatment, but only exerts auxiliary functions. These auxiliary functions are only for the component The utilization of known activity is a commonly used adjuvant therapy in the medical field. If the aforementioned auxiliary components are used in combination with the pharmaceutical composition of the present invention, they should still fall within the protection scope of the present invention.
  • Non-aqueous solvate refers to solvates other than hydrates.
  • the compound represented by formula (I) obtained by the present invention through specific substitution positions and specific substitution types has an effect on thyroid hormone receptor ⁇ (THR- ⁇ ) and thyroid hormone receptor ⁇ (THR- ⁇ ).
  • - ⁇ ) have better agonistic activity, especially for THR- ⁇ , the agonistic activity and agonistic selectivity of the compound of the present invention are significantly improved.
  • the compounds of the present invention also have significantly improved pharmacokinetic properties.
  • the compound of the present invention is suitable for the preparation of THR- ⁇ agonists and indications applicable to the treatment of THR- ⁇ agonists (including dyslipidemia, hypercholesterolemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) ) Has excellent application prospects in drugs.
  • THR- ⁇ agonists including dyslipidemia, hypercholesterolemia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD)
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the raw materials and instruments used in the present invention are all known products and are obtained by purchasing commercially available products.
  • N-cyanoacetylurethane (72.0mg, 0.46mmol) into a 25mL single-necked round bottom flask, add water (9.4mL) and pyridine (2.8mL) to it, stir to dissolve at room temperature, and then remove the system. Place in an ice water bath and continue to cool and stir for 30 minutes.
  • the diazotization reaction liquid is slowly added dropwise to the system in which N-cyanoacetylurethane is dissolved, and the dropping rate is controlled so that the internal temperature of the system does not exceed 5°C. After dripping, leave the system to heat and stir in an ice water bath to react.
  • TLC TLC monitored the consumption of raw materials. Stop heating, allow the system to cool to room temperature, then place it in an ice-water bath to continue cooling and stirring. When the internal temperature of the system drops to 5°C, add ice water to the system and stir vigorously for 20 minutes.
  • Method 2 Add maleic hydrazide (5.6g, 50mmol) into a round bottom flask, add 80ml heavy water, add 500mg Pd/C, replace with hydrogen three times, heat and reflux for 72h under hydrogen atmosphere, cool to room temperature, filter, filter cake Add to a round bottom flask and repeat the above operation. After the reaction is completed, filter, add 100 ml of methanol to the filter cake, reflux for 30 min, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 2.5 g of 4,5-dideuterium-maleic hydrazide, with a yield of 43.87%.
  • N-cyanoacetylurethane (47.0mg, 0.30mmol) into a 50mL single-neck round bottom flask, add water (6.3mL) and pyridine (1.9mL) to it, stir at room temperature to dissolve and clarify, then the system Transfer to an ice water bath to continue cooling and stirring for 30 minutes.
  • the diazotization reaction liquid is slowly added dropwise to the system in which N-cyanoacetylurethane is dissolved, and the dropping rate is controlled so that the internal temperature of the system does not exceed 5°C. After dripping, leave the system to heat and stir in an ice-water bath to react. After 1h, TLC monitored the end of the reaction.
  • TLC TLC monitored the consumption of raw materials. Stop heating, allow the system to cool to room temperature, and then place it in an ice-water bath to continue cooling and stirring. When the internal temperature of the system drops to 5°C, add ice water to the system and stir vigorously for 30 minutes.
  • Test Example 1 The agonistic activity test of the compound of the present invention on THR- ⁇
  • THR- ⁇ thyroid hormone receptor ⁇
  • Test Example 2 Mouse pharmacokinetic test of the compound of the invention
  • Polyethylene glycol 400 (PEG400), manufacturer: Chengdu Kelon Chemical Reagent Factory; hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), manufacturer: Shanghai Dibai Chemical Technology Co., Ltd.; HPC LF, Manufacturer: Chengdu Yuannuo Tiancheng Technology Co., Ltd.; Heparin Sodium, manufacturer: Chengdu Kelon Chemical Reagent Factory.
  • mice Chengdu Dashuo Experimental Animal Co., Ltd.
  • Group IV accurately weigh 1.15mg of the sample to be tested, first add DMA 0.228ml to dissolve it, then add PEG400 1.139ml, 0.1M phosphate buffer 5.012ml, and finally add 40% HP-B-CD to a final volume of 11.39ml , Sonicate, vortex and mix to prepare a transparent clear solution of 0.1mg/ml.
  • PO group Precisely weigh 5.06 mg of the sample to be tested, add 2% HPC LF (containing 0.1% Tween-80) to a final volume of 20.04ml, sonicate, vortex and mix to make a uniform suspension solution of 0.25mg/ml .
  • the LC/MS/MS method was established to determine the plasma concentration of the original drug, the plasma concentration-time curve was drawn, and the main pharmacokinetic parameters were calculated using WinNonlin 6.3 software (see Table 2).
  • the compound of the present invention can reach the exposure of MGL-3196 5 mg/kg at a dose of 2 mg/kg in mice; and compound 2 of the present invention can be used at a lower dose. Has a longer half-life than MGL-3196. It is proved that the compound of the present invention has better pharmacokinetic properties than MGL-3196.
  • the present invention provides the compound represented by formula (I) or its optical isomer, salt, prodrug, hydrate or non-aqueous solvate.
  • the compound represented by formula (I) obtained by the present invention through specific substitution positions and specific substitution types has a positive effect on thyroid hormone receptor ⁇ (THR- ⁇ ) and thyroid hormone receptor ⁇ (THR- ⁇ ). All have better agonistic activity, especially for THR- ⁇ , the agonistic activity and agonistic selectivity of the compound of the present invention are significantly improved.
  • the compounds of the present invention also have significantly improved pharmacokinetic properties.
  • the compound of the present invention has application prospects in the preparation of THR- ⁇ agonists and in the treatment of THR- ⁇ agonists applicable indications (including dyslipidemia, hypercholesterolemia, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease) excellent.

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Abstract

本发明公开了一种卤素取代的苯醚类化合物及其用途。具体提供了式(I)所示的化合物或其光学异构体、药学上可接受的盐、前药、水合物或非水溶剂合物。实验证明，与对照化合物MGL-3196相比，本发明通过特定取代位置和特定取代类型得到的式(I)所示化合物对THR-β有更好的激动活性，对THR-β/THR-α的选择性显著提高。此外，本发明化合物还具有显著提高的药代动力学性质。本发明化合物在制备THR-β激动剂，以及治疗THR-β激动剂适用的适应症（包括血脂异常、高胆固醇血症、非酒精性脂肪性肝炎、非酒精性脂肪肝病）的药物中应用前景优良。

Description

卤素取代的苯醚类化合物及其用途 技术领域
本发明属于药物制备领域，具体涉及一种卤素取代的苯醚类化合物及其用途。
背景技术
MGL-3196是一种氯原子取代的苯醚类化合物，其是高度选择性的甲状腺激素受体β(THR-β)激动剂，EC50值为0.21μM，其结构式为
Figure PCTCN2020110252-appb-000001
目前正在进行后期临床试验，显示了对血脂异常,高胆固醇血症,非酒精性脂肪性肝炎(NASH)的疗效。
研究发现，MGL-3196作为一种甲状腺激素受体β激动剂，其在体内的药代动力学性质和激动活性还有待提高。因此，对MGL-3196进行结构改性，研发出性能更优异的药物成为研究的热点之一。
但是，化学改性在不同程度上改变了化合物的结构，会导致化合物的物理性质和化学性质都发生不同程度的变化，而这些变化对化合物药学性质的影响是不可预测的。因此，如何选择化学改性的方法才能得到性能更优异的药物成为本领域的难点。
氘代是一种常用的改性的方法。氘代药物是指将药物分子中的部分氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一般会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期可能会延长。
但是，由于生物系统的代谢过程复杂，药物在生物体内的药代动力学性质受到多方面因素影响，也表现出相应的复杂性。与相应的非氘代药物相比，氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期，反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery and Development，P405-406)，劣化其药代动力学性质；另一方面，药物分子上某些位置的氢因为空间位阻等原因也不易被氘代，因此，药物的氘代并非随心所欲，可氘代的位点也是不可预期的。
本发明期望通过合适的化学改性，得到一类活性增强、药代动力学性质提高的药物。
发明内容
本发明的目的在于提供一类活性高、药代动力学性质良好、毒副作用小以及代谢稳定性好的药物。
本发明提供了一种式(I)所示的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物：
Figure PCTCN2020110252-appb-000002
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD；X，Y分别独立地选自F，Cl，Br，I；
其中，B为N，A为CH或CD时，X，Y不同时为Cl。
进一步地，所述化合物具有式(II)所示结构：
Figure PCTCN2020110252-appb-000003
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD。
进一步地，所述化合物具有式(III)所示结构：
Figure PCTCN2020110252-appb-000004
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD。进一步地，所述化合物具有式(IV)所示结构：
Figure PCTCN2020110252-appb-000005
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A选自N，CH，CD；
优选的，R 7，R 9，R 10分别独立地选自H；R 1-R 6分别独立地选自H、D；A选自CH，CD。
进一步地，所述化合物具有式(V)所示结构：
Figure PCTCN2020110252-appb-000006
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A选自N，CH，CD；
优选的，R 7，R 9，R 10分别独立地选自H；R 1-R 6分别独立地选自H、D；A选自CH，CD。
进一步地，所述化合物具有式(VI)所示结构：
Figure PCTCN2020110252-appb-000007
其中，R 1-R 7，R 9，R 10分别独立地选自H、D；X，Y分别独立地选自F，Cl，Br，I，优选地，X，Y分别独立地选自Cl或Br。
进一步地，所述化合物选自如下化合物之一：
Figure PCTCN2020110252-appb-000008
Figure PCTCN2020110252-appb-000009
本发明还提供了上述化合物或其光学异构体、盐、前药、水合物或非水溶剂合物在制备THR-β激动剂中用途。
进一步地，所述THR-β激动剂是降低胆固醇，治疗血脂异常、非酒精性脂肪肝病的药物。
进一步地，所述THR-β激动剂是治疗家族性高胆固醇血症、非酒精性脂肪性肝炎的药物。
本发明还提供了上述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物在制备THR-α激动剂中用途，优选的，所述THR-α激动剂为治疗弥漫性毒性甲状腺肿的药物。
本发明还提供了一种降低胆固醇，治疗血脂异常，治疗非酒精性脂肪肝的药物，它是以上述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物为活性成分，再加上药学上可接受的辅料制备而成的制剂。
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015％)，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于97％，更佳地大于99％，更佳地大于99.5％。
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种光学异构体、盐、前药、水合物或非水溶剂合物。
本文所述活性成分，是指用于药品制造中的任何一种物质或物质的混合物，此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或其他直接作用或者能影响机体的功能或结构。
所述药学上可接受的辅料，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。
“非水溶剂合物”是指除了水合物以外的溶剂合物。
实验证明，与对照化合物MGL-3196相比，本发明通过特定取代位置和特定取代类型得到的式(I)所示化合物对甲状腺激素受体β(THR-β)和甲状腺激素受体α(THR-α)均有更好的激动活性，特别是对THR-β，本发明化合物的激动活性和激动选择性显著提高。此外，本发明化合物还具有显著提高的药代动力学性质。本发明化合物在制备THR-β激动剂，以及治疗THR-β激动剂适用的适应症(包括血脂异常、高胆固醇血症、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪肝病(NAFLD))的药物中应用前景优良。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、 替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料、仪器都是已知产品，通过购买市售产品所得。
实施例1、化合物2的合成
Figure PCTCN2020110252-appb-000010
(1)化合物3-溴-5-氯-4-((6-氯-5-二(三氘代甲基)甲基哒嗪-3-基)氧)苯胺(化合物2-1)的合成
Figure PCTCN2020110252-appb-000011
合成3,6-二氯-4-(1,1,1,3,3,3-六氘丙-2-基)哒嗪(化合物A)：
Figure PCTCN2020110252-appb-000012
用文献方法(Canadian Journal of Chemistry,2014,92,305)制备得到2-三氘代甲基-3，3，3-三氘代丙酸A-4。称取2-三氘代甲基-3，3，3-三氘代丙酸(1.4g，15mmol)置于100mL三颈圆底烧瓶中，并向其中加入20mL水， 室温搅拌溶解澄清。随后向体系中加入3,6-二氯哒嗪(2.2g，15mmol)，室温搅拌。接着向体系中加入硝酸银(2.5g，15mmol)，完毕将体系移置于油浴中升温加热搅拌反应。当体系内温升至50℃时，向体系中滴加浓硫酸(3.5mL)，滴毕，体系在该温度下保温搅拌10min。尔后，当体系内温升至60℃时，向体系中滴加6mL溶有过硫酸铵(10.3g，45mmol)的水溶液。待体系内温升至70℃时，任其在该温度下保温搅拌反应30min。停止加热，体系自然冷却至室温。再将体系移置于冰水浴中降温冷却搅拌，15min后，向体系中滴加NaOH(6.0M)溶液调节体系的PH值至8左右。向体系中加入乙酸乙酯(20mL)剧烈搅拌，静置分层，水相用乙酸乙酯(10mL x 3)反萃，合并有机相，依次用水(10mL x 3)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压浓缩得粗品，经柱层析分离得类白色固体3,6-二氯-4-(1,1,1,3,3,3-六氘丙-2-基)哒嗪(化合物A)1.7g。收率：58％。MS(ESI)m/e 197.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.98(d,J＝0.8Hz,1H),3.12(s,1H)。
称取3-溴-5-氯-4-二(三氘代甲基)甲基哒嗪(A,450mg，2.28mmol)置于100mL三颈圆底烧瓶中，并向其中加入10mL二甲亚砜，室温搅拌溶解澄清。对体系进行氩气置换操作，反复十次，确保体系中的惰性气体氛围。随后依次向体系中加入4-氨基-2-溴-6-氯苯酚(508.0mg，2.28mmol)，无水碳酸钾(1.3g，9.12mmol)。加毕，将体系移置于90℃的油浴中，升温加热搅拌反应过夜。24h后，监测原料消耗完毕。停止加热，任体系自然冷却至室温。向体系中加入乙酸乙酯(20mL)和水(20mL)，剧烈搅拌，后静置分层，水相用乙酸乙酯(20mL*3)反萃，合并有机相，依次用水(10mL*3)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压浓缩除去溶剂得粗品，后经柱层析分离得浅黄褐色固体3-溴-5-氯-4-((6-氯-5-二(三氘代甲基)甲基哒嗪-3-yl)氧)苯胺(2-1，463.0mg)。收率：52.9％。MS(ESI)m/e 382.0(M+H) +。
(2)化合物6-(4-氨基-2-溴-6-氯苯氧基)-4-二(三氘代甲基)甲基哒嗪-3(2H)-酮(化合物2-2)的合成
Figure PCTCN2020110252-appb-000013
称取3-溴-5-氯-4-((6-氯-5-二(三氘代甲基)甲基哒嗪-3-yl)氧)苯胺(341.0mg，0.89mmol)置于50mL三颈圆底烧瓶中，并向其中加入冰醋酸(10mL)，室温搅拌。随后向体系中加入无水醋酸钠(256.0mg，3.12mmol)。加毕，将体系移置于105℃的油浴中，搅拌回流反应。24h后，停止加热，任体系自然冷却至室温。旋蒸除去溶剂，向体系中加入水(50mL)，后将其移置于冰水浴中降温冷却搅拌。待体系内温降至5℃时，向体系中滴加氢氧化钠(1.0M)溶液，调节体系PH值至9左右。尔后，向体系中加入乙酸乙 酯(30mL)，剧烈搅拌，后静置分层，水相用乙酸乙酯(25mL*2)反萃，合并有机相，分别用水(20mL)，饱和食盐水(20mL)各洗涤一次，无水硫酸钠干燥，减压浓缩得淡黄色固体。向装有该固体的100mL三颈圆底烧瓶中依次加入甲醇(10mL)，NaOH(1.0M)溶液(10mL)，完毕，将体系移置于105℃的油浴中回流反应。16h后，停止加热，撤去油浴，任体系恢复至室温。旋蒸除去溶剂，加入乙酸乙酯(60mL)和水(40mL)，剧烈搅拌，静置分层，水层用乙酸乙酯(25mL*2)反萃，合并有机层，依次用水(20mL*2)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，旋蒸除去溶剂得粗品，后经柱层析分离得浅黄色固体6-(4-氨基-2-溴-6-氯苯氧基)-4-二(三氘代甲基)甲基哒嗪-3(2H)-酮(2-2，200.0mg)。收率：61.5％。MS(ESI)m/e 364.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),7.26(s,1H),6.82(d,J＝4.0Hz,1H),6.70(d,J＝4.0Hz,1H),5.60(s,2H),2.99(s,1H)。
(3)化合物乙基(2-氰基-2-(2-(3-溴-5-氯-4-((5-二(三氘代甲基)甲基-6-氧代-1,6-二氢哒嗪-3-yl)氧)苯基)亚联氨基)乙酰基)氨基甲酸酯(化合物2-3)的合成
Figure PCTCN2020110252-appb-000014
称取6-(4-氨基-2-溴-6-氯苯氧基)-4-二(三氘代甲基)甲基哒嗪-3(2H)-酮(153mg，0.42mmol)置于25mL单颈圆底烧瓶中，并向其中加入水(5.6mL)，室温搅拌。随后向体系中加入浓盐酸(2.8mL)。完毕，将体系移置于冰水浴中降温冷却搅拌。待体系内温降至0℃时，向体系中滴加0.4mL溶有亚硝酸钠(36.5mg，0.53mmol)的水溶液。加毕，任体系继续保温搅拌反应30min。称取N-氰基乙酰尿烷(72.0mg，0.46mmol)置于25mL单颈圆底烧瓶中，向其中加入水(9.4mL)，吡啶(2.8mL),室温搅拌溶解澄清，后将体系移置于冰水浴中继续降温冷却搅拌30min。将重氮化反应液缓慢滴加入溶有N-氰基乙酰尿烷的体系中，控制滴加速度，使体系内温不超过5℃。滴毕，任体系在冰水浴中保温搅拌反应。1h后，TLC监测反应结束。对体系进行抽滤操作，滤饼用水少量多次淋洗，再用正己烷淋洗数次，干燥后得橘红色固体乙基(2-氰基-2-(2-(3-溴-5-氯-4-((5-二(三氘代甲基)甲基-6-氧代-1,6-二氢哒嗪-3-基)氧)苯基)亚联氨基)乙酰基)氨基甲酸酯(2-3，153.0mg)。不经进一步纯化，直接用于下步反应中。收率：68.6％。MS(ESI)m/e 531.1(M+H) +。
(4)化合物2-(3-溴-5-氯-4-((5-二氘代甲基甲基-6-氧代-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物2)的合成
Figure PCTCN2020110252-appb-000015
称取乙基(2-氰基-2-(2-(3-溴-5-氯-4-((5-二(三氘代甲基)甲基-6-氧代-1,6-二氢哒嗪-3-yl)氧)苯基)亚联氨基)乙酰基)氨基甲酸酯(153mg，0.29mmol)置于25mL单颈圆底烧瓶中，并向其中加入冰醋酸(5mL)，室温搅拌。随后向体系中加入无水醋酸钠(118mg，1.44mmol)。完毕，将体系移置于120℃的油浴中升温加热搅拌反应。1.5h后，TLC监测原料消耗完毕。停止加热，任体系冷却至室温，后置于冰水浴中继续降温冷却搅拌，待体系内温降至5℃时，向体系中加入冰水，剧烈搅拌20min。尔后对其进行抽滤操作，滤饼用水少量多次淋洗，再溶解于乙酸乙酯中，无水硫酸钠干燥，旋蒸除去溶剂得粗品，经Pre-TLC分离纯化得浅橘红色固体2-(3-溴-5-氯-4-((5-二(三氘代甲基)甲基-6-氧代-1,6-二氢哒嗪-3-yl)氧)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物2，54.0mg)。收率：38.6％。MS(ESI)m/e 485.0(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ13.29(s,1H),12.24(s,1H),7.90(d,J＝4.0Hz,1H),7.82(d,J＝4.0Hz,1H),7.45(s,1H),3.02(s,1H)。
实施例2、2-(3-溴-5-氯-4-((4-氘-5-(1,1,1,3,3,3-六氘代丙-2-基)-6-氧-1,6-二氢吡嗪-3-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-氰(化合物3)的合成
Figure PCTCN2020110252-appb-000016
(1)化合物3-溴-5-氯-4-((6-氯-5-(丙-2-基-1,1,1,3,3,3-六氘)吡嗪-3-基-4-氘)氧)苯胺的合成
Figure PCTCN2020110252-appb-000017
合成3,6-二氯-4-氘-5-(1,1,1,3,3,3-六氘代丙-2-基)哒嗪(化合物B):
Figure PCTCN2020110252-appb-000018
称取化合物2,3-二氯马来酸酐B-1(8.35g，50mmol)，加入100ml圆底烧瓶中，加入40ml水，加入水合肼(2.5g，50mmol)，加热至回流，保温反应4h，冷却至室温，冰水浴30min，过滤，滤饼用100ml水淋洗，烘干，得到4,5-二氯马来酰肼(B-2)5.0g，收率：55.3％，MS(ESI)m/e 181.0(M+H) +。
合成4,5-二氘-马来酰肼(B-3)：方法一：称取4,5-二氯马来酰肼(2.0g，11.05mmol)加入100ml单口圆底烧瓶中，加入50ml氘代甲醇，加入10ml重水，加入200mg Pd/C，氘气置换3次，室温反应40h，过滤，滤液减压浓缩干，加入6ml甲醇打浆，过滤，滤饼烘干，得化合物4,5-二氘马来酰肼1.0g，收率：79％，MS(ESI)m/e 115.2(M+H) +。 13C NMR(101MHz,DMSO-d 6)δ156.76,130.50。方法二：将马来酰肼(5.6g，50mmol)加入圆底烧瓶中，加入80ml重水，加入500mg Pd/C，氢气置换三次，在氢气氛围下加热回流72h，冷却至室温，过滤，滤饼加入圆底烧瓶中，重复以上操作。反应结束后过滤，滤饼加入100ml甲醇，回流30min，过滤，滤液减压浓缩干，得到4,5-二氘-马来酰肼2.5g，收率：43.87％。
4,5-二氘-3,6-二氯哒嗪(B-4)的合成
称取4,5-二氘马来酰肼(1.0g，8.74mmol)于100ml圆底烧瓶中，加入三氯氧磷15ml，115℃回流4h，减压浓缩干，冰水浴冷却，加入20ml冰水，用氨水调节pH＝9.0，加入30ml二氯甲烷萃取，水层用20ml二氯甲烷再萃取一次，合并有机层，有机层分别用水，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩干，得到1.2g化合物4,5-二氘-3,6-二氯哒嗪，收率：90.9％。 13C NMR(101MHz,DMSO-d 6)δ156.3,131.9(t,J＝27Hz)。MS(ESI)m/e 151(M+H) +。
将化合物3,6-二氯-4,5-二氘哒嗪B-4(604mg,4.0mmol)加入10ml水中，加入化合物A-4(372mg，4.0mmol)，搅拌下加入AgNO3(680mg，4mmol)，升温至50℃，缓慢滴加浓硫酸1ml，滴加完毕后，升温至60℃，保温反应10min。将过硫酸铵(2.74g，12mmol)溶于6ml水中，滴加到反应体系中，滴加完毕后，升温至70℃，保温反应30min，TLC监控反应直至原料反应完 全，关闭加热，冰水浴冷却，用6N NaOH水溶液调节pH＝8.0，用30ml乙酸乙酯萃取，有机层用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩干，柱层析分离纯化(石油醚/乙酸乙酯＝10:1)，得到化合物B(500mg),收率：63.1％，MS(ESI)m/e 198.1(M+H) +。
称取3,6-二氯-4-二(三氘代甲基)甲基-5-氘哒嗪B(285.0mg，1.44mmol)置于25mL单颈圆底烧瓶中，并向其中加入8mL二甲亚砜，室温搅拌溶解澄清。随后依次向体系中加入4-氨基-2-溴-6-氯苯酚(320.0mg，1.44mmol)，无水碳酸钾(995.0mg，7.20mmol)。加毕，对体系进行氩气置换操作，反复十次，确保体系中的惰性气体氛围。后将体系移置于90℃的油浴中，升温加热搅拌反应过夜。4h后，TLC监测原料消耗完毕。停止加热，任体系自然冷却至室温。向体系中加入乙酸乙酯(20mL)和水(20mL)，剧烈搅拌，后静置分层，水相用乙酸乙酯(30mL*3)反萃，合并有机相，依次用水(20mL*3)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥。减压浓缩除去溶剂得粗品，后经柱层析分析得类白色固体3-溴-5-氯-4-((6-氯-5-(丙-2-基-1,1,1,3,3,3-六氘)吡嗪-3-基-4-氘)氧)苯胺(3-1，293.0mg)。收率：53.0％。MS(ESI)m/e 383.0(M+H) +。
(2)化合物6-(4-氨基-2-溴-6-氯苯氧基)-4-(丙-2-基-1,1,1,3,3,3-六氘)吡嗪-3(二氢)-酮-5-氘(3-2)的合成
Figure PCTCN2020110252-appb-000019
称取3-溴-5-氯-4-((6-氯-5-二氘代甲基甲基-4-氘哒嗪-3-yl)氧)苯胺(230.0mg，0.60mmol)置于50mL单颈圆底烧瓶中，并向其中加入冰醋酸(10mL)，室温搅拌。随后向体系中加入无水醋酸钠(172.0mg，2.10mmol)。加毕，将体系移置于105℃的油浴中，搅拌回流反应。22h后，停止加热，任体系自然冷却至室温。旋蒸除去溶剂，向体系中加入水(50mL)，后将其移置于冰水浴中降温冷却搅拌。待体系内温降至5℃时，向体系中滴加氢氧化钠(1.0M)溶液，调节体系PH值至9左右。尔后，向体系中加入乙酸乙酯(50mL)，剧烈搅拌，后静置分层，水相用乙酸乙酯(25mL*2)反萃，合并有机相，分别用水(20mL)，饱和食盐水(20mL)各洗涤一次，无水硫酸钠干燥，减压浓缩得淡黄色固体。向装有该固体的100mL三颈圆底烧瓶中依次加入甲醇(10mL)，NaOH(1.0M)溶液(10mL)，完毕，将体系移置于105℃的油浴中回流反应。11h后，停止加热，撤去油浴，任体系恢复至室温。旋蒸除去溶剂，加入乙酸乙酯(80mL)和水(50mL)，剧烈搅拌，静置分层，水层用乙酸乙酯(25mL*2)反萃，合并有机层，依次用水(20mL*2)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，旋蒸除去溶剂得粗品，后经柱层析分离得淡黄色固体6-(4-氨基-2-溴-6-氯苯氧基)-4-二氘代甲基甲基-5-氘 哒嗪-3(2H)-酮(3-2，115.0mg)。收率：52.5％。MS(ESI)m/e365.1(M+H) +。
(3)化合物乙基(2-(2-(3-溴-5-氯-4-((6-氧-5-(丙-2-基-1,1,1,3,3,3-六氘)-1,6-二氢吡嗪-3-基-4-氘)氧)苯基)亚联氨基)-2-氰基乙酰基)氨基甲酸脂(3-3)的合成
Figure PCTCN2020110252-appb-000020
称取6-(4-氨基-2-溴-6-氯苯氧基)-4-二氘代甲基甲基-5-氘哒嗪-3(2H)-酮.(100.0mg，0.27mmol)置于25mL单颈圆底烧瓶中，并向其中加入水(3.7mL)，室温搅拌。随后向体系中加入浓盐酸(1.9mL)。完毕，将体系移置于冰水浴中降温冷却搅拌。待体系内温降至0℃时，向体系中滴加0.5mL溶有亚硝酸钠(24.0mg，0.34mmol)的水溶液。加毕，任体系继续保温搅拌反应30min。另称取N-氰基乙酰尿烷(47.0mg，0.30mmol)置于50mL单颈圆底烧瓶中，向其中加入水(6.3mL)，吡啶(1.9mL),室温搅拌溶解澄清，后将体系移置于冰水浴中继续降温冷却搅拌30min。将重氮化反应液缓慢滴加入溶有N-氰基乙酰尿烷的体系中，控制滴加速度，使体系内温不超过5℃。滴毕，任体系在冰水浴中保温搅拌反应。1h后，TLC监测反应结束。对体系进行抽滤操作，滤饼用水少量多次淋洗，再用正己烷淋洗数次，干燥后得乙基(2-氰基-2-(2-(3-溴-5-氯-4-((5-二氘代甲基甲基-4-氘-6-氧代-1,6-二氢哒嗪-3-yl)氧)苯基)亚联氨基)乙酰基)氨基甲酸酯(3-3，104.0mg)。不经进一步纯化，直接用于下步反应中。收率：71.7％。MS(ESI)m/e 532.1(M+H) +。
(4)化合物2-(3-溴-5-氯-4-((4-氘-5-(1,1,1,3,3,3-六氘代丙-2-基)-6-氧-1,6-二氢吡嗪-3-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-氰(化合物3)的合成
Figure PCTCN2020110252-appb-000021
称取乙基(2-氰基-2-(2-(3-溴-5-氯-4-((5-二氘代甲基甲基-4-氘-6-氧代-1,6-二氢哒嗪-3-yl)氧)苯基)亚联氨基)氰基乙酰基)氨基甲酸酯(104.0mg，0.20mmol)置于25mL单颈圆底烧瓶中，并向其中加入冰醋酸(5mL)，室温搅拌。随后向体系中加入无水醋酸钠(82.0mg，1.00mmol)。完毕，将体系移置于120℃的油浴中升温加热搅拌反应。2h后，TLC监测原料消耗完毕。 停止加热，任体系冷却至室温，后置于冰水浴中继续降温冷却搅拌，待体系内温降至5℃时，向体系中加入冰水，剧烈搅拌30min。尔后对其进行抽滤操作，滤饼用水少量多次淋洗，再溶解于乙酸乙酯中，无水硫酸钠干燥，旋蒸除去溶剂得粗品，经Pre-TLC分离纯化得浅橘色固体2-(3-溴-5-氯-4-((4-氘-5-(1,1,1,3,3,3-六氘代丙-2-基)-6-氧-1,6-二氢吡嗪-3-基)氧)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-氰(化合物3，68.0mg)。收率：71.6％。MS(ESI)m/e486.2(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ13.22(s,1H),12.24(s,1H),7.89(d,J＝4.0Hz,1H),7.82(d,J＝4.0Hz,1H),3.02(s,1H)。
实施例3、2-(3,5-二溴-4-((6-氧-5-(丙-2-基-1,1,1,3,3,3-六氘)-1,6-二氢吡嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-氰(化合物14)的合成
Figure PCTCN2020110252-appb-000022
(1)3,5-二溴-4-((6-氯-5-(丙-2-基-1,1,1,3,3,3-六氘)哒嗪-3-基)氧)苯胺的合成：
Figure PCTCN2020110252-appb-000023
将化合物3,6-二氯-4-(丙-2基-1,1,1,3,3,3-六氘)哒嗪A(330mg，1.67mmol)溶于5ml DMSO，加入化合物4-氨基-2,6-二溴苯酚(559mg，2.09mmol)，搅拌下加入K2CO3(923mg，6.68mmol)，Ar置换3次，升温至90℃，反应3h，冷却，加入水，乙酸乙酯萃取，有机层分别用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩干，柱层析分离纯化(石油醚/乙酸乙酯＝5:1)，得到化合物3,5-二溴-4-((6-氯-5-(丙-2-基-1,1,1，3,3,3-d6)哒嗪-3-基)氧)苯胺(14-2，210mg)，收率：30％，MS(ESI)m/e 426.0.0(M+H) +。
(2)6-(4-氨基-2,6-二溴苯氧基)-4-(丙2基-1,1,1，3，3，3-d6)哒嗪-3(2氢)-酮的合成
Figure PCTCN2020110252-appb-000024
将化合物3,5-二溴-4-((6-氯-5-(丙-2-基-1,1,1,3,3,3-d6)哒嗪-3-基)氧)苯胺(185mg，0.43mmol)溶于5ml乙酸中，搅拌下加入无水乙酸钠(142mg，1.7mmol)，105℃反应过夜，冷却至室温，减压浓缩干，用6NNaOH溶液调节Ph＝9，用20ml乙酸乙酯萃取，水层再用15ml乙酸乙酯反萃一次，合并有机层，分别用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩干。加入10ml甲醇，加入10ml 1NNaOH水溶液，105℃反应过夜，冷却，减压浓缩掉大部分甲醇，加入20ml乙酸乙酯萃取，有机层用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩干，柱层析分离纯化(石油醚/乙酸乙酯＝3:2)，得到化合物6-(4-氨基-2,6-二溴苯氧基)-4-(丙2基-1,1,1，3，3，3-d6)哒嗪-3(2H)-酮(14-3，130mg)，收率：73.9％，MS(ESI)m/e 408.0(M+H) +。
(3)乙基-(2-氰基-2-(2-(3,5-二溴-4-((6-氧-5-(丙-2-基-1,1,1,3,3,3-d6)-1,6-二氢哒嗪-3-yl-4-d)氧)苯基)亚联氨基)乙基)氨基甲酸酯的合成
Figure PCTCN2020110252-appb-000025
将化合物6-(4-氨基-2,6-二溴苯氧基)-4-(丙2基-1,1,1，3，3，3-d6)哒嗪-3(2H)-酮(125mg，0.31mmol)加入圆底烧瓶中，加入4.6ml水，加入2.2ml浓盐酸，冰水浴30min。将N-氰基乙酰尿烷(52mg，0.33mmol)加入圆底烧瓶中，加入8ml水，加入2.2ml吡啶，冰水浴30min。将上一步的反应液滴加到反应体系中，滴加完毕后，保温搅拌30min，过滤，滤饼用30ml水淋洗，干燥，得到紫红色固体产品乙基-(2-氰基-2-(2-(3,5-二溴-4-((6-氧-5-(丙-2-yl-1,1,1，3,3,3-d6)-1,6-二氢哒嗪-3-yl-4-d)氧)苯基)亚联氨基)乙基)氨基甲酸酯(14-4，130mg)，收率：72.8％，MS(ESI)m/e 576.1(M+H) +。
(4)2-(3,5-二溴-4-((6-氧-5-(丙-2-yl-1,1,1，3,3,3-d6)-1,6-二氢哒嗪-3-yl)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈的合成
Figure PCTCN2020110252-appb-000026
将化合物乙基-(2-氰基-2-(2-(3,5-二溴-4-((6-氧-5-(丙-2-yl-1,1,1,3,3,3-d6)- 1,6-二氢哒嗪-3-yl-4-d)氧)苯基)亚联氨基)乙基)氨基甲酸酯(125mg，0.22mmol)溶于5ml乙酸中，加入乙酸钠(73mg，0.88mmol)，125℃回流2h，冰水浴冷却，加入30ml水，搅拌20min，过滤，滤饼用水淋洗3次，干燥，将所得国体加入3ml乙酸乙酯中，打浆30min，过滤，滤饼减压浓缩干，得到化合物2-(3,5-二溴-4-((6-氧-5-(丙-2-yl-1,1,1，3,3,3-d6)-1,6-二氢哒嗪-3-yl)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(化合物14，95mg)，收率：81.4％，MS(ESI)m/e 529.0(M+H) +1H NMR(400MHz,DMSO-d6)δ13.44–13.12(m,1H),12.23(s,1H),7.92(s,2H),7.44(s,1H),3.02(s,1H).
实施例4、化合物1的合成
化合物2-(3-溴-5-氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物1)
Figure PCTCN2020110252-appb-000027
用已知化合物3,6-二氯-4-异丙基哌嗪(PCT Int.Appl.,2013045519)为原料，参照实施例1的方法制备得到化合物1。
LC/MS(ESI +)calcd for C 17H 12BrClN 6O 4(M+H +)m/z,477.98；found,479.0,481.0.
1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),12.22(s,1H),7.88(d,J＝2.4Hz,1H),7.81(d,J＝2.4Hz,1H),7.44(s,1H),3.05(dt,J＝13.8,6.9Hz,1H),1.20(d,J＝6.9Hz,6H).
实施例5、化合物13的合成
2-(3,5-二溴-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物13)
Figure PCTCN2020110252-appb-000028
用已知化合物3,6-二氯-4-异丙基哌嗪(PCT Int.Appl.,2013045519)为原料，参照实施例3的方法制备得到化合物13。
LC/MS(ESI +)calcd for C 17H 12Br 2N 6O 4(M+H +)m/z,524.13；found,523.1，525.1.
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),7.91(s,2H),7.42(s,1H),3.06(dt,J＝13.7,6.9Hz,1H),1.20(d,J＝6.8Hz,6H).
实施例6、化合物15的合成
2-(3,5-二溴-4-((6-氧代-5-(丙烷-2-基-1,1,1,3,3,3-d6)-1,6-二氢哒嗪-3-基-4-d)氧基)苯基)-3,5-二氧基-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物15)
Figure PCTCN2020110252-appb-000029
用上述化合物B为原料，参照实施例3的方法制备得到化合物15。
LC/MS(ESI +)calcd for C 17H 5D 7Br 2N 6O 4(M+H +)m/z,531.17；found,530.0，532.0.
1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),12.23(s,1H),7.92(s,2H),3.02(s,1H).
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物对THR-β的激动活性实验
1)实验方法
用类似于文献方法(J.Med.Chem.2014,57,3912.)测得化合物对THR-β的激动活性：
用DMSO制备100X参比化合物或化合物，并进行1:3等比稀释。用1X反应缓冲液将100X梯度稀释参比化合物或化合物稀释为4X，并加入实验板中。用1X反应缓冲液制备4X TRα-LBD或TRβ-LBD,4X RXRα的混合溶液，并加入实验板中。用1X反应缓冲液制备2X biotin-SRC2-2,2X Eu-anti-GST,2X streptavidin-d2的混合溶液，并加入实验板中。1000rpm离心1min并在室温及避光条件下孵育4小时。在EnVision 2104板读取器上读取665nm和615nm荧光信号值，并计算Ratio 665nm/615nm。计算得到THR-βEC50(nM)。
采用上述类似的方法测得本发明化合物对甲状腺激素受体α(THR-α)的激动活性，计算得到THR-αEC50(nM)。并计算出本发明化合物的激动选择性THR-β/THR-α。
选择性THR-β/THR-α＝THR-αEC50÷THR-βEC50。
2)实验结果
表1.本发明化合物对THR-β和THR-α的激动活性及选择性
Figure PCTCN2020110252-appb-000030
Figure PCTCN2020110252-appb-000031
结果如表1所示。可以看出，与对照化合物MGL-3196相比，本发明的化合物1、2、3、13、14、15对THR-β和THR-α的激动活性均明显提高，特别是对THR-β，本发明化合物的激动活性显著提高。此外，与对照化合物MGL-3196相比，在THR-β和THR-α中，本发明的化合物对THR-β的激动选择性也显著提高。
试验例2、本发明化合物的小鼠药代动力学测试
1)实验材料及仪器：
聚乙二醇400(PEG400)，生产厂家：成都市科龙化工试剂厂；羟丙基β环糊精(HP-β-CD)，生产厂家：上海笛柏化学品技术有限公司；HPC LF，生产厂家：成都远诺天成科技有限公司；肝素钠，生产厂家：成都市科龙化工试剂厂。
实验动物：ICR小鼠(成都达硕实验动物有限公司)。
2)实验方法
待测样品配制：
IV组：精密称取待测样品1.15mg，先加入DMA 0.228ml使之溶解，再依次加入PEG400 1.139ml，0.1M磷酸缓冲液5.012ml，最后加入40％HP-B-CD至终体积11.39ml，超声、涡漩混匀，配制成0.1mg/ml的透明澄清溶液。
PO组：精密称取待测样品5.06mg，加入2％HPC LF(内含0.1％Tween-80)至终体积20.04ml，超声、涡漩混匀,配制成0.25mg/ml的均匀混悬溶液。
实验过程：
健康成年ICR小鼠9只(每个时间点3只动物)；禁食过夜(自由饮水)后，分别尾静脉及灌胃给药。IV组分别于给药后5min,15min,0.5h,1h,2h,4h,8h,12h,24h由颌下静脉采血0.1ml，4℃离心5min分离血浆，于-20℃保存待测。PO组于给药前及给药后0.5,1,2,4,6,8,12,24h由颌下静脉采血0.1ml，处理方法同静脉注射给药组。
建立LC/MS/MS法测定血浆中的原形药物浓度，绘制血药浓度-时间曲线，采用WinNonlin 6.3软件计算主要药动学参数(见表2)。
3)实验结果
表2、小鼠药代动力学实验
Figure PCTCN2020110252-appb-000032
从表2可以看出，本发明化合物在小鼠中2mg/kg的给药剂量就能达到MGL-3196 5mg/kg给药剂量的暴露量；而且本发明化合物2在更低的给药剂量下具有比MGL-3196更长的半衰期。证明本发明化合物比MGL-3196具有更好的药代动力学特性。
综上，本发明提供了式(I)所示的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物。与对照化合物MGL-3196相比，本发明通过特定取代位置和特定取代类型得到的式(I)所示化合物对甲状腺激素受体β(THR-β)和甲状腺激素受体α(THR-α)均有更好的激动活性，特别是对THR-β，本发明化合物的激动活性和激动选择性显著提高。此外，本发明化合物还具有显著提高的药代动力学性质。本发明化合物在制备THR-β激动剂，以及治疗THR-β激动剂适用的适应症(包括血脂异常、高胆固醇血症、非酒精性脂肪性肝炎、非酒精性脂肪肝病)的药物中应用前景优良。

Claims (10)

  1. 式(I)所示的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物：
    Figure PCTCN2020110252-appb-100001
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD；X，Y分别独立地选自F，Cl，Br，I；
    其中，B为N，A为CH或CD时，X，Y不同时为Cl。
  2. 根据权利要求1所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物具有式(II)所示结构：
    Figure PCTCN2020110252-appb-100002
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD。
  3. 根据权利要求2所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物具有式(IV)所示结构：
    Figure PCTCN2020110252-appb-100003
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A选自N，CH，CD；
    优选的，R 7，R 9，R 10分别独立地选自H；R 1-R 6分别独立地选自H、D；A选自CH，CD。
  4. 根据权利要求1所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物具有式(III)所示结构：
    Figure PCTCN2020110252-appb-100004
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A，B分别独立地选自N，CH，CD。
  5. 根据权利要求4所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物具有式(V)所示结构：
    Figure PCTCN2020110252-appb-100005
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；A选自N，CH，CD；
    优选的，R 7，R 9，R 10分别独立地选自H；R 1-R 6分别独立地选自H、D；A选自CH，CD。
  6. 根据权利要求1所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物具有式(VI)所示结构：
    Figure PCTCN2020110252-appb-100006
    其中，R 1-R 7，R 9，R 10分别独立地选自H、D；X，Y分别独立地选自F，Cl，Br，I，优选地，X，Y分别独立地选自Cl或Br。
  7. 根据权利要求1～6任一项所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物，其特征在于：所述化合物选自如下化合物之一：
    Figure PCTCN2020110252-appb-100007
    Figure PCTCN2020110252-appb-100008
  8. 权利要求1～7任一项所述的化合物或其光学异构体、盐、前药、水 合物或非水溶剂合物在制备THR-β激动剂中用途；
    优选的，所述THR-β激动剂是降低胆固醇，治疗血脂异常、非酒精性脂肪肝病的药物；
    更优选的，所述THR-β激动剂是治疗家族性高胆固醇血症、非酒精性脂肪性肝炎的药物。
  9. 权利要求1～7任一项所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物在制备THR-α激动剂中用途，优选的，所述THR-α激动剂为治疗弥漫性毒性甲状腺肿的药物。
  10. 一种降低胆固醇，治疗血脂异常，治疗非酒精性脂肪肝的药物，其特征在于：它是以权利要求1～7任一项所述的化合物或其光学异构体、盐、前药、水合物或非水溶剂合物为活性成分，再加上药学上可接受的辅料制备而成的制剂。
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