WO2021078274A1 - 哒嗪酮或哒嗪类化合物及其衍生物和药物组合物 - Google Patents

哒嗪酮或哒嗪类化合物及其衍生物和药物组合物 Download PDF

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WO2021078274A1
WO2021078274A1 PCT/CN2020/123330 CN2020123330W WO2021078274A1 WO 2021078274 A1 WO2021078274 A1 WO 2021078274A1 CN 2020123330 W CN2020123330 W CN 2020123330W WO 2021078274 A1 WO2021078274 A1 WO 2021078274A1
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alkyl
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吕彬华
崔大为
庞旭东
汪祝兵
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Priority to EP20879564.1A priority Critical patent/EP4050008A4/en
Priority to US17/755,164 priority patent/US20230109134A1/en
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Definitions

  • the present invention relates to the field of medicine, in particular to pyridazinone or pyridazine compounds and their derivatives and pharmaceutical compositions.
  • Thyroid hormone is mainly used to maintain homeostasis in the human body, so it is essential for human growth and development. Hypothyroidism can cause abnormalities in heart function, weight, metabolism, cholesterol, muscles, and behavior. Thyroid hormones can regulate body weight and cholesterol levels, but are prone to various side effects, especially on the heart and skeletal muscles. Thyroid hormones mainly achieve biological activity in the body through thyroid hormone receptors. Thyroid hormone receptors are divided into two subtypes, ⁇ and ⁇ . Among them, the thyroid hormone ⁇ receptor is mainly related to heart rate control, and the thyroid hormone ⁇ receptor is mainly related to lowering cholesterol and promoting metabolism.
  • Synthetic thyroid hormone beta receptor agonists can selectively act on thyroid hormone beta receptors. In preclinical animal experiments, they have been found to have significant weight loss, lipid-lowering and insulin sensitization effects. At the same time, they have less side effects such as tachycardia and skeletal muscle reduction compared with natural thyroid hormones, so they are expected to become new A generation of drugs for the treatment of inflammation and metabolic diseases (such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis, etc.). At present, companies such as Madrigal and Viking are developing specific agonists for thyroid hormone ⁇ receptors, such as MGL-3196 (Martha J. Kelly, Sherrie Pietranico-Cole, J. Douglas Larigan, etc., J. Med. Chem. 2014, 57 :3912-3923) In the early clinical stage, the structural formula of MGL-3196 is as follows:
  • the existing thyroid hormone ⁇ receptor agonists also have many shortcomings, such as short action time in the body, low bioavailability, and multiple administrations, which limit the effectiveness of thyroid hormone ⁇ receptor agonists. .
  • the purpose of the present invention is to improve a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, diastereomers Constructs, resonance bodies, and pharmaceutically acceptable salts thereof.
  • the compound represented by the formula (I) or (Ia) has excellent agonistic effects and pharmacodynamic properties on thyroid hormone beta receptors.
  • the first aspect of the present invention provides a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, diastereomers Isomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof,
  • X is selected from H or -C(R 17 R 18 )OZ
  • Y is selected from H or -C(R 19 R 20 )OW
  • the limitation is that X and Y are not hydrogen at the same time
  • R 1 , R 2 , and R 3 are each independently selected from the following group: hydrogen, deuterium, undeuterated or one or more (preferably 1-4) deuterated or fully deuterated C1-C4 alkyl groups, Hydroxy, or two of R 1 , R 2 , and R 3 are combined with adjacent C to form a substituted or unsubstituted C3-C8 cycloalkyl, and the substitution refers to substitution by one or more substituents selected from the following group : C1-C4 alkyl, C3-C8 cycloalkyl, hydroxyl, amino, carbonyl, C2-C8 ester, cyano, ether, thioether, C2-C8 amide, or sulfonamide;
  • R 4 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, deuterium, and halogen;
  • R 5 is substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C6-C20 aryl , Substituted or unsubstituted C6-C20 aryl-C1-C8 alkyl-, or substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heteroaryl-C1-C8 alkane Group-, substituted or unsubstituted C1-C4 alkyl-(substituted or unsubstituted C1-C4 alkyl-O) m -substituted or unsubstituted C1-C4 alkyl-, where m is 1-8 A positive integer, the substitution refers to substitution by one or more substituents selected from
  • R 10 is selected from a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted 4-10 membered heterocycloalkyl group, the substitution means being selected from the following One or more substituents of the group are substituted: C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, halogen, hydroxyl, amino, amino, C2-C8 carbonyl, C2-C8 ester group, cyano Group, ether group, thioether group, C2-C8 amide group, or sulfonamide group;
  • X 1 and X 2 are each independently selected from the following group: oxygen or sulfur;
  • X 3 is nitrogen
  • R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from the following group: hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, Substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, or R 11 and R 12 combine with adjacent X 1 , X 2 and P to form a substituted or unsubstituted 5-7 membered heterocycloalkyl, and the substitution refers to substitution by one or more substituents selected from the following group: Deuterium, C1-C20 alkyl, halogenated C1-C20 alkyl, C1-C6 alkoxy, C3-C10
  • R 16 is selected from the following group: hydrogen, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C1-C20 deuterated alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted A substituted C3-C10 cycloalkenyl group, a substituted or unsubstituted C6-C10 aryl group, an amino group, a substituted or unsubstituted 4-10 membered heterocycloalkyl group, wherein the substitution refers to one or more C6-C10 aryl groups Substitution;
  • R 17 , R 18 , R 19 , and R 20 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C1-C3 alkyl, and the restriction is that when X is connected to N and Y is hydrogen , R 17 and R 18 are not hydrogen at the same time.
  • the compound is a compound of formula Ib:
  • X is selected from H
  • Y is selected from -C(R 19 R 20 )OW.
  • X is selected from -C(R 17 R 18 )OZ
  • Y is selected from H or -C(R 19 R 20 )OW.
  • X is selected from -C(R 17 R 18 )OZ
  • Y is selected from H.
  • X is selected from -C(R 17 R 18 )OZ
  • Y is selected from H.
  • X is selected from -C(R 17 R 18 )OZ
  • Y is selected from H.
  • the heterocyclic ring of the heterocycloalkyl group and the heteroaryl group independently have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S. .
  • At least one of R 1 , R 2 , R 3 , and R 4 is deuterated or deuterated.
  • At least two of R 1 , R 2 , R 3 , and R 4 are deuterated or deuterated.
  • At least three of R 1 , R 2 , R 3 , and R 4 are deuterated or deuterated.
  • R 1 , R 2 , R 3 , and R 4 are deuterated or deuterated.
  • R 1 , R 2 , R 3 , and R 4 are all deuterated or deuterated.
  • At least one of R 1 , R 2 , R 3 , and R 4 is selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • At least two of R 1 , R 2 , R 3 , and R 4 are selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • At least three of R 1 , R 2 , R 3 , and R 4 are selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • R 1 and R 3 are independently selected from the following group: one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • R 2 and R 4 are independently selected from the following group: hydrogen and deuterium.
  • R 1 and R 3 are CD 3 .
  • R 2 is deuterium
  • R 4 is deuterium
  • R 7 and R 9 are deuterium.
  • At least one of R 1 , R 2 , and R 3 is selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • At least two of R 1 , R 2 , and R 3 are selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • R 1 , R 2 , and R 3 are independently selected from the following group: deuterium, one or more deuterated or fully deuterated C1-C4 alkyl groups.
  • the deuterium isotope content of deuterium at the deuterated position is greater than the natural deuterium isotope content.
  • the deuterium isotope content of deuterium at the deuterated position is at least 30% larger than the natural deuterium isotope content (0.015%), preferably 50%, more preferably 75%, more preferably 95%, optimally 99%, such as 100%.
  • only one of X and Y is hydrogen.
  • X is hydrogen and Y is not hydrogen.
  • Y is hydrogen
  • X is not hydrogen
  • neither X nor Y is hydrogen.
  • R 1 , R 2 , and R 3 are each independently selected from the following group: hydrogen, deuterium, non-deuterated or one or more (preferably 1-4) deuterated or fully deuterated ⁇ C1-C4 alkyl.
  • R 1 , R 2 , and R 3 are each independently hydrogen or a non-deuterated C1-C4 alkyl group.
  • R 1 , R 2 , and R 3 are each independently hydrogen or methyl.
  • R 4 is hydrogen or deuterium.
  • R 5 is substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted Substituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl-C1-C4 alkyl-, substituted or unsubstituted C6-C12 heteroaryl, substituted or unsubstituted C6-C12 heteroaryl- C1-C4 alkyl-, substituted or unsubstituted C1-C4 alkyl- (substituted or unsubstituted C1-C4 alkyl-O) m -substituted or unsubstituted C1-C4 alkyl-.
  • Z and W are each independently -C(O)OR 5 .
  • R 5 is a substituted or unsubstituted C1-C8 alkyl group.
  • R 7 is hydrogen or deuterium.
  • R 9 is hydrogen or deuterium.
  • R 6 is halogen
  • R 8 is halogen
  • R 6 , R 7 , R 8 , and R 9 are each independently selected from the following group: hydrogen, deuterium, and halogen.
  • R 17 , R 18 , R 19 , and R 20 are each independently selected from the following group: hydrogen, substituted or unsubstituted C1-C3 alkyl, and the limitation is that when X is connected to N and Y When it is hydrogen, R 17 and R 18 are not hydrogen at the same time.
  • R 17 , R 18 , R 19 , and R 20 are each independently selected from the following group: hydrogen, methyl, and the restriction is that when X is connected to N and Y is hydrogen, R 17 , R 18 is not hydrogen at the same time.
  • R 17 is hydrogen and R 18 is hydrogen, substituted or unsubstituted C1-C3 alkyl.
  • R 17 and R 18 are not hydrogen at the same time.
  • R 19 is hydrogen and R 20 is hydrogen, substituted or unsubstituted C1-C3 alkyl.
  • R 17 is hydrogen
  • R 18 is hydrogen or methyl
  • R 19 is hydrogen
  • R 20 is hydrogen or methyl
  • the compound is a compound represented by formula (II-A) or formula (II-B):
  • X, Y, R 1 , R 2 , R 3 , R 4 , R 6 , and R 8 are as defined above.
  • the compound is a compound represented by formula (III-A) or formula (III-B):
  • X, Y, R 1 , R 2 , R 3 , and R 4 are as defined above.
  • the compound has a pyridazinone or pyridazine compound represented by formula (IV-A), (IV-B), (IV-C) and (IV-D) or its stereoisomers Conformers, tautomers, enantiomers, diastereomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof,
  • R 1 , R 2 , R 3 , R 4 , R 17 , R 18 , R 19 , R 20 , Z and W are as defined above.
  • the compound has the pyridazinone or pyridazine compound represented by formula (VA), (VB), (VC) and (VD) or its stereoisomers, tautomers Isomers, enantiomers, diastereomers, resonance isomers, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof,
  • R 4 , R 17 , R 18 , R 19 , R 20 , Z and W are as defined above.
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a method for preparing the pyridazinone or pyridazine compound represented by the formula (I) or (Ia) as described in the first aspect of the present invention or its stereoisomers or tautomers , Enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, the method includes the steps:
  • R and R' are leaving groups.
  • the alkaline condition is an alkaline reagent selected from the group consisting of NaH, cesium carbonate, triethylamine, DIPEA, or a combination thereof.
  • the leaving group is halogen, preferably Cl, Br or I.
  • the compound of formula (VI) is protected with a protecting group (PG is a protecting group, such as SEM or THP) to generate an intermediate (VI-C), and then reacts with YR' under basic conditions to generate a compound of formula (I) (X is hydrogen);
  • PG is a protecting group, such as SEM or THP
  • the third aspect of the present invention provides a pharmaceutical composition, the composition comprising:
  • a therapeutically effective amount of the pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers as described in the first aspect of the present invention Conformers, diastereomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof;
  • the pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, and non-pairs The content of enantiomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof is 0.01-99.99 wt.%, preferably 0.1-99.9 wt.%, more preferably 1 -99wt.%, more preferably 5-95wt.%, more preferably 10-90wt.%, more preferably 20-80wt.%, most preferably 30-70wt.%, based on the weight of the composition.
  • the pharmaceutical composition further contains other active ingredients.
  • the other active ingredient is an active ingredient for preventing and/or treating a disease selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or combination.
  • the pharmaceutical composition further comprises other drugs for preventing and/or treating diseases selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof .
  • the pharmaceutical composition further comprises a drug selected from the group consisting of interferon ⁇ (standard INF ⁇ and polyglycolated INF ⁇ ), nucleoside drugs (such as Telbivudine, Lamivudine, Clevudine, Adefovir, Tenofovir) , Besifovir, Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide Fumarate (TAF) and HDP-PMPA (CMX157), etc.), shell protein allosteric modulators (such as BAY41-4109, RG-7907, NVR3-778, ABI-H0731) ABI-H2158, JNJ-56136379, GLS 4JHS, etc.), cccDNA inhibitors, TLR3/7/8/9 agonists (such as RG-7854, GS9620, etc.), hepatitis B virus entry inhibitors (such as Myrcludex B, etc.), nuclear interference Gly, interferon
  • Emricasan smooth receptor (SMO) inhibitors (e.g. Vismodegib), galectin inhibitors (e.g. GR-MD-02), CC chemokine receptor types 2 and 5 (CCR2 and CCR5) Dual antagonists (such as Cenicriviroc), hexulose kinase (KHK) inhibitors (PF-06835919), glucagon-like peptide-1 (GLP-1) receptor agonists (such as liraglutide, semaglutide) , Anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibody (such as seuzumab), Aramchol, a complex of cholic acid and arachidonic acid, or a combination thereof.
  • SMO smooth receptor
  • Glectin inhibitors e.g. GR-MD-02
  • CCR2 and CCR5 Dual antagonists (such as Cenicriviroc), hexulose kinase (KHK) inhibitors (PF-
  • the other active ingredients are active ingredients for preventing and/or treating diseases selected from the group consisting of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, liver cirrhosis (such as Primary biliary cirrhosis), gallstones, atherosclerosis, obesity, diabetes, or a combination thereof.
  • diseases selected from the group consisting of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, liver cirrhosis (such as Primary biliary cirrhosis), gallstones, atherosclerosis, obesity, diabetes, or a combination thereof.
  • the dosage form of the pharmaceutical composition is an oral preparation or a parenteral preparation (such as injection, infusion)
  • the dosage form of the pharmaceutical composition is selected from the following group: injection, capsule, tablet, pill, powder, granule, aerosol, suppository, film, drop pill, and topical liniment.
  • the pharmaceutical composition is a controlled-release, sustained-release preparation or nano-formulation.
  • the fourth aspect of the present invention provides a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, Enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof, or use of the pharmaceutical composition according to the third aspect of the present invention , Characterized in that it is used for (i) preparation of thyroid hormone receptor agonist pharmaceutical preparations or drugs; (ii) preparation of pharmaceutical preparations or drugs for diseases related to reduced thyroid hormone receptor activity; and/or (ii) for preparation Pharmaceutical preparations or drugs for preventing and/or treating diseases selected from the group consisting of inflammation, cancer, cardiovascular disorders, infections, immune disorders, metabolic disorders, or combinations thereof.
  • the disease associated with the decrease in thyroid hormone receptor activity is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.
  • the thyroid hormone receptor is thyroid hormone alpha receptor and/or thyroid hormone beta receptor.
  • the thyroid hormone receptor is thyroid hormone ⁇ receptor.
  • the disease is selected from the group consisting of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, liver cirrhosis (such as primary biliary cirrhosis), gallstones, atherosclerosis Sclerosis, obesity, hyperlipidemia, diabetes.
  • the hyperlipidemia is high triglycerides and/or high cholesterol.
  • the obesity is obesity caused by a high-fat diet.
  • the disease is selected from the group consisting of primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), Alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), liver fibrosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, type I diabetes, II Type diabetes, obesity.
  • PBC primary sclerosis
  • PSC primary sclerosing cholecystitis
  • cholestasis autoimmune hepatitis
  • viral hepatitis such as hepatitis B
  • Alcoholic liver disease non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH)
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic fatty liver disease
  • liver fibrosis arteriosclerosis
  • the cancer is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, or a combination thereof.
  • a thyroid hormone receptor agonist comprising an agonist effective amount of the pyridazinone represented by formula (I) or (Ia) as described in the first aspect of the present invention or Pyridazine compounds or their stereoisomers, tautomers, enantiomers, diastereomers, resonance forms, their pharmaceutically acceptable salts, hydrates, solvates, or crystals type.
  • the sixth aspect of the present invention provides a non-therapeutic and non-diagnostic in vitro method for enhancing or enhancing the activity of thyroid hormone receptors.
  • the method is characterized in that the method comprises the steps of: in vitro culture system, subjecting thyroid hormone to Body or cell expressing thyroid hormone receptor and the pyridazinone or pyridazine compound represented by formula (I) or (Ia) as described in the first aspect of the present invention or its stereoisomers or tautomers , Enantiomers, diastereomers, resonators, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof are contacted to enhance or increase the activity of thyroid hormone receptors.
  • the seventh aspect of the present invention provides a method for preventing and/or treating a disease selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, diabetes, and a therapeutically effective amount of such
  • a disease selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, diabetes, and a therapeutically effective amount of such
  • the body, resonance body, pharmaceutically acceptable salt, hydrate, solvate, or crystal form thereof are administered to the desired patient.
  • Figure 1 is the plasma concentration-time curve of the compound of MGL-3196 (curve number 1) and WO2009037172A1Example 5 (curve number 2) in Test Example 1, wherein the plasma concentration is the concentration of MGL-3196.
  • Figure 2 is the plasma concentration-time curve of MGL-3196 (curve number 1) and compound 6A (curve number 2) in Test Example 2, wherein the plasma concentration is the concentration of MGL-3196.
  • Figure 3 is the plasma concentration-time curve of MGL-3196 (curve number 1) and compound 6B (curve number 2) in Test Example 3, where the plasma concentration is the concentration of MGL-3196.
  • Figure 4 is the plasma concentration-time curve of MGL-3196 (curve number 1), compound 2A (curve number 3) and compound 2B (curve number 2) in Test Example 4, where the plasma concentration is MGL-3196 concentration.
  • a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, and enantiomers Conformers, diastereomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof.
  • the pyridazinone or pyridazine compound represented by the formula (I) or the isomer formula (Ia) compound of the present invention has an excellent selective agonistic effect on the thyroid hormone ⁇ receptor and better pharmacodynamic performance. On this basis, the inventor completed the present invention.
  • the terms “including”, “including”, and “containing” are used interchangeably, and include not only closed definitions, but also semi-closed and open definitions. In other words, the term includes “consisting of” and “consisting essentially of”.
  • R1 the same meaning as “R 1” and “R 1” can be replaced with each other, the same as other similarly defined meanings.
  • the terms used have the general meanings known to those skilled in the art.
  • the substitution means that one or more (preferably 1, 2, 3, or 4) hydrogen and/or deuterium of a group are each independently replaced by a substituent.
  • alkyl refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chains.
  • the alkyl group has a limited number of carbon atoms (such as C1-C20 alkyl), it means that the alkyl group contains 1-20 carbon atoms.
  • C1-C4 alkyl refers to an alkyl group containing 1-4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • cycloalkyl refers to a saturated or partially saturated unitary ring, bicyclic or polycyclic (fused, bridged, or spiro) ring system group.
  • a certain cycloalkyl group has a limited number of carbon atoms (such as C3-C20), it means that the cycloalkyl group has 3-20 carbon atoms.
  • C3-C8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, and cyclopentyl , Cycloheptyl, or similar groups.
  • “Spirocycloalkyl” refers to a bicyclic or polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • “Fused cycloalkyl” refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic rings. Bond, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system .
  • cycloalkenyl refers to a unit ring with at least one carbon-carbon double bond on the ring carbon chain, bicyclic or polycyclic (fused, bridged, or spiro), but cannot be an aromatic structure.
  • alkenyl group has a limited number of carbon atoms (such as C3-C8), it means that the cycloalkenyl group contains 3-8 ring carbon atoms.
  • cyano means -CN
  • heterocycloalkyl is also called “heterocyclyl”, which refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 4-7 membered monocyclic ring, 7-11 membered bicyclic ring, Or 8-16 membered tricyclic ring system), in which at least one heteroatom is present in the ring with at least one carbon atom.
  • the number of members is limited in front of the heterocycloalkyl group, it refers to the number of ring atoms of the heterocycloalkyl group.
  • a 4-20 membered heterocycloalkyl group refers to a heterocycloalkyl group with 4-20 ring atoms.
  • Each heterocyclic ring containing heteroatoms may have one or more (such as 1, 2, 3 or 4) heteroatoms, and these heteroatoms are selected from nitrogen, oxygen or sulfur atoms, among which nitrogen or sulfur atoms It can be oxidized, and nitrogen atoms can also be quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl group, 4-piperidinone group, tetrahydropyranyl group, morpholino group, thiomorpholino group, thiomorpholine sulfoxide group, thiomorpholine sulfone group, 1,3-dioxanyl group and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; heterocyclic groups may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • aryl refers to an aromatic cyclic hydrocarbon compound group, for example having 1, 2, 3, 4, or 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or condensed (such as naphthalene, anthracene, etc.). When the number of carbon atoms in front of an aryl group is limited, it refers to the number of ring carbon atoms of the aryl group.
  • a C6-C20 aryl group refers to an aryl group with 6-20 ring carbon atoms, "substituted aryl group" It means that one or more (preferably 1-3) positions in the aryl group are substituted and can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heteroaryl refers to an aromatic heterocyclic ring system having one to more (preferably 1, 2, 3, or 4) heteroatoms, which can be monocyclic (monocyclic) or fused together or co- Valence connected polycyclic ring (bicyclic, tricyclic or polycyclic), each heteroatom-containing heterocyclic ring may have one or more (such as 1, 2, 3, 4) independently selected from Heterocycles of the following group: oxygen, sulfur and nitrogen.
  • the heteroaryl group is limited by the number of members, it refers to the number of ring atoms of the heteroaryl group.
  • a 4-20 membered heteroaryl group refers to a heteroaryl group having 4-20 ring atoms.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc.
  • “Heteroaryl” may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • groups which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group,
  • halogen refers to F, Cl, Br or I.
  • halo refers to substitution by halogen.
  • amino refers to a -NRR' group with a structure, wherein R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • ether group refers to a -OR group with a structure, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, Aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl, preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted Or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl, cycloalkenyl, aryl
  • thioether group refers to a -SR group with a structure, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl , Aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl, preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 heteroaryl, substituted or unsubstituted Substituted C4-C8 heterocycloalkyl, wherein alkyl, cycloalkyl,
  • acyl refers to a -COR group with a structure, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aromatic Group or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • ester group refers to a -COOR group with a structure, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, Aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above.
  • amide group refers to a group with R-CO-NR- or -CO-NRR', where R is hydrogen or an alkyl group, when the amide group has a limited number of carbon atoms (such as C2-C8 amide group)
  • the amide group contains 2-8 carbon atoms, R and R'are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, Aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl, preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted Or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or
  • sulfonamido refers to a -SO 2 NRR' group with a structure, wherein R and R'are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkene Group or substituted cycloalkenyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl, preferably, R can represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C5-C10 Heteroaryl, substituted or unsubstituted C4-C8 heterocycloalkyl, wherein alkyl,
  • alkoxy refers to the RO- group, where R is an alkyl group, and the alkyl group is as defined herein.
  • R is an alkyl group
  • alkyl group is as defined herein.
  • a C1-C6 alkoxy group refers to the alkyl group.
  • the alkyl group in the oxy group has 1 to 6 carbon atoms.
  • Representative examples of alkoxy include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.
  • deuterated refers to substitution by deuterium (D).
  • amino means -NH2.
  • nitro means -NO2.
  • cyano means -CN
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • Typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • compound of the present invention pyridazinone or pyridazine compound of the present invention
  • compound of formula (I) or (Ia) of the present invention or “formula (I) or (Ia) of the present invention”
  • the indicated compound” or “the compound of formula (I) or (Ia)” can be used interchangeably, and refer to the pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers , Tautomers, enantiomers, diastereomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof,
  • each group is as described in the first aspect of the invention in the above text. It should be understood that the term also includes mixtures of the aforementioned components.
  • the other elements such as N, C, O, F, etc.
  • H such as N, C, O, F, etc.
  • the most abundant Naturally occurring elements such as 14 N, 12 C, 16 O and 19 F.
  • the group (such as X, Y, Z, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 etc.
  • Either (I) or (Ia) the group on the compound) is the corresponding group in the specific compound described in Table 1, respectively.
  • the compound is preferably the compound prepared in the embodiment.
  • the compound is selected from the compounds listed in Table 1.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term “salt”.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or freeze-dried in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acid salts that can form a salt include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzyl Acid salt, benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate Salt, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate Acid salt (
  • 2-hydroxyethanesulfonate lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, Oxalate, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinic acid Salt, sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, tosylate (such as p-toluenesulfonate), dodecanoate, etc.
  • naphthalenesulfonate e.g. 2-naphthalenesulfonate
  • nicotinate nitrate
  • Oxalate pectinate
  • persulfate persulfate
  • phenylpropionate such as 3-
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl.
  • Hypamine a salt formed with N,N-bis(dehydroabietyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Base amines and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates E.g., dimethyl sulfate, diethyl, dibutyl
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the ratio of the mixture of isomers containing isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention .
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the scheme disclosed in the schematic and/or examples.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compound of formula (VI) is reacted with XR or YR' (R, R'are leaving groups, such as Cl, Br or I) under alkaline conditions (such as NaH, cesium carbonate, triethylamine or DIPEA, etc.)
  • alkaline conditions such as NaH, cesium carbonate, triethylamine or DIPEA, etc.
  • the intermediate of formula (VI-A) or formula (VI-B) is then subjected to basic conditions (such as NaH, cesium carbonate, triethylamine or DIPEA, etc.) and YR' or XR (R', R Is a leaving group, such as Cl, Br or I) further react to obtain the target compound (I).
  • the compound of formula (VI) is protected with a protecting group (PG is a protecting group, such as SEM or THP) to generate intermediate (VI-C), and then reacts with YR' under basic conditions to generate intermediate (X) of formula (I) Is hydrogen);
  • PG is a protecting group, such as SEM or THP
  • the present invention also provides a pharmaceutical composition, said composition comprising:
  • the pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, diastereomers The content of isomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof is 0.01-99.99wt.%, preferably 0.1-99.9wt.%, more preferably 1- 99wt.%, more preferably 5-95wt.%, more preferably 10-90wt.%, more preferably 20-80wt.%, most preferably 30-70wt.%, based on the weight of the composition.
  • the present invention provides a method for preparing a pharmaceutical composition, which comprises the steps of: combining a pharmaceutically acceptable carrier with the pyridazinone or pyridazine compound represented by the formula (I) or (Ia) of the present invention or its Stereoisomers, tautomers, enantiomers, diastereomers, resonators, and their pharmaceutically acceptable salts, hydrates, solvates, crystal forms or prodrugs are mixed, Thereby forming a pharmaceutical composition.
  • the compound of formula (I) or (Ia) can be combined with other drugs known to treat or improve similar conditions.
  • the administration mode and dosage of the original drug can be kept unchanged, while the compound of formula (I) or (Ia) is administered at the same time or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula (I) or (Ia) can be preferably used.
  • the combination of drugs also includes taking the compound of formula (I) or (Ia) and one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula (I) or (Ia) or the known drug may be lower than the dose of the compound used alone.
  • bile acid receptor (FXR) agonists such as Obeticholic acid, Tropifexor, GS-9674, ZG5266
  • peroxisome proliferator activated receptor (PPAR) Agonists (such as Elafibranor, Saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor ⁇ (THR ⁇ ) agonists (such as MGL-3196), diacylglycerol-O-acyltransferase (DGAT) inhibitors (such as Pradigastat, PF- 06865571), acetyl-Coenzyme A carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (such as Vismodegib), Galectin inhibitors (such as GR-MD-02), CC chemokine receptor type 2 and 5 (CCR
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 0.1-2000 mg of the compound of the present invention per agent, more preferably, contains 1-1000 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of formula (I) or (Ia) of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the inflammation, cardiovascular disease, infection, immune disease, metabolic disease or cancer involved in the present invention include (but not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), bile Stasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or liver fibrosis; arteriosclerosis, dyslipidemia, high cholesterol Hyperemia or hypertriglyceridemia; type I diabetes, type II diabetes, or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, or colorectal cancer.
  • PBC primary sclerosis
  • PSC primary sclerosing cholecystitis
  • bile Stasis autoimmune hepatitis
  • viral hepatitis such
  • the present invention also provides a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, and diastereomers , Resonance body, its pharmaceutically acceptable salt, hydrate, solvate, or crystal form, or use of the pharmaceutical composition according to the present invention, for (i) preparation of thyroid hormone receptor agonist pharmaceutical preparations Or drugs; (ii) preparation of pharmaceutical preparations or drugs for diseases related to decreased thyroid hormone receptor activity; and/or (ii) preparation of pharmaceutical preparations for the prevention and/or treatment of diseases including (but not limited to) the following groups or Drugs: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.
  • a pyridazinone or pyridazine compound represented by formula (I) or (Ia) or its stereoisomers, tautomers, enantiomers, and diastereomers , Resonance body, its pharmaceutically acceptable
  • prevention means a method of preventing the onset of a disease and/or its accompanying symptoms or protecting a subject from acquiring the disease.
  • prevention also includes delaying the onset of the disease and/or its accompanying symptoms and reducing the risk of a subject's disease.
  • treatment refers to any treatment of a disease in a mammal, including (but not limited to): (a) inhibiting the disease, that is, slowing down or preventing the development of clinical symptoms; and/or ( b) Alleviate the disease, that is, cause the regression of clinical symptoms, and/or (c) reduce or eliminate the disease and/or its accompanying symptoms.
  • the thyroid hormone receptor is thyroid hormone alpha receptor and/or thyroid hormone beta receptor.
  • the thyroid hormone receptor is thyroid hormone ⁇ receptor.
  • diseases associated with decreased thyroid hormone receptor activity include (but are not limited to): inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.
  • the diseases include (but are not limited to): non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, liver cirrhosis (such as primary biliary cirrhosis), gallstones, arteries Atherosclerosis, obesity, hyperlipidemia, diabetes.
  • the hyperlipidemia is high triglycerides and/or high cholesterol.
  • the obesity is obesity caused by a high-fat diet.
  • the disease includes (but is not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B) ), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), liver fibrosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, type I diabetes , Type II diabetes, obesity.
  • PBC primary sclerosis
  • PSC primary sclerosing cholecystitis
  • cholestasis autoimmune hepatitis
  • viral hepatitis such as hepatitis B
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic fatty liver disease
  • the cancer includes (but is not limited to): lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, or a combination thereof .
  • the compounds of formula (I) or (Ia) described in the present invention are used to prepare drugs for preventing and/or treating obesity.
  • the present invention also provides a non-therapeutic and non-diagnostic method for enhancing or improving the activity of thyroid hormone receptor in vitro.
  • the method comprises the steps of: in an in vitro culture system, thyroid hormone receptor or expression of thyroid hormone receptor.
  • the cell and the pyridazinone or pyridazine compound represented by the formula (I) or (Ia) of the present invention or its stereoisomers, tautomers, enantiomers, diastereomers Isomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof are contacted to enhance or increase the activity of thyroid hormone receptors.
  • the present invention also provides a method for preventing and/or treating diseases including (but not limited to) the following group: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, diabetes, said method Including the steps: adding a therapeutically effective amount of the pyridazinone or pyridazine compound represented by formula (I) or (Ia) of the present invention or its stereoisomers, tautomers, and enantiomers
  • the isomers, diastereomers, resonance isomers, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof are administered to the desired patient.
  • disorder includes diseases and their symptoms.
  • the present invention also provides a thyroid hormone receptor agonist, said agonist comprising an agonist effective amount of the pyridazinone or pyridazine compound represented by formula (I) or (Ia) of the present invention or its stereo Isomers, tautomers, enantiomers, diastereomers, resonance forms, pharmaceutically acceptable salts, hydrates, solvates, or crystal forms thereof.
  • the compound represented by formula (I) or (Ia) of the present invention has better metabolic properties and pharmacodynamic properties in vivo (such as in rats);
  • the compound represented by the formula (I) or (Ia) of the present invention has a higher drug concentration in the liver tissue of the body (such as in the rat body), and thus has a better pharmacodynamic performance.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc.
  • the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).
  • LC-MS Liquid chromatography mass spectrometry
  • Agilent 1200 Infinity Series mass spectrometer HPLC measurement uses Agilent 100 high pressure chromatograph (Microsorb 5 micron C18 100x3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
  • the mixture was filtered through Celite, and the filter cake was washed with ethyl acetate.
  • the organic phase was separated and collected, and the aqueous phase was extracted with ethyl acetate.
  • the combined organic phase was washed with saturated brine, dried and filtered.
  • the filtrate was concentrated under reduced pressure and passed through silica gel column chromatography to obtain the target product (0.5 g, yield 53%).
  • the third step Preparation of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one
  • the fourth step (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl) (Oxygen) phenyl) hydrazone) acetyl) preparation of ethyl carbamate
  • the fifth step 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5 -Preparation of dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • the first step 1-(3-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2( 3H)-yl)phenoxy)-5-isopropyl-6-oxypyridazine-1(6H)-yl)ethyl isopropyl carbonate and 1-((6-(2,6-dichloro- 4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine- Preparation of 3-yl)oxy)ethyl isopropyl carbonate
  • Compound 2B 1-((6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2( 3H)-yl)phenoxy)-4-isopropylpyridazin-3-yl)oxy)ethyl isopropyl carbonate
  • Compound 3B 1-((6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2( 3H)-yl)phenoxy)-4-(propan-2-yl-1,1,1,3,3,3-d6)pyridazin-3-yl)oxy)ethyl isopropyl carbonate
  • Compound 4B 1-((6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2( 3H)-yl)phenoxy)-4-(propan-2-yl-d7)pyridazin-3-yl)oxy)ethyl isopropyl carbonate
  • Compound 5B 1-((6-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2( 3H)-yl)phenoxy)-4-(propan-2-yl-d7)pyridazin-3-yl-5-d)oxy)ethyl isopropyl carbonate
  • Compound 6A (3-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)- (Yl)phenoxy)-5-isopropyl-6-oxypyridazine-1(6H)-yl)methyl isopropyl carbonate
  • Example 7 1-(3-(2,6-Dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H )-Yl)phenoxy)-5-isopropyl-6-oxypyridazine-1(6H)-yl)ethyl ethyl carbonate and 1-((6-(2,6-dichloro-4- (6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-4-isopropylpyridazine-3- (B) Oxygen) Preparation of Ethyl Ethyl Carbonate
  • the first step 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydro Preparation of pyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • the second step (6-cyano-2-(3,5-dichloro-4-(5-(propyl-2-yl)-6-oxy-1-(tetrahydro-2H-pyran-2- Yl)-1,6-dihydropyridazin-3-yloxy)phenyl)-3,5-dioxo-2,3-dihydro-1,2,4-triazine-4(5H)- (Base) Preparation of methyl isobutyrate
  • the third step Isobutyric acid-(6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl )Oxy)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4(3H)-yl)methyl ester
  • Example 8 the compounds of Examples 9-10 were synthesized by the same method with different raw materials:
  • the first step di-tert-butyl ((6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1-(tetrahydro-2H-pyran- 2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4(3H )-Yl) methyl) phosphate preparation
  • reaction solution was stirred at room temperature for 10 min and then di-tert-butyl chloromethyl phosphate (299 mg, 1.16 mmol) was added dropwise. After the dropwise addition, the reaction solution was raised to 65°C and reacted for 46 hours. The obtained mixture was quenched with water, and then purified by preparation to obtain the target compound (15 mg, yield 4%).
  • the second step ((6-cyano-2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1-(tetrahydro-2H-pyran-2-yl) -1,6-Dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4(3H)-yl) (Methyl) dihydrogen phosphate preparation
  • Example 5 Male SD rats, weighing about 220g, were fasted overnight and divided into 2 groups with 4 rats in each group. The first group was given 10 mg/kg of the MGL-3196 compound solution prepared in Example 1 by gavage, and the second group was given by gavage. The stomach was given 10 mg/kg of the compound solution of WO2009037172A1 Example 5 (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), in which the carrier of the MGL-3196 compound solution and the compound solution of WO2009037172A1 Example 5 is DMSO/ PEG400. In each group, blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC/MS/MS.
  • the blood concentration is the concentration of MGL-3196.
  • Example 6 Male SD rats, weighing about 220g, were fasted overnight and divided into 2 groups with 4 rats in each group. The first group was given 10 mg/kg of the MGL-3196 compound solution prepared in Example 1 by gavage, and the second group was given by gavage.
  • the compound 6A solution prepared in Example 6 was administered to the stomach at 10 mg/kg (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), wherein the MGL-3196 compound solution and the compound 6A solution prepared in Example 6 are The carrier is DMSO/PEG400.
  • blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC/MS/MS.
  • Example 6 Male SD rats, weighing about 220g, were fasted overnight and divided into 3 groups, 4 rats in each group. The first group was given 10 mg/kg of the MGL-3196 compound solution prepared in Example 1 by gavage, and the second group was given by gavage.
  • the compound 6B solution prepared in Example 6 was administered to the stomach at 10 mg/kg (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), wherein the MGL-3196 compound solution and the compound 6B solution prepared in Example 6 are The carrier is DMSO/PEG400.
  • blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC/MS/MS.
  • Example 1 Male SD rats, weighing about 220g, were fasted overnight and divided into 3 groups, 4 rats in each group.
  • the first group was given 10 mg/kg of the MGL-3196 compound solution prepared in Example 1 by gavage, and the second group was given by gavage.
  • the compound 2A solution prepared in Example 2 was administered with 10 mg/kg in the stomach (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), and the third group was administered 10 mg/kg of the compound 2B prepared in Example 2 by intragastric administration.
  • Solution (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), wherein the carrier of the MGL-3196 compound solution, the compound 2A solution and the compound 2B solution is DMSO/PEG400.
  • blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration, and the concentration of the active ingredient MGL-3196 in plasma was determined by LC/MS/MS.
  • mice weighing 20-30g, fasted overnight were divided into 4 groups, 8 mice in each group.
  • the first group was given 10 mg/kg of the MGL-3196 compound solution prepared in Example 1 by intragastric administration, and the second group was administered
  • the compound 2A solution prepared in Example 2 was administered at 10 mg/kg in the stomach (the dosage is calculated according to the relative content of the MGL-3196 compound prepared in Example 1), and the third group was administered intragastrically with 10 mg/kg of the compound 2B prepared in Example 2.
  • the fourth group was given 10 mg/kg of the compound 6B solution prepared in Example 6 by intragastric administration (the dosage was prepared in accordance with Example 1 The relative content of MGL-3196 compound is calculated), wherein the carrier of MGL-3196 compound solution, compound 2A solution, compound 2B and compound 6B solution is DMSO/PEG400.
  • mouse livers were collected at 1hr and 6hr after administration, and the concentration of the active ingredient MGL-3196 in the liver was determined by LC/MS/MS.
  • mice 6-week-old C57Bl/6J mice were given a high-fat diet for 34 weeks. Starting from day 0 (day 1 of week 35), mice were orally orally administered with vehicle (2% Klucel LF, 0.1% Tween 80 aqueous solution); 1, 3, or 10 mg/kg of compound 2A prepared in Example 2 was administered. , Compound 2B or the compound MGL-3196 prepared in Example 1, 9 mice in each group, administered continuously for 23 days. In a parallel study, starting from day 0 (day 1 of week 35), mice were orally administered with vehicle (Dulbecco's phosphate buffered saline, pH adjusted to 9.0 with 1N NaOH) or 10, 30 or 100 ⁇ g/kg.
  • vehicle 2% Klucel LF, 0.1% Tween 80 aqueous solution
  • 1, 3, or 10 mg/kg of compound 2A prepared in Example 2 was administered.
  • Compound 2B or the compound MGL-3196 prepared in Example 1 9 mice in each group, administered continuously for 23 days.
  • mice were orally administered with
  • Iodothyronine (T3) was administered to 9 mice in each group for 23 consecutive days. Monitor body weight and food intake during the study. BMD and body composition analysis were performed on the 22nd day. At the autopsy on the 23rd day, organs were weighed and the blood samples were evaluated for cholesterol and other blood biochemical parameters.
  • the compound 2A and compound 2B prepared in Example 2 of the present invention and the compound 6B prepared in Example 6 have a good effect on reducing cholesterol and liver fat.

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Abstract

涉及哒嗪酮或哒嗪类化合物及其衍生物和药物组合物。具体地，提供一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型。所述的式(I)或(Ia)化合物对甲状腺激素β受体具有优异的激动作用和药效学性能。

Description

哒嗪酮或哒嗪类化合物及其衍生物和药物组合物 技术领域
本发明涉及医药领域，具体地涉及哒嗪酮或哒嗪类化合物及其衍生物和药物组合物。
背景技术
甲状腺激素在人体内主要用于维持体内平衡，因此对于人体生长和发育至关重要。甲状腺功能减退会导致心脏功能、体重、代谢、胆固醇、肌肉以及行为等异常表现。甲状腺激素可以调节体重和胆固醇水平，但是易产生各种副作用，尤其是对心脏和骨骼肌。甲状腺激素在体内主要通过甲状腺激素受体来实现生物体活性。甲状腺激素受体分为α和β两种亚型，其中甲状腺激素α受体主要与心率控制相关，而甲状腺激素β受体主要与降低胆固醇和促进新陈代谢相关。
人工合成的甲状腺激素β受体激动剂可以选择性的作用于甲状腺激素β受体。在临床前动物实验中发现，它们可以起到显著的减重、调脂及胰岛素增敏作用，同时相对于天然甲状腺激素具有较少的致心动过速及骨骼肌减少等副作用，因此有望成为新一代的治疗炎症和代谢性疾病(如非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化及肝硬化等)的药物。目前Madrigal和Viking等公司正在开发针对甲状腺激素β受体的特异性激动剂，如MGL-3196(Martha J.Kelly,Sherrie Pietranico-Cole,J.Douglas Larigan等，J.Med.Chem.2014,57：3912-3923)处于早期临床阶段，MGL-3196的结构式如下所示：
Figure PCTCN2020123330-appb-000001
然而，现有的甲状腺激素β受体激动剂也存在许多缺点，如在体内的作用时间短，生物利用度低，需要多次给药等，限制了甲状腺激素β受体激动剂的疗效的发挥。
因此，本领域仍需要开发具有更优药效性能的甲状腺激素β受体激动剂，从而提高疾病的治疗效果。
发明内容
本发明的目的在于提高一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐。所述的式(I)或(Ia)所示的化合物对甲状腺激素β受体具有优异的激动作用和药效学性能。
本发明第一方面，提供一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、 溶剂合物、或晶型，
Figure PCTCN2020123330-appb-000002
式中，
X选自H或-C(R 17R 18)OZ，Y选自H或-C(R 19R 20)OW，限定条件是X和Y不同时为氢；
Z和W各自独立地选自-C(O)OR 5、-C(O)NHR 5、-C(O)NR 5R 10、-C(O)R 5、-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X 3R 14R 15)、-P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝O)(X 1R 11)(X 2R 12)、-CH 2P(＝O)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-P(＝S)(X 1R 11)(X 2R 12)、-P(＝S)(X 1R 11)(X 3R 14R 15)、-P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝S)(X 1R 11)(X 2R 12)、-CH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-P(＝NR 13)(X 1R 11)(X 2R 12)、-P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-CH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝O)(X 1R 11)(X 2R 12)、-OP(＝O)(X 1R 11)(X 3R 14R 15)、-OP(＝O)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝O)(X 1R 11)(X 2R 12)、-OCH 2P(＝O)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝S)(X 1R 11)(X 2R 12)、-OP(＝S)(X 1R 11)(X 3R 14R 15)、-OP(＝S)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝S)(X 1R 11)(X 2R 12)、-OCH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝NR 13)(X 1R 11)(X 2R 12)、-OP(＝NR 13)(X 1R 11)(X 3R 14R 15)、-OP(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-OCH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)；
R 1、R 2、R 3各自独立地选自下组：氢、氘、未氘代的或一个或者多个(优选为1-4个)氘代或全氘代的C1-C4烷基、羟基，或者R 1、R 2、R 3其中两者与相邻的C结合形成取代或未取代的C3-C8环烷基，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C3-C8环烷基、羟基、氨基、羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺 基、或磺酰胺基；
R 4、R 6、R 7、R 8、R 9各自独立地选自下组：氢、氘、卤素；
R 5为取代或者未取代的C1-C20烷基、取代或者未取代的C3-C20环烷基、取代或者未取代的4-20元杂环烷基、取代或者未取代的C6-C20芳基、取代或者未取代的C6-C20芳基-C1-C8烷基-、或取代或者未取代的5-12元杂芳基、取代或者未取代的5-12元杂芳基-C1-C8烷基-、取代或者未取代的C1-C4烷基-(取代或者未取代的C1-C4烷基-O) m-取代或者未取代的C1-C4烷基-，其中，m为1-8的正整数，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、C3-C8环烷基、卤素、羟基、氨基、氨基、C2-C8羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺基、或磺酰胺基；
R 10选自取代或未取代的C1-C6的烷基、取代或未取代的C3-C8环烷基或取代或未取代的4-10元杂环烷基，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、C3-C8环烷基、卤素、羟基、氨基、氨基、C2-C8羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺基、或磺酰胺基；
X 1、X 2各自独立地选自下组：氧、或硫；
X 3为氮；
R 11、R 12、R 13、R 14、R 15各自独立地选自下组基团：氢、取代或未取代的C1-C20烷基、取代或未取代的C1-C20氘代烷基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基，或者R 11和R 12与相邻的X 1、X 2和P结合形成取代或未取代的5-7元杂环烷基，所述取代指被选自下组的一个或多个取代基取代：氘、C1-C20烷基、卤代C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、4-10元杂环烷基、C6-C10芳基、卤代C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COR 16、-COOR 16、-OCOOR 16、氰基、羟基、酰胺基、磺酰胺基；
R 16选自下组基团：氢、取代或未取代的C1-C18烷基、取代或未取代的C1-C20氘代烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代的C6-C10芳基、氨基、取代或未取代的4-10元杂环烷基，其中所述取代指被一个或多个C6-C10芳基取代；
R 17、R 18、R 19、R 20各自独立地选自下组基团：氢、氘、取代或未取代的C1-C3烷基，限定条件是当X连接在N上且Y为氢时，R 17、R 18不同时为氢。
在另一优选例中，所述的化合物为式Ib化合物：
Figure PCTCN2020123330-appb-000003
在另一优选例中，X选自H，而Y选自-C(R 19R 20)OW。
在另一优选例中，X选自-C(R 17R 18)OZ，Y选自H或-C(R 19R 20)OW。
在另一优选例中，在式(I)中，X选自-C(R 17R 18)OZ，Y选自H。
在另一优选例中，在式(I)中，X选自-C(R 17R 18)OZ，Y选自H。
在另一优选例中，在式(Ia)中，X选自-C(R 17R 18)OZ，Y选自H。
在另一优选例中，所述的杂环烷基和杂芳基的杂环上各自独立地具有1-3个(优选为1、2或3个)选自N、O和S的杂原子。
在另一优选例中，R 1、R 2、R 3、R 4中至少一个是氘代的或者氘。
在另一优选例中，R 1、R 2、R 3、R 4中至少两个是氘代的或者氘。
在另一优选例中，R 1、R 2、R 3、R 4中至少三个是氘代的或者氘。
在另一优选例中，R 1、R 2、R 3、R 4中四个均是氘代的或者氘。
在另一优选例中，R 1、R 2、R 3、R 4中四个均是全氘代的或者氘。
在另一优选例中，R 1、R 2、R 3、R 4中至少一个选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3、R 4中至少两个选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3、R 4中至少三个选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3、R 4独立地选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 3独立地选自下组：一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 2、R 4独立地选自下组：氢、氘。
在另一优选例中，R 1和R 3为CD 3。
在另一优选例中，R 2为氘。
在另一优选例中，R 4为氘。
在另一优选例中，R 7和R 9为氘。
在另一优选例中，R 1、R 2、R 3中至少一个选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3中至少两个选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3独立地选自下组：氘、一个或者多个氘代或全氘代的C1-C4烷基。
在另一优选例中，所述化合物中，氘在氘代位置的氘同位素含量大于天然氘同位素含量。
在另一优选例中，所述化合物中，氘在氘代位置的氘同位素含量比天然氘同位素含量(0.015％)大至少30％，较佳地50％，更佳地75％，更佳地95％，最佳地99％，如100％。
在另一优选例中，X和Y只有一个为氢。
在另一优选例中，X为氢，Y不为氢。
在另一优选例中，Y为氢，X不为氢。
在另一优选例中，X和Y均不为氢。
在另一优选例中，R 1、R 2、R 3各自独立地选自下组：氢、氘、未氘代的或一个或者多个(优选为1-4个)氘代或全氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3各自独立为氢或未氘代的C1-C4烷基。
在另一优选例中，R 1、R 2、R 3各自独立为氢或甲基。
在另一优选例中，R 4为氢或氘。
在另一优选例中，R 5为取代或者未取代的C1-C20烷基、取代或者未取代的C3-C10环烷基、取代或者未取代的4-10元杂环烷基、取代或者未取代的C6-C12芳基、取代或者未取代的C6-C12芳基-C1-C4烷基-、取代或者未取代的C6-C12杂芳基、取代或者未取代的C6-C12杂芳基-C1-C4烷基-、取代或者未取代的C1-C4烷基-(取代或者未取代的C1-C4烷基-O) m-取代或者未取代的C1-C4烷基-。
在另一优选例中，Z和W各自独立为-C(O)OR 5。
在另一优选例中，R 5为取代或者未取代的C1-C8烷基。
在另一优选例中，R 7为氢或氘。
在另一优选例中，R 9为氢或氘。
在另一优选例中，R 6为卤素。
在另一优选例中，R 8为卤素。
在另一优选例中，R 6、R 7、R 8、R 9各自独立地选自下组：氢、氘、卤素。
在另一优选例中，R 17、R 18、R 19、R 20各自独立地选自下组：氢、取代或未取代的C1-C3烷基，限定条件是当X连接在N上且Y为氢时，R 17、R 18不同时为氢。
在另一优选例中，R 17、R 18、R 19、R 20各自独立地选自下组：氢、甲基，限定条件是当X连接在N上且Y为氢时，R 17、R 18不同时为氢。
在另一优选例中，R 17为氢，R 18为氢、取代或未取代的C1-C3烷基。
在另一优选例中，当X连接在N上且Y为氢时，R 17、R 18不同时为氢。
在另一优选例中，R 19为氢，R 20为氢、取代或未取代的C1-C3烷基。
在另一优选例中，R 17为氢，R 18为氢或甲基。
在另一优选例中，R 19为氢，R 20为氢或甲基。
在另一优选例中，所述化合物为式(II-A)或式(II-B)所示化合物：
Figure PCTCN2020123330-appb-000004
Figure PCTCN2020123330-appb-000005
其中，X、Y、R 1、R 2、R 3、R 4、R 6、R 8如上所定义。
在另一优选例中，所述化合物为式(III-A)或式(III-B)所示化合物：
Figure PCTCN2020123330-appb-000006
其中，X、Y、R 1、R 2、R 3、R 4如上所定义。
在另一优选例中，所述化合物具有式(IV-A)、(IV-B)、(IV-C)和(IV-D)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
Figure PCTCN2020123330-appb-000007
Figure PCTCN2020123330-appb-000008
其中，R 1、R 2、R 3、R 4、R 17、R 18、R 19、R 20、Z和W如上所定义。
在另一优选例中，所述的化合物具有式(V-A)、(V-B)、(V-C)和(V-D)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
Figure PCTCN2020123330-appb-000009
Figure PCTCN2020123330-appb-000010
其中，R 4、R 17、R 18、R 19、R 20、Z和W如如上所定义。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2020123330-appb-000011
Figure PCTCN2020123330-appb-000012
Figure PCTCN2020123330-appb-000013
Figure PCTCN2020123330-appb-000014
Figure PCTCN2020123330-appb-000015
Figure PCTCN2020123330-appb-000016
Figure PCTCN2020123330-appb-000017
Figure PCTCN2020123330-appb-000018
Figure PCTCN2020123330-appb-000019
Figure PCTCN2020123330-appb-000020
Figure PCTCN2020123330-appb-000021
Figure PCTCN2020123330-appb-000022
Figure PCTCN2020123330-appb-000023
Figure PCTCN2020123330-appb-000024
Figure PCTCN2020123330-appb-000025
本发明第二方面，提供一种制备如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型的方法，所述的方法包括步骤：
Figure PCTCN2020123330-appb-000026
(1)式(VI)化合物在碱性条件下与XR或YR'反应生成式(VI-A)、式(VI-B)或式(Ib)的中间体；
(2)所述式(VI-A)或式(VI-B)或式(Ib)的中间体在碱性条件下和YR'或XR反应得到式(I)或式(Ia)所示的化合物；
其中，R、R'为离去基团。
在另一优选例中，所述碱性条件为选自下组的碱性试剂：NaH、碳酸铯、三乙胺、DIPEA，或其组合。
在另一优选例中，所述的离去基团为卤素，较佳地Cl、Br或I。
或者包括步骤：
Figure PCTCN2020123330-appb-000027
(1)式(VI)化合物用保护基保护(PG为保护基，如SEM或者THP)生成中间体(VI-C)，然后在碱性条件下与YR'反应生成式式(I)的化合物(X为氢)；
本发明第三方面，提供一种药物组合物，所述的组合物包含：
1)治疗有效量的如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型；和
2)药学上可接受的载体。
在另一优选例中，所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型的含量为0.01-99.99wt.％，较佳地0.1-99.9wt.％，更佳地1-99wt.％，更佳地5-95wt.％，更佳地10-90wt.％，更佳地20-80wt.％，最佳地30-70wt.％，以组合物的重量计。
在另一优选例中，所述药物组合物还包含其它活性成分。
在另一优选例中，所述其它活性成分为用于预防和/或治疗选自下组的疾病的活性成分：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病，或其组合。
在另一优选例中，所述的药物组合物还包含其它预防和/或治疗选自下组的疾病药物：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病，或其组合。
在另一优选例中，所述药物组合物还包含选自下组的药物：干扰素α(标准INFα和聚乙醇化的INFα)、核苷类药物(如Telbivudine、Lamivudine、Clevudine、Adefovir、Tenofovir、Besifovir、Tenofovir Disoproxil Fumarate(TDF)、Tenofovir Alafenamide Fumarate(TAF)及HDP-PMPA(CMX157)等)、壳蛋白变构调节剂(如BAY41-4109、RG-7907、NVR3-778、ABI-H0731、ABI-H2158、JNJ-56136379、GLS 4JHS等)、cccDNA抑制剂、TLR3/7/8/9激动剂(如RG-7854、GS9620等)、乙肝病毒进入抑制剂(如Myrcludex B等)、干扰核苷酸(如ARB 1467、ARB 1740等)、HBV表面抗原抑制剂(如RG7834、REP2139、REP2165 等)、CRISPER/Cas9、或其组合胆汁酸受体(FXR)激动剂(如Obeticholic acid、Tropifexor、GS-9674、ZG5266)、过氧化物酶体增殖物激活受体(PPAR)激动剂(如Elafibranor，Saroglitazar、Remogliflozin Etabonate)、甲状腺激素受体β(THRβ)激动剂(如MGL-3196)、二酰甘油-O-酰基转移酶(DGAT)抑制剂(如Pradigastat、PF-06865571)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976、PF-05221304)、半胱天冬酶抑制剂(如Emricasan)、平滑受体(SMO)抑制剂(如Vismodegib)、半乳糖凝结素抑制剂(如GR-MD-02)、C-C趋化因子受体2型和5型(CCR2和CCR5)的双重拮抗剂(如Cenicriviroc)、已酮糖激酶(KHK)抑制剂(PF-06835919)、胰高血糖素样肽-1(GLP-1)受体激动剂(如利拉鲁肽、semaglutide)、抗赖氨酰氧化酶样蛋白-2(LOXL2)单抗(如simtuzumab)、胆酸和花生四烯酸的复合物Aramchol，或其组合。
在另一优选例中，所述其它活性成分为用于预防和/或治疗选自下组的疾病的活性成分：非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化、肝硬化(如原发性胆汁性肝硬化)、胆结石、动脉粥样硬化、肥胖、糖尿病，或其组合。
在另一优选例中，所述药物组合物的剂型为口服制剂或肠道外给药制剂(如注射剂、输液剂)
在另一优选例中，所述药物组合物的剂型选自下组：注射剂、囊剂、片剂、丸剂、散剂、颗粒剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂。
在另一优选例中，所述药物组合物为控释型、缓释型制剂或纳米制剂。
本发明第四方面，提供一种如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，或如本发明第三方面所述的药物组合物的用途，其特征在于，用于(i)制备甲状腺激素受体激动剂药物制剂或药物；(ii)制备与甲状腺激素受体活性降低相关疾病的药物制剂或药物；和/或(ii)用于制备预防和/或治疗选自下组的疾病的药物制剂或药物：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症，或其组合。
在另一优选例中，与甲状腺激素受体活性降低相关疾病选自下组：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病，或其组合。
在另一优选例中，所述的甲状腺激素受体为甲状腺激素α受体和/或甲状腺激素β受体。
在另一优选例中，所述的甲状腺激素受体为甲状腺激素β受体。
在另一优选例中，所述疾病选自下组：非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化、肝硬化(如原发性胆汁性肝硬化)、胆结石、动脉粥样硬化、肥胖、高血脂、糖尿病。
在另一优选例中，所述的高血脂为高甘油三酯和/高胆固醇。
在另一优选例中，所述的肥胖是由高脂肪饮食引起的肥胖。
在另一优选例中，所述疾病选自下组：原发性硬化(PBC)、原发性硬化性胆囊炎(PSC)、 胆汁淤积症、自身免疫肝炎、病毒性肝炎(如乙肝)、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)、肝纤维化、动脉硬化症、血脂障碍、高胆固醇血症、高甘油三酯血症、I型糖尿病、II型糖尿病、肥胖。
在另一优选例中，所述癌症选自下组：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、血癌、骨癌、肾癌、胃癌、肝癌、大肠癌，或其组合。
本发明第五方面，提供一种甲状腺激素受体激动剂，所述的激动剂包含激动有效量的如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型。
本发明第六方面，提供一种体外非治疗性和非诊断性的增强或提高甲状腺激素受体活性的方法，其特征在于，所述的方法包括步骤：在体外培养体系中，将甲状腺激素受体或表达甲状腺激素受体的细胞与如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型进行接触，从而增强或提高甲状腺激素受体活性。
本发明第七方面，提供一种预防和/或治疗选自下组的疾病的方法：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症、糖尿病，将治疗有效量的如本发明第一方面所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型施用于所需患者。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为测试例1中MGL-3196(曲线编号为1)、WO2009037172A1Example 5的化合物(曲线编号为2)的血药浓度-时间曲线，其中血药浓度为MGL-3196的浓度。
图2为测试例2中MGL-3196(曲线编号为1)、化合物6A(曲线编号为2)的血药浓度-时间曲线，其中血药浓度为MGL-3196的浓度。
图3为测试例3中MGL-3196(曲线编号为1)、化合物6B(曲线编号为2)的血药浓度-时间曲线，其中血药浓度为MGL-3196的浓度。
图4为测试例4中MGL-3196(曲线编号为1)、化合物2A(曲线编号为3)和化合物2B(曲线编号为2)的血药浓度-时间曲线，其中血药浓度为MGL-3196的浓度。
具体实施方式
本发明人经过长期而深入的研究，意外开发了一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型。本发明的式(I)所示的哒嗪酮或哒嗪类化合物或其异构体式(Ia)化合物，对甲状腺激素β受体具有优异的有选择性激动作用和更好药效学性能。在此基础上，发明人完成了本发明。
术语
如本文所用，术语“包含”、“包括”、“含有”可互换使用，不仅包括封闭式定义，还包括半封闭、和开放式的定义。换言之，所述术语包括了“由……构成”、“基本上由……构成”。
应当理解，本领域的普通技术人员可以选择本发明的化合物上的取代基和取代型式以产生化学上稳定的化合物，所述化合物可以通过本领域己知的技术以及下文所阐述的方法合成。如果被超过一个取代基团取代，应当理解，这多个基团可以是在同一个碳上或在不同碳上，只要产生稳定的结构即可。
如本文所用，“R1”、“R 1”和“R 1”的含义相同，可相互替换，其它类似定义的含义相同。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。如本文所用，所述的取代是指基团一个或多个(优选为1、2、3或4个)氢和/或氘各自独立地被取代基取代。
如本文所用，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-C20烷基)指所述的烷基含有1-20个碳原子，例如，C1-C4烷基指含有1-4个碳原子的烷基，代表性实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-C20)时，指所述的环烷基具有3-20个碳原子。在一些优选实施例中，术语“C3-C8环烷基”指具有3-8个碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。如下是环烷基的代表性实例，包括但不限于：
Figure PCTCN2020123330-appb-000028
如本文所用，术语“环烯基”指环碳链上具有至少一个碳-碳双键的单元环，二环或多环(稠环、桥环或螺环)，但不能为芳香结构，当环烯基前具有碳原子数限定(如C3-C8)时，指所述的环烯基含有3-8个环碳原子。
如本文所用，术语“羰基”为＝O基团，且双键(＝)与碳连接形成有机官能团(C＝O)。
如本文所用，术语"氰基"表示-CN。
术语“杂环烷基”又称为“杂环基”，是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环，7-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。当杂环烷基前有元数限定时，指的是杂环烷基的环原子个数，例如4-20元杂环烷基指的是具有4-20个环原子的杂环烷基，每个含有杂原子的杂环上可以带有一个或多个(如1，2，3或4个)杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者非取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”是指芳香环状烃类化合物基团，例如具有1、2、3、4或5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。当芳基前有碳原子数限定时，指的是芳基的环碳原子个数，例如C6-C20芳基指的是具有6-20个环碳原子的芳基，“取代的芳基”是指芳基中的一个或多个(优选为1-3)位置被取代，可在任何位置上取代。 典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指具有一个到多个(优选为1、2、3或4个)杂原子的芳族杂环系，其可以是单环(单环的)或者稠合在一起或共价地连接的多环(二环的、三环的或多环的)，每个含有杂原子的杂环上可以带有一个多个(如1、2、3、4个)各自独立选自下组的杂环子：氧、硫和氮。当杂芳基前有元数限定时，指的是杂芳基的环原子个数，例如4-20元杂芳基指的是具有4-20个环原子的杂芳基。
杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，术语“卤代”是指被卤素取代。
术语“胺基”是指带有结构的-NRR'基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“醚基”是指带有结构的-OR基团，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环烷基或取代的杂环烷基，优选地，R可以代表氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烯基、取代或未取代的C6-C12芳基、取代或未取代的C5-C10杂芳基、取代或未取代的C4-C8杂环烷基，其中烷基、环烷基、环烯基、芳基、杂芳基和杂环烷基如上文所定义。
术语“硫醚基”是指带有结构的-SR基团，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳 基、杂环烷基或取代的杂环烷基，优选地，R可以代表氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烯基、取代或未取代的C6-C12芳基、取代或未取代的C5-C10杂芳基、取代或未取代的C4-C8杂环烷基，其中烷基、环烷基、环烯基、芳基、杂芳基和杂环烷基如上文所定义。
术语“酰基”是指带有结构的-COR基团，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。
术语“酯基”是指带有结构的-COOR基团，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。
术语“酰胺基”指具R-CO-NR-基团或-CO-NRR'基团，其中R为氢或烷基，当酰胺基前具有碳原子数限定(如C2-C8酰胺基)指所述的酰胺基含有2-8个碳原子，R和R'各自独立为氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环烷基或取代的杂环烷基，优选地，R可以代表氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烯基、取代或未取代的C6-C12芳基、取代或未取代的C5-C10杂芳基、取代或未取代的C4-C8杂环烷基，其中烷基、环烷基、环烯基、芳基、杂芳基和杂环烷基如上文所定义。
术语“磺酰胺基”是指带有结构的-SO 2NRR'基团，其中R和R'各自独立为氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂芳基或取代的杂芳基、杂环烷基或取代的杂环烷基，优选地，R可以代表氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烯基、取代或未取代的C6-C12芳基、取代或未取代的C5-C10杂芳基、取代或未取代的C4-C8杂环烷基，其中烷基、环烷基、环烯基、芳基、杂芳基和杂环烷基如上文所定义。
术语“烷氧基”指R-O-基团，其中R为烷基，烷基为如上本文所定义，当烷氧基前具有碳原子数限定，如C1-C6烷氧基基指所述的烷氧基中的烷基具有1-6个碳原子。烷氧基的代表性示例包括(但不限于)：甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基，或类似基团。
本发明中，术语“氘代”是指被氘(D)取代。
如本文所用，在单独或作为其他取代基一部分时，术语"氨基"表示-NH2。
如本文所用，在单独或作为其他取代基一部分时，术语"硝基"表示-NO2。
如本文所用，在单独或作为其他取代基一部分时，术语"氰基"表示-CN。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限 于)：氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e、P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
活性成分
如本文所用，“本发明化合物”、“本发明的哒嗪酮或哒嗪类化合物”、或“本发明式(I)或(Ia)化合物”或“本发明式(I)或(Ia)所示的化合物”、或“式(I)或(Ia)化合物”可互换使用，指具有式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
Figure PCTCN2020123330-appb-000029
其中，各基团的定义如上文本发明第一方面所述。应理解，该术语还包括上述组分的混合物。
在本发明中，“式I”与“式(I)”可互换使用，“式Ia”与“式(Ia)”可互换使用，同类类推，如“式Ib”与“式(Ib)”可互换使用。
在本发明中，所述式(I)或(Ia)化合物中的除H之外的其他元素(如N、C、O、F等)全部或基本上(>99wt％)为丰度最高的天然存在的元素，例如 14N、 12C、 16O和 19F。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
在另一优选例中，在本发明所述的式(I)或(Ia)化合物中，所述的基团(如X、Y、Z、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20等式(I)或(Ia)化合物上的基团)中任一个分别为表1中所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
在另一优选例中，所述化合物选自表1所列化合物。
表1
Figure PCTCN2020123330-appb-000030
Figure PCTCN2020123330-appb-000031
Figure PCTCN2020123330-appb-000032
Figure PCTCN2020123330-appb-000033
Figure PCTCN2020123330-appb-000034
Figure PCTCN2020123330-appb-000035
Figure PCTCN2020123330-appb-000036
Figure PCTCN2020123330-appb-000037
Figure PCTCN2020123330-appb-000038
Figure PCTCN2020123330-appb-000039
Figure PCTCN2020123330-appb-000040
Figure PCTCN2020123330-appb-000041
Figure PCTCN2020123330-appb-000042
Figure PCTCN2020123330-appb-000043
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的) 盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸式盐包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(如对甲苯磺酸盐)、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
本发明中的化合物、盐或溶剂化物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示意图中及(或)示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式， 是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本发明所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本发明所涉及的化合物，也包含在本发明范围中。
制备方法
下面更具体地描述本发明式(I)或(Ia)化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
示例性地，式(I)所示化合物是如下制备的：
Figure PCTCN2020123330-appb-000044
使式(VI)化合物在碱性条件下(如NaH、碳酸铯、三乙胺或DIPEA等)与XR或YR'(R、R'为离去基团，如Cl、Br或I)反应生成式(VI-A)或式(VI-B)的中间体；该中间体再在碱性条件下(如NaH、碳酸铯、三乙胺或DIPEA等)和YR'或XR(R'、R为离去基团，如Cl、Br或I)进一步反应得到目标化合物(I)。
或者按照以下步骤合成：
Figure PCTCN2020123330-appb-000045
式(VI)化合物用保护基保护(PG为保护基，如SEM或者THP)生成中间体(VI-C)，然后在碱性条件下与YR'反应生成式式(I)的中间体(X为氢)；
药物组合物和施用方法
本发明还提供了一种药物组合物，所述的组合物包含：
1)治疗有效量的本发明所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型；和
2)药学上可接受的载体。
在一个优选例中，所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型的含量为0.01-99.99wt.％，较佳地0.1-99.9wt.％，更佳地1-99wt.％，更佳地5-95wt.％，更佳地10-90wt.％，更佳地20-80wt.％，最佳地30-70wt.％，以组合物的重量计。
本发明提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、晶型或前药进行混合，从而形成药物组合物。
应理解，式(I)或(Ia)化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式(I)或(Ia)的化合物。当式(I)或(Ia)化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式(I)或(Ia)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)或(Ia)化合物与其它一种或几种已知药物。当式(I)或(Ia)化合物与其它一种或几种药物进行药物联用时，式(I)或(Ia)化合物或已知药物的剂量可能比它们单独用药的剂量低。
本发明所述的其它活性性成分包括但并不限于：胆汁酸受体(FXR)激动剂(如Obeticholic acid、Tropifexor、GS-9674、ZG5266)、过氧化物酶体增殖物激活受体(PPAR)激动剂(如Elafibranor，Saroglitazar、Remogliflozin Etabonate)、甲状腺激素受体β(THRβ)激动剂(如MGL-3196)、二酰甘油-O-酰基转移酶(DGAT)抑制剂(如Pradigastat、PF-06865571)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976、PF-05221304)、半胱天冬酶抑制剂(如Emricasan)、平滑受体(SMO)抑制剂(如Vismodegib)、半乳糖凝结素抑制剂(如GR-MD-02)、C-C趋化因子受体2型和5型(CCR2和CCR5)的双重拮抗剂(如Cenicriviroc)、 已酮糖激酶(KHK)抑制剂(PF-06835919)、胰高血糖素样肽-1(GLP-1)受体激动剂(如利拉鲁肽、semaglutide)、抗赖氨酰氧化酶样蛋白-2(LOXL2)单抗(如simtuzumab)、胆酸和花生四烯酸的复合物Aramchol等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.1-2000mg本发明化合物/剂，更佳地，含有1-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020123330-appb-000046
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味 剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述的式(I)或(Ia)化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明所涉及的炎症、心血管疾病、感染、免疫性疾病、代谢性疾病或癌症包括(但并不限于)：原发性硬化(PBC)、原发性硬化性胆囊炎(PSC)、胆汁淤积症、自身免疫肝炎、病毒性肝炎(如乙肝)、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)或肝纤维化；动脉硬化症、血脂障碍、高胆固醇血症或高甘油三酯血症；I型糖尿病、II型糖尿病或肥胖；肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、血癌、骨癌、肾癌、胃癌、肝癌或大肠癌。
用途
本发明还提供一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，或如本发明所述的药物组合物的用途，用于(i)制备甲状腺激素受体激动剂药物制剂或药物；(ii)制备与甲状腺激素受体活性降低相关疾病的药物制剂或药物；和/或(ii)用于制备预防和/或治疗包括(但不限于)下组的疾病的药物制剂或药物：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病，或其组合。
在本发明中，术语“预防”表示预防疾病和/或它的附随症状的发作或者保护对象免于获得疾病的方法。本文中使用的"预防"还包括延迟疾病和/或它的附随症状的发作和降低对象的得病的风险。
在本发明中，术语“治疗”是指哺乳动物中的疾病的任何治疗，包括(但不限于)：(a)抑制所述疾病，即，减慢或阻止临床症状的发展；和/或(b)缓解所述疾病，即，造成临床症状的消退，和/或(c)减轻或消除疾病和/或它的附随症状。
在一个优选例中，所述的甲状腺激素受体为甲状腺激素α受体和/或甲状腺激素β受体。优选地，所述的甲状腺激素受体为甲状腺激素β受体。
在发明中，与甲状腺激素受体活性降低相关疾病包括(但不限于)：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症，或其组合。
在另一优选例中，所述疾病包括(但不限于)：非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化、肝硬化(如原发性胆汁性肝硬化)、胆结石、动脉粥样硬化、肥胖、高血脂、糖尿病。
在另一优选例中，所述的高血脂为高甘油三酯和/高胆固醇。
在另一优选例中，所述的肥胖是由高脂肪饮食引起的肥胖。
在另一优选例中，所述疾病包括(但不限于)：原发性硬化(PBC)、原发性硬化性胆囊炎(PSC)、胆汁淤积症、自身免疫肝炎、病毒性肝炎(如乙肝)、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)、肝纤维化、动脉硬化症、血脂障碍、高胆固醇血症、高甘油三酯血症、I型糖尿病、II型糖尿病、肥胖。
在另一优选例中，所述癌症包括(但不限于)：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、血癌、骨癌、肾癌、胃癌、肝癌、大肠癌，或其组合。
典型地，本发明所述的式(I)或(Ia)化合物用于制备预防和/或者治疗肥胖的的药物。
本发明还提供一种体外非治疗性和非诊断性的增强或提高甲状腺激素受体活性的方法，所述的方法包括步骤：在体外培养体系中，将甲状腺激素受体或表达甲状腺激素受体的细胞与如本发明所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型进行接触，从而增强或提高甲状腺激素受体活性。
本发明还提供一种一种预防和/或治疗包括(但不限于)下组的疾病的方法：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症、糖尿病，所述的方法包括步骤：将治疗有效量的如本发明所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型施用于所需患者。
在本发明应该理解的是，术语“病症”包括疾病及其症状。
甲状腺激素受体激动剂
本发明还提供一种甲状腺激素受体激动剂，所述的激动剂包含激动有效量的本发明所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型。
本发明的主要优点包括：
(1)本发明所述式(I)或(Ia)所示化合物在体内(如大鼠体内)具有更优的代谢性质和药效性能；
(2)本发明所述式(I)或(Ia)所示化合物在体内(如大鼠体内)肝脏组织中具有更高的药物浓度，从而具有更好的药效性能。
(3)本发明所述式(I)或(Ia)所示化合物或其代谢产物对甲状腺激素β受体具有优异的有选择性激动作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Agilent 1200 Infinity Series质谱仪检测的。HPLC的测定使用Agilent 100高压色谱仪(Microsorb 5 micron C18 100x3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用烟台黄海硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度单位均为摄氏度。
实施例1
2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈的制备
Figure PCTCN2020123330-appb-000047
第一步：3,6-二氯-4-异丙基哒嗪的制备
在室温下，将异丁酸(1.4g,0.0151mol)加入到3,6-二氯哒嗪(2.25g,0.015mol)的乙腈(3.5mL)、环丁砜(10.7mL)和水(24.5mL)的混合溶液中，随后加入硝酸银(1.3g,0.mol)。反应混合物加热到55℃，一次性加入浓硫酸(2.4mL)的水(7.5mL)溶液，随后在35分钟内滴加过硫酸铵(5.2g,0.022mol)的水(7.5mL)溶液.反应混合物在70℃反应20分重随后冷却到室温，并在室温搅拌24小时。得到的反应混合物冷却到0℃并缓慢用氨水(10mL)调节pH到8。得到的混合物用水(50mL)稀释后过滤，滤饼用乙酸乙酯洗涤(50mL)。滤液收集有机相，水相用乙酸乙酯(2x50mL)萃取。合并的有机相依次用水(40mL)和饱和食盐水(40mL)洗涤,干燥后过滤。滤液真空浓缩得到粗产品，随后用硅胶柱层析得到目标化合物(1.9g,产率67％)。
LC-MS:m/z 191(M+H) +。
第二步：3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧)苯胺的制备
在氩气保护下于室温将4-氨基-2,6-二氯苯酚(0.5g,2.8mmol)、无水碳酸钾(1.6g,11.2mmol)和碘化亚铜(0.32g,1.7mmol)加入到3,6-二氯-4-异丙基哒嗪(0.54g,2.8mmol)的无水DMSO(2mL)的溶液中。反应混合物在90℃反应24小时，然后冷却到室温并倒入水中(100mL)。得到的混合物用稀盐酸(1N)调节pH到8，然后加入乙酸乙酯(50mL)。混合物用硅藻土过滤，滤饼用乙酸乙酯洗涤。有机相分离收集，水相用乙酸乙酯萃取。合并的有机相用饱和食盐水洗涤、干燥后过滤。滤液减压浓缩后通过硅胶柱层析得到目标产 物(0.5g,产率53％)。
LC-MS:m/z 338(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.629(s,1H),6.674(s,2H),5.649(brs,2H),3.114(m,1H),1.237(d,J＝6.8Hz,6H).
第三步：6-(4-氨基-2,6-二氯苯氧基)-4-异丙基哒嗪-3(2H)-酮的制备
3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧)苯胺(1.0g,3.0mmol)、冰醋酸(30mL)和醋酸钠(860mg,10.5mmol)的混合物在100℃反应24小时，然后冷却到室温，并在室温搅拌2天。得到的混合物用水稀释，然后用氢氧化钠水溶液(1N)调节pH到9。得到的悬浮物用乙酸乙酯萃取。水相分离后用浓盐酸调节pH到5，然后用乙酸乙酯萃取。有机相合并、干燥后过滤。滤液真空干燥浓缩。得到的残留物用甲醇(20mL)稀释，然后加入氢氧化钠水溶液(1N,20mL,20mmol)。得到的反应混合物在120℃反应24小时，然后冷却到室温并减压除去溶剂。残留物用水(100mL)稀释，然后用乙酸乙酯萃取。有机相合并，然后用稀盐酸水溶液(pH 5)和饱和食盐水洗涤后干燥、过滤。滤液真空减压浓缩，得到的残留物用制备色谱得到目标化合物(0.48g,产率50％)。
LC-MS:m/z 314(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ12.125(s,1H),7.270(s,1H),6.671(s,2H),5.624(brs,2H),3.013(m,1H),1.177(d,J＝6.8Hz,6H).
第四步：(2-氰基-2-(2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)腙)乙酰基)氨基甲酸乙酯的制备
6-(4-氨基-2,6-二氯苯氧基)-4-异丙基哒嗪-3(2H)-酮(134mg,0.42mmol)的水(5.6mL)悬浮液中加入浓盐酸(2.8mL)。反应物冷却到0℃然后加入亚硝酸钠(36.5mg,0.529mmol)的水(0.2mL)溶液。得到的混合物在0℃搅拌30分钟，然后快速过滤并迅速加入到预冷到0℃的N-氰基乙酰尿烷(72mg,0.46mmol)、水(9.4mL)和吡啶(2.8mL)的混合溶液中。得到的悬浮液在0℃搅拌30分钟然后过滤。固体依次用水和石油醚洗涤后在80℃真空干燥过夜得到目标产物(114mg,产率56％)。
LC-MS:m/z 481(M+H) +。1H NMR(400MHz,DMSO-d 6)δ12.25(s,1H),12.22(s,1H),10.89(s,1H),7.99(s,2H),7.36(s,1H),4.21(q,J＝7.1Hz,2H),3.06(m,1H),1.27(t,J＝7.1Hz,3H),1.20(m,6H).
第五步：2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈的制备
在室温下将醋酸钠(0.3g,3.6mmol)加入到(2-氰基-2-(2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)腙)乙酰基)氨基甲酸乙酯(0.35g,0.72mmol)的冰醋酸(7.2mL)溶液中。反应物在120℃反应1.5小时后冷却到0℃,用水(20mL)稀释后搅拌30分钟。过滤后，用水和石油醚依次洗涤，然后空气干燥30分钟后,再用乙腈和水打浆得到目标产物(0.16g,产率50％)。
LC-MS:m/z 435(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ13.200(brs,1H),12.257(s,1H),7.795(s,2H),7.458(s,1H),3.059(m,1H),1.177(d,J＝6.9Hz,6H).
实施例2
1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)乙基异丙基碳酸酯和1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)乙基异丙基碳酸酯的制备
Figure PCTCN2020123330-appb-000048
第一步：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)乙基异丙基碳酸酯及1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)乙基异丙基碳酸酯的制备
在圆底烧瓶中依次加入化合物2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-氰(500mg，1.15mmol)、碳酸铯(747mg，2.30mmol)、异丙基碳酸-1-氯乙酯(287mg，1.72mmol)和N,N-二甲基甲酰胺(20mL)。反应液在室温反应20小时。粗品经制备液相纯化得到两个化合物：化合物2A(34mg)和化合物2B(77mg)。
化合物2A：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000049
LC-MS:m/z 587(M+Na) +。 1H NMR(400MHz，DMSO-d 6)δ7.82(s,2H),7.53(s,1H),6.89(q,J＝6.0Hz,1H),4.67-4.73(m,1H),3.06-3.13(m,1H),1.29(d,J＝6.0Hz,3H),1.21(d,J＝7.2Hz,6H),1.18(d,J＝6.4Hz,6H)。
化合物2B：1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000050
LC-MS:m/z 565(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.80(s,2H),7.66(s,1H),6.96(q,J＝5.2Hz,1H),4.73-4.79(m,1H),3.01-3.08(m,1H),1.61(d,J＝5.2Hz,3H),1.24(dd,J＝6.8Hz,12.4Hz,6H),1.18(dd,J＝6.4Hz,9.6Hz,6H)。
实施例3
1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-1,1,1,3,3,3-d6)哒嗪-1(6H)-基)乙基异丙基碳酸酯和1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-1,1,1,3,3,3-d6)哒嗪-3-基)氧)乙基异丙基碳酸酯的制备
按照实施例1和实施例2的制备方法，用2-(三氘代甲基)-3,3,3-三氘代丙酸代替异丁酸作为起始原料，合成了化合物3A和3B。
化合物3A：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-1,1,1,3,3,3-d6)哒嗪-1(6H)-基)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000051
LC-MS:m/z 571(M+H) +。
化合物3B：1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-1,1,1,3,3,3-d6)哒嗪-3-基)氧)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000052
LC-MS:m/z 571(M+H) +。
实施例4
1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-d7)哒嗪-1(6H)-基)乙基异丙基碳酸酯和1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-d7)哒嗪-3-基)氧)乙基异丙基碳酸酯的制备
按照实施例1和实施例2的制备方法，用2-(甲基-d3)丙基-2,3,3,3-d4酸代替异丁酸作为起始原料，合成了化合物4A和4B。
化合物4A：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-d7)哒嗪-1(6H)-基)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000053
LC-MS:m/z 572(M+H) +。
化合物4B：1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-d7)哒嗪-3-基)氧)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000054
LC-MS:m/z 572(M+H) +。
实施例5
1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-d7)哒嗪-1(6H)-基-4-d)乙基异丙基碳酸酯及1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-d7)哒嗪-3-基-5-d)氧)乙基异丙基碳酸酯的制备
按照实施例1和实施例2的制备方法，用2-(甲基-d3)丙基-2,3,3,3-d4酸代替异丁酸，用3,6-二氯哒嗪-4,5-d2代替3,6-二氯哒嗪作为起始原料，合成了化合物5A和5B。
化合物5A：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-6-氧-5-(丙烷-2-基-d7)哒嗪-1(6H)-基-4-d)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000055
LC-MS:m/z 573(M+H) +。
化合物5B：1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-(丙烷-2-基-d7)哒嗪-3-基-5-d)氧)乙基异丙基碳酸酯
Figure PCTCN2020123330-appb-000056
LC-MS:m/z 573(M+H) +。
实施例6
化合物6：(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)甲基异丙基碳酸酯和(6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基异丙基碳酸酯的制备
按照实施例2的制备方法，用氯甲基异丙基碳酸酯代替异丙基碳酸-1-氯乙酯作为起始原料，合成了化合物6。
化合物6A：(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)甲基异丙基碳酸酯
Figure PCTCN2020123330-appb-000057
LC-MS:m/z 551(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.79(s,2H),7.54(s,1H),5.72(s,2H),4.69-4.75(m,1H),3.05-3.12(m,1H),1.19-1.22(m,12H)。
化合物6B：((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)甲基异丙基碳酸酯
Figure PCTCN2020123330-appb-000058
LC-MS:m/z 551(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.80(s,2H),7.68(s,1H),6.08(s,2H),4.77-4.86(m,1H),3.01-3.11(m,1H),1.21-1.25(m,12H)。
实施例7 1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)乙基乙基碳酸酯和1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)乙基乙基碳酸酯的制备
按照实施例2的制备方法，用乙基碳酸-1-氯乙酯代替异丙基碳酸-1-氯乙酯作为起始原料，合成了化合物7。
化合物7A：1-(3-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-5-异丙基-6-氧哒嗪-1(6H)-基)乙基乙基碳酸酯
Figure PCTCN2020123330-appb-000059
LC-MS:m/z 551(M+H) +。
化合物7B：1-((6-(2,6-二氯-4-(6-氰基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧)-4-异丙基哒嗪-3-基)氧)乙基乙基碳酸酯
Figure PCTCN2020123330-appb-000060
LC-MS:m/z 551(M+H) +。
实施例8
异丁酸-(6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲酯的制备
Figure PCTCN2020123330-appb-000061
第一步：2-(3,5-二氯-4-((5-异丙基-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈的制备
在Schlenk管中依次加入化合物2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1,6-二氢哒嗪-3-基氧 基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-氰(500mg，1.15mmol)、对甲苯磺酸吡啶盐(29mg，0.16mmol)、3,4-二氢吡喃(386mg，4.6mmol)和1,4-二氧六环(5mL)。加完后反应液加热至65℃，并在此温度下反应16小时。得到的混合物减压浓缩，残余物经由液相制备纯化得到目标化合物(350mg，收率59％)。
LC-MS:m/z 519(M+H) +。
第二步：(6-氰-2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3-二氢-1,2,4-三嗪-4(5H)-基)甲基异丁酸酯的制备
在圆底烧瓶中加入化合物2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(214mg，0.41mmol)和N,N-二甲基甲酰胺(10mL)，随后加入氢化钠(41mg，1.03mmol)。得到的混合物搅拌10min后滴加异丁酸氯甲酯(113mg，0.82mmol)。加完后反应液升至55℃，并在此温度下反应17小时。得到的混合物加水淬灭，然后经制备纯化得到目标化合物(110mg，收率43％)。
LC-MS:m/z 663(M+HCOO -) -。
第三步：异丁酸-(6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲酯的制备
在圆底烧瓶中加入化合物(6-氰-2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3-二氢-1,2,4-三嗪-4(5H)-基)甲基异丁酸酯(110mg，0.18mmol)和二氯甲烷(10mL)，随后滴加三氟乙酸(1mL)。加完后反应液在室温反应6小时，然后淬灭后减压浓缩。得到的粗品经制备液相纯化得到目标化合物(31mg，收率33％)。
LC-MS:m/z 535(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.22(s,1H),7.80(s,2H),7.45(s,1H),5.85(s,2H),3.11-3.00(m,1H),2.62-2.54(m,1H),1.20(d,J＝7.2Hz,6H),1.10(d,J＝6.8Hz,6H)。
按实施例8以不同原料按同样方法合成实施例9-10的化合物：
实施例9 特戊酸-(6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲酯的制备
Figure PCTCN2020123330-appb-000062
LC-MS:m/z 549(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.24(s,1H),7.80(s,2H), 7.45(s,1H),5.83(s,2H),3.09-3.02(m,1H),2.62-2.54(m,1H),1.24-1.16(m,15H)。
实施例10 L-丙氨酸-(6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲酯三氟乙酸盐的制备
Figure PCTCN2020123330-appb-000063
LC-MS:m/z 536(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.19(s,1H),8.38(s,3H),7.75(s,2H),7.36(s,1H),5.91(dd,J＝10.4Hz,19.2Hz,2H),4.07-4.08(m,1H),2.94-3.01(m,1H),1.32(d,J＝7.2Hz,3H),1.12(d,J＝6.8Hz,6H)。
实施例11((6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1-(四氢-2H-吡喃-2-yl)-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)二氢磷酸酯的制备
Figure PCTCN2020123330-appb-000064
第一步：二叔丁基((6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1-(四氢-2H-吡喃-2-yl)-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)磷酸酯的制备
在圆底烧瓶中加入化合物2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-氰(300mg，0.58mmol)和N,N-二甲基甲酰胺(10mL)，随后加入氢化钠(58mg，1.44mmol)。反应液在室温搅拌10min后滴加二叔丁基氯甲基磷酸酯(299mg，1.16mmol)。滴加完毕反应液升至65℃反应46小时。得到的混合物加水淬灭，然后经制备纯化得到目标化合物(15mg，收率4％)。
LC-MS:m/z 785(M+HCOO -) -。
第二步：((6-氰基-2-(3,5-二氯-4-((5-异丙基-6-氧-1-(四氢-2H-吡喃-2-yl)-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)二氢磷酸酯的制备
在圆底烧瓶中加入化合物二叔丁基(6-氰-2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1-(四氢-2H-吡喃-2-基)-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3-二氢-1,2,4-三嗪-4(5H)-基)甲基磷酸酯(15mg，0.02mmol)和二氯甲烷(3mL)，随后滴加三氟乙酸(0.2mL)，加完后室温反应5小时。得到的混合物经制备纯化得到目标化合物(6mg，收率54％)。
LC-MS:m/z 545(M+H) +。 1H NMR(400MHz，DMSO-d 6):δ12.25(s,1H),7.81(s,2H),7.45(s,1H),5.51(d,J＝7.2Hz,2H),3.05(m,1H),1.20(d,J＝6.8Hz,6H)。 31PNMR(162MHz，DMSO-d 6):δ-3.2(s)。
实施例12(6-氰基-2-(3,5-二氯-4-((1-((异丁酰氧基)甲基)-5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧)苯基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基异丁酸酯的制备
Figure PCTCN2020123330-appb-000065
在Schlenk管中加入化合物2-(3,5-二氯-4-(5-(丙基-2-基)-6-氧-1,6-二氢哒嗪-3-基氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-氰(50mg，0.12mmol)和N,N-二甲基甲酰胺(3mL)，搅拌溶解，随后加入氢化钠(14mg，0.35mmol)。得到的混合物在室温搅拌10分钟后滴加异丁酸氯甲酯(63mg，0.46mmol)，加完后反应物在60℃反应23小时。得到的混合物经制备液相纯化得到目标化合物(15mg，收率21％)。
LC-MS:m/z 657(M+Na) +。 1H NMR(400MHz，CDCl 3):δ7.65(s,2H),7.09(s,1H),6.02(s,2H),5.79(s,2H),3.29-3.20(m,1H),2.64-2.57(m,1H),2.55-2.48(m,1H),1.28(d,J＝6.8Hz,6H),1.20(d,J＝6.8Hz,6H),1.11(d,J＝6.8Hz,6H)。
测试例1
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，平均分成2组，每组4只大鼠，第一组灌胃给予10mg/kg实施例1制备的MGL-3196化合物溶液，第二组灌胃给予10mg/kg WO2009037172A1 Example 5的化合物溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，其中MGL-3196化合物溶液、WO2009037172A1 Example 5的化合物溶液的载体为DMSO/PEG400。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12 和24h采血，用LC/MS/MS测定血浆中活性成分MGL-3196的浓度。
化合物MGL-3196的结构如下：
Figure PCTCN2020123330-appb-000066
专利WO2009037172A1 Example 5的化合物结构如下：
Figure PCTCN2020123330-appb-000067
药代动力学测试结果
实施例1制备的MGL-3196、WO2009037172A1 Example 5的化合物的血药浓度-时间曲线如图1所示，药代动力学参数如表2所示：
表2 药代动力学参数总结(n＝4，均值)
Figure PCTCN2020123330-appb-000068
备注：血药浓度为MGL-3196的浓度。
测试例2
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，平均分成2组，每组4只大鼠，第一组灌胃给予10mg/kg实施例1制备的MGL-3196化合物溶液，第二组灌胃给予10mg/kg实施例6制备的化合物6A溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，其中MGL-3196化合物溶液、实施例6制备的化合物6A溶液的载体为 DMSO/PEG400。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中活性成分MGL-3196的浓度。
药代动力学测试结果
实施例1制备的MGL-3196、实施例6制备的化合物6A的血药浓度-时间曲线如图2所示，药代动力学参数如表3所示：
表3 药代动力学参数总结(n＝4，均值)
Figure PCTCN2020123330-appb-000069
测试例3
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，平均分成3组，每组4只大鼠，第一组灌胃给予10mg/kg实施例1制备的MGL-3196化合物溶液，第二组灌胃给予10mg/kg实施例6制备的化合物6B溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，其中MGL-3196化合物溶液、实施例6制备的化合物6B溶液的载体为DMSO/PEG400。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中活性成分MGL-3196的浓度。
药代动力学测试结果
实施例1制备的MGL-3196、实施例6制备的化合物6B的血药浓度-时间曲线如图3所示，药代动力学参数如表4所示：
表4 药代动力学参数总结(n＝4，均值)
Figure PCTCN2020123330-appb-000070
Figure PCTCN2020123330-appb-000071
测试例4
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，平均分成3组，每组4只大鼠，第一组灌胃给予10mg/kg实施例1制备的MGL-3196化合物溶液，第二组灌胃给予10mg/kg实施例2制备的化合物2A溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，第三组灌胃给予10mg/kg实施例2制备的化合物2B溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，其中MGL-3196化合物溶液、化合物2A溶液和化合物2B溶液的载体为DMSO/PEG400。每组分别在给药后0.5，1.0，2.0，4.0，6.0，8.0，12和24h采血，用LC/MS/MS测定血浆中活性成分MGL-3196的浓度。
药代动力学测试结果
实施例1制备的MGL-3196、实施例2制备的化合物2A和化合物2B的血药浓度-时间曲线如图4所示，药代动力学参数如表5所示：
表5 药代动力学参数总结：(n＝4，均值)
Figure PCTCN2020123330-appb-000072
综上，从表2-5和图1-4中可以看出，相对于对照化合物实施例1制备的MGL-3196和WO2009037172A1 Example 5的化合物，本发明化合物2A、化合物2B和化合物6B化合物在大鼠体内体现出更好的代谢性质，半衰期更长，最大血药浓度(Cmax)和血浆暴露量AUC更高(化合物2A是MGL-3196化合物的2.4倍，化合物2B是MGL-3196化合物的1.87倍，化合物6B是MGL-3196化合物的2.0倍)。结果表明，化合物2A、化合物2B和化合物6B化合物具有优异的生物利用度和药效。
测试例5
药代动力学测试评价
ICR小鼠，体重20-30g，禁食过夜后，平均分成4组，每组8只小鼠，第一组灌胃给予10mg/kg实施例1制备的MGL-3196化合物溶液，第二组灌胃给予10mg/kg实施 例2制备的化合物2A溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，第三组灌胃给予10mg/kg实施例2制备的化合物2B溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，第四组灌胃给予10mg/kg实施例6制备的化合物6B溶液(给药量是按照实施例1制备的MGL-3196化合物的相对含量计算)，其中MGL-3196化合物溶液、化合物2A溶液、化合物2B和化合物6B溶液的载体为DMSO/PEG400。每组分别在给药后收集1hr、6hr点小鼠肝脏，用LC/MS/MS测定肝脏中活性成分MGL-3196的浓度。
表6 肝组织药物浓度总结(n＝4，均值)
Figure PCTCN2020123330-appb-000073
从表6中可以看出，相对于对照化合物实施例1制备的MGL-3196，本发明化合物2A、化合物2B和化合物6B在小鼠肝脏内在1hr和6hr具有更高的药物浓度。
测试例6
经饮食诱导的肥胖(DIO)C57Bl/6J小鼠模型研究
6周龄C57Bl/6J小鼠给予高脂肪饮食34周。从第0天(35周第1天)开始，分别口服灌胃给予小鼠溶媒(2％Klucel LF，0.1％吐温80水溶液)；给予1、3或10mg/kg实施例2制备的化合物2A、化合物2B或实施例1制备的化合物MGL-3196，每组9只小鼠，连续给药23天。在平行研究中，从第0天(35周第1天)开始，分别口服灌胃给予小鼠溶媒(Dulbecco磷酸盐缓冲盐水，用1N NaOH调节pH至9.0)或10、30或100μg/kg三碘甲腺原氨酸(T3)，每组9只小鼠，连续给药23天。在研究期间监测体重和食物摄入。在第22天进行BMD和身体成份分析。第23天尸检时，进行器官称重，并评估血液样品的胆固醇和其他血液生化参数。
本发明实施例2制备的化合物2A和化合物2B以及实施例6制备的化合物6B具有很好的降胆固醇和肝脏脂肪药效作用。
在本发明提及的所有文献都在本发明中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本发明所附权利要求书所限定的范围。

Claims (13)

  1. 一种式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
    Figure PCTCN2020123330-appb-100001
    式中，
    X选自H或-C(R 17R 18)OZ，
    Y选自H或-C(R 19R 20)OW，限定条件是X和Y不同时为氢；
    Z和W各自独立地选自-C(O)OR 5、-C(O)NHR 5、-C(O)NR 5R 10、-C(O)R 5、-P(＝O)(X 1R 11)(X 2R 12)、-P(＝O)(X 1R 11)(X 3R 14R 15)、-P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝O)(X 1R 11)(X 2R 12)、-CH 2P(＝O)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-P(＝S)(X 1R 11)(X 2R 12)、-P(＝S)(X 1R 11)(X 3R 14R 15)、-P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝S)(X 1R 11)(X 2R 12)、-CH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-P(＝NR 13)(X 1R 11)(X 2R 12)、-P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-CH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-CH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝O)(X 1R 11)(X 2R 12)、-OP(＝O)(X 1R 11)(X 3R 14R 15)、-OP(＝O)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝O)(X 1R 11)(X 2R 12)、-OCH 2P(＝O)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝O)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝S)(X 1R 11)(X 2R 12)、-OP(＝S)(X 1R 11)(X 3R 14R 15)、-OP(＝S)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝S)(X 1R 11)(X 2R 12)、-OCH 2P(＝S)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝S)(X 3R 14R 15)(X 3R 14R 15)、-OP(＝NR 13)(X 1R 11)(X 2R 12)、-OP(＝NR 13)(X 1R 11)(X 3R 14R 15)、-OP(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)、-OCH 2P(＝NR 13)(X 1R 11)(X 2R 12)、-OCH 2P(＝NR 13)(X 1R 11)(X 3R 14R 15)、-OCH 2P(＝NR 13)(X 3R 14R 15)(X 3R 14R 15)；
    R 1、R 2、R 3各自独立地选自下组：氢、氘、未氘代的或一个或者多个(优选为1-4个) 氘代或全氘代的C1-C4烷基、羟基，或者R 1、R 2、R 3其中两者与相邻的C结合形成取代或未取代的C3-C8环烷基，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C3-C8环烷基、羟基、氨基、羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺基、或磺酰胺基；
    R 4、R 6、R 7、R 8、R 9各自独立地选自下组：氢、氘、卤素；
    R 5为取代或者未取代的C1-C20烷基、取代或者未取代的C3-C20环烷基、取代或者未取代的4-20元杂环烷基、取代或者未取代的C6-C20芳基、取代或者未取代的C6-C20芳基-C1-C8烷基-、或取代或者未取代的5-12元杂芳基、取代或者未取代的5-12元杂芳基-C1-C8烷基-、取代或者未取代的C1-C4烷基-(取代或者未取代的C1-C4烷基-O) m-取代或者未取代的C1-C4烷基-，其中，m为1-8的正整数，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、C3-C8环烷基、卤素、羟基、氨基、氨基、C2-C8羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺基、或磺酰胺基；
    R 10选自取代或未取代的C1-C6的烷基、取代或未取代的C3-C8环烷基或取代或未取代的4-10元杂环烷基，所述取代指被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、C3-C8环烷基、卤素、羟基、氨基、氨基、C2-C8羰基、C2-C8酯基、氰基、醚基、硫醚基、C2-C8酰胺基、或磺酰胺基；
    X 1、X 2各自独立地选自下组：氧、或硫；
    X 3为氮；
    R 11、R 12、R 13、R 14、R 15各自独立地选自下组基团：氢、取代或未取代的C1-C20烷基、取代或未取代的C1-C20氘代烷基、取代或未取代的C3-C10环烷基、取代或未取代的C4-C10杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基，或者R 11和R 12与相邻的X 1、X 2和P结合形成取代或未取代的5-7元杂环烷基，所述取代指被选自下组的一个或多个取代基取代：氘、C1-C20烷基、卤代C1-C20烷基、C1-C6烷氧基、C3-C10环烷基、4-10元杂环烷基、C6-C10芳基、卤代C6-C10芳基、C5-C10杂芳基、卤素、氨基、硝基、-COR 16、-COOR 16、-OCOOR 16、氰基、羟基、酰胺基、磺酰胺基；
    R 16选自下组基团：氢、取代或未取代的C1-C18烷基、取代或未取代的C1-C20氘代烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代的C6-C10芳基、氨基、取代或未取代的4-10元杂环烷基，其中所述取代指被一个或多个C6-C10芳基取代；
    R 17、R 18、R 19、R 20各自独立地选自下组基团：氢、氘、取代或未取代的C1-C3烷基，限定条件是当X连接在N上且Y为氢时，R 17、R 18不同时为氢。
  2. 如权利要求1所述的化合物，所述化合物具有式(IV-A)、(IV-B)、(IV-C)和(IV-D)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
    Figure PCTCN2020123330-appb-100002
    其中，R 1、R 2、R 3、R 4、R 17、R 18、R 19、R 20、Z和W如权利要求1所述。
  3. 如权利要求1所述的化合物，所述的化合物具有式(V-A)、(V-B)、(V-C)和(V-D)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，
    Figure PCTCN2020123330-appb-100003
    其中，R 4、R 17、R 18、R 19、R 20、Z和W如权利要求1所述。
  4. 如权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，其特征在于，所述化合物选自下组：
    Figure PCTCN2020123330-appb-100004
    Figure PCTCN2020123330-appb-100005
    Figure PCTCN2020123330-appb-100006
    Figure PCTCN2020123330-appb-100007
    Figure PCTCN2020123330-appb-100008
    Figure PCTCN2020123330-appb-100009
    Figure PCTCN2020123330-appb-100010
    Figure PCTCN2020123330-appb-100011
    Figure PCTCN2020123330-appb-100012
    Figure PCTCN2020123330-appb-100013
    Figure PCTCN2020123330-appb-100014
    Figure PCTCN2020123330-appb-100015
    Figure PCTCN2020123330-appb-100016
    Figure PCTCN2020123330-appb-100017
  5. 一种制备如权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型的方法，其特征在于，所述的方法包括步骤：
    Figure PCTCN2020123330-appb-100018
    (1)式(VI)化合物在碱性条件下与XR或YR'反应生成式(VI-A)、式(VI-B)或式(Ib)；
    (2)所述式(VI-A)或式(VI-B)或式(Ib)在碱性条件下和YR'或XR反应得到式(I)或式(Ia)所示的化合物；
    其中，R、R'为离去基团。
  6. 一种药物组合物，其特征在于，所述的组合物包含：
    1)治疗有效量的权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型；和2)药学上可接受的载体。
  7. 一种权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型，或如权利要求6所述的药物组合物的用途，其特征在于，用于(i)制备甲状腺激素受体激动剂药物制剂或药物；(ii)制备与甲状腺激素受体活性降低相关疾病的药物制剂或药物；和/或(ii)用于制备预防和/或治疗选自下组的疾病的药物制剂或药物：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症，或其组合。
  8. 一种权利要求6所述的药物组合物，其特征在于，所述的药物组合物还包含其它预防和/或治疗选自下组的疾病药物：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病，或其组合。
  9. 如权利要求7所述的用途，其特征在于，所述的甲状腺激素受体为甲状腺激素α受体和/或甲状腺激素β受体。
  10. 如权利要求7所述的用途，其特征在于，所述疾病选自下组：非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化、肝硬化(如原发性胆汁性肝硬化)、胆结石、动脉粥样硬化、肥胖、高血脂、糖尿病。
  11. 一种甲状腺激素受体激动剂，其特征在于，所述的激动剂包含激动有效量的如权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型。
  12. 一种体外非治疗性和非诊断性的增强或提高甲状腺激素受体活性的方法，其特征在于，所述的方法包括步骤：在体外培养体系中，将甲状腺激素受体或表达甲状腺激素受体的细胞与如权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型进行接触，从而增强或提高甲状腺激素受体活性。
  13. 一种预防和/或治疗选自下组的疾病的方法：炎症、癌症、心血管病症、感染、免疫性病症、代谢性病症、糖尿病，其特征在于，将治疗有效量的如权利要求1所述的式(I)或(Ia)所示的哒嗪酮或哒嗪类化合物或其立体异构体、互变异构体、对映异构体、非对映异构体、共振体、其药学上可接受的盐、水合物、溶剂合物、或晶型施用于所需患者。
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