WO2020228577A1 - 一种哒嗪酮衍生物及其应用 - Google Patents

一种哒嗪酮衍生物及其应用 Download PDF

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WO2020228577A1
WO2020228577A1 PCT/CN2020/088905 CN2020088905W WO2020228577A1 WO 2020228577 A1 WO2020228577 A1 WO 2020228577A1 CN 2020088905 W CN2020088905 W CN 2020088905W WO 2020228577 A1 WO2020228577 A1 WO 2020228577A1
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formula
oxy
ring
dichloro
phenyl
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French (fr)
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王伟
邓舟
周游
李志斌
鲁先平
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深圳微芯生物科技股份有限公司
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Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a pyridazinone derivative, and a preparation method and application thereof.
  • Thyroid hormone plays a key role in normal growth and development and maintaining metabolic balance (Paul M Yen, Physiological Reviews), Volume 81(3): 1097-1126 (2001)). TH can promote lipid hydrolysis and increase the availability of fatty acids, thereby providing energy for the body, and finally leading to the reduction of lipids and weight loss. Studies have shown that the TH level of obese patients changes greatly compared with normal people. TH has two main forms: 3,5,3',5'-tetraiodo-L-thyronine (T4) and 3,5,3',-tetraiodo-L-thyronine (T3) . Although T4 is the main form of thyroid secretion, T3 is the more physiologically active form.
  • T4 is converted to T3 by tissue-specific deiodinase, which is present in all tissues, but mainly in the liver and kidney.
  • tissue-specific deiodinase which is present in all tissues, but mainly in the liver and kidney.
  • Relevant studies have shown that T3 or T3 analogs can effectively treat obesity, especially after the intervention with low-calorie foods, the weight loss effect is more obvious. Therefore, controlling the TH level can effectively adjust the energy balance.
  • hypothyroidism hypothyroidism
  • LDL-C low-density lipoprotein-cholesterol
  • TRs nuclear receptors-thyroid hormone receptors
  • TRs form heterodimers with retinoid receptors that act as ligand-induced transcription factors.
  • TRs have a ligand binding domain, a DNA binding domain and an amino terminal domain, and regulate gene expression by interacting with the corresponding elements of NDA and with various nuclear co-activators and co-repressors.
  • TRs are respectively encoded by different genes ⁇ and ⁇ located on human chromosomes 17 and 3. Different protein subtypes are produced by selective splicing of primary transcripts.
  • TR ⁇ 1, TR ⁇ 1 and TR ⁇ 2 can bind to T3, but TR ⁇ 2 does not bind to TH.
  • TR ⁇ 1 exists in most tissues, especially the liver.
  • TR ⁇ 1 is also widely distributed, and TH has similar activity when combined with TR ⁇ 1 and TR ⁇ 1, but its distribution range is smaller than TR ⁇ 1.
  • TH mainly regulates gene expression on target organs (liver) through receptors to maintain metabolic balance, including maintaining lipid balance in liver and adipose tissue. Therefore, while avoiding the above-mentioned harmful events, the beneficial aspects of TH and its analogues such as lower cholesterol or increased basal metabolism, as well as the special accumulation in the liver, have clinical significance, which will open a new way to treat patients with the following diseases: metabolic diseases Such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other diseases such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, etc.
  • metabolic diseases Such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other diseases such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, etc.
  • thyroid hormone beta receptor agonists for the treatment and/prevention of diseases regulated by thyroid hormone.
  • the technical problem to be solved by the present invention is to provide a pyridazinone derivative and its preparation method and application.
  • the pyridazinone derivative provided by the present invention has good thyroid hormone beta receptor agonistic activity and can become Drugs used to treat or prevent diseases related to this effect.
  • the present invention provides a pyridazinone derivative with the structure represented by formula (I).
  • the experimental results show that the pyridazinone derivative provided by the present invention serves as a thyroid Hormone beta receptor agonists have good activity and can be used to treat and/prevent diseases caused by thyroid hormone regulation.
  • the present invention provides a pyridazinone derivative having a structure represented by formula (I):
  • X is -CH 2 -or -O-;
  • R 1 and R 2 are independently selected from Cl, Br, or C1-C6 alkyl groups
  • R 3 and R 4 are independently selected from hydrogen, halogen, C1-C6 alkyl, -OR 5 , -NR 5 R 6 , -CONR 5 R 6 , C6-C10 aryl or C5-C10 heteroaryl , And R 3 and R 4 are not hydrogen at the same time; wherein, R 5 and R 6 are each independently selected from hydrogen, C1-C15 alkyl, C6-C10 aryl or C5-C10 heteroaryl, or R 5 and R 6 together with the atoms to which they are connected form a 3- to 7-membered saturated ring group;
  • R 3 and R 4 together with the carbon atoms and bonds they are connected to form a 4-7 membered saturated ring or a 4-7 membered partially saturated ring;
  • Y is selected from formula (Y-1), formula (Y-2), formula (Y-3), formula (Y-4), formula (Y-5), formula (Y-6), formula (Y-7 ), formula (Y-8), formula (Y-9), formula (Y-10), formula (Y-11), formula (Y-12), formula (Y-13), or formula (Y-14 ),
  • Z is selected from -O-, -NR 9 -or -(CH 2 )-O-;
  • W is selected from C or SO
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • R 7 and R 8 are each independently selected from hydrogen, C1-C6 alkyl, C6-C10 aryl or C5-C10 heteroaryl, or R 7 and R 8 together with the atoms to which they are connected form 3-6 A saturated ring with three to six members or a partially saturated ring with three to six members;
  • R 9 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkylformyl, C6-C10 arylformyl, or C5-C10 heteroarylformyl.
  • the R 1 is preferably Cl, Br, methyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl Or n-hexyl, more preferably Cl or Br.
  • the R 2 is preferably Cl, Br, methyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl Or n-hexyl, more preferably Cl or Br.
  • the selection of R 3 , R 4 and Y is preferably: when Y is selected from formula (Y-1), formula (Y-2), formula (Y-3), formula (Y-4), formula ( Y-5), formula (Y-6), formula (Y-7), formula (Y-8), formula (Y-9), formula (Y-10), formula (Y-11), formula (Y -12), preferably formula (Y-1), formula (Y-2), formula (Y-3), formula (Y-4), formula (Y-11), formula (Y-12), formula ( Y-13) or formula (Y-14): the R 3 is preferably -NR 5 R 6 , C6-C10 aryl, C5-C10 heteroaryl -OR 5 or -CONR 5 R 6 , wherein , R 5 and R 6 are each independently selected from hydrogen, C1-C6 alkyl, C6-C10 aryl or C5-C10 heteroaryl, or R 5 and R 6 together with their connected atoms form 3 ⁇ A 7-membered saturated ring group, wherein the ring
  • R 3 and R 4 together with the carbon atoms and bonds to which they are connected form a 4- to 7-membered partially saturated ring or a 4- to 7-membered unsaturated ring.
  • the R 3 and R 4 are connected to them
  • the carbon atoms together form a benzene ring, furan ring, pyrrole ring, N-methylpyrrole ring, cyclopentane, cyclohexane, morpholine ring, piperidine ring, N-methylpiperidine ring, pyran ring, pyridine ring , Pyridazine ring or pyrazine ring.
  • the R 4 is hydrogen or C1 ⁇ C6 alkyl, preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl; and R 3 is a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl; and R 3 is a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n
  • the value of R in Y is preferably as follows:
  • the R 7 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, phenyl, naphthyl , Anthryl, phenanthryl, pyridyl, furyl, pyranyl, imidazolyl or morpholinyl; said R 8 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, phenyl, naphthyl, anthryl, phenanthryl, pyridyl, furanyl, imidazolyl, pyranyl or morpholinyl;
  • R 7 and R 8 together with the atoms to which they are connected form a 3-6 membered saturated ring or a 3-6 membered saturated or partially saturated ring, and more preferably form a cyclopropyl, cyclobutyl, cyclopentyl, acridine Butidine or 1,3,2-dioxaphosphoranyl.
  • the R 9 is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl.
  • the pyridazinone derivatives are formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), Formula (I-7), Formula (I-8), Formula (I-9), Formula (I-10), Formula (I-11), Formula (I-12), or Formula (I-13),
  • X is -CH 2 -or -O-;
  • R 1 and R 2 are independently selected from Cl, Br, or C1-C6 alkyl groups
  • Y is selected from formula (Y-1), formula (Y-2), formula (Y-3), formula (Y-4), formula (Y-5), formula (Y-6), formula (Y-7 ), formula (Y-8), formula (Y-9), formula (Y-10), formula (Y-11), formula (Y-12), formula (Y-13) or formula (Y-14) ,
  • Z is selected from -O-, -NR 9 -or -(CH 2 )-O-;
  • W is selected from C or SO
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • R 7 and R 8 are each independently selected from hydrogen, C1-C6 alkyl, C6-C10 aryl or C5-C10 heteroaryl, or R 7 and R 8 together with the atoms to which they are connected form 3-6 A saturated ring with three to six members or a partially saturated ring with three to six members;
  • R 9 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkylformyl, C6-C10 arylformyl, or C5-C10 heteroarylformyl.
  • the pyridazinone derivatives are formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), Formula (I-20) or Formula (I-21),
  • X is -CH 2 -or -O-;
  • R 1 and R 2 are independently selected from Cl, Br, or C1-C6 alkyl groups
  • Y is selected from formula (Y-2), formula (Y-3), formula (Y-5), formula (Y-6), formula (Y-7), formula (Y-8), formula (Y-9) ), formula (Y-10), formula (Y-11), formula (Y-12), formula (Y-13) or formula (Y-14),
  • Z is selected from -O-, -NR 9 -or -(CH 2 )-O-;
  • W is selected from C or SO
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • R 7 and R 8 are each independently selected from hydrogen, C1-C6 alkyl, C6-C10 aryl or C5-C10 heteroaryl, or R 7 and R 8 together with the atoms to which they are connected form 3-6 A saturated ring with three to six members or a partially saturated ring with three to six members;
  • R 9 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkylformyl, C6-C10 arylformyl, or C5-C10 heteroarylformyl.
  • the present invention has no special requirements for the preparation method of the aforementioned pyridazinone derivatives, and those skilled in the art can select a suitable preparation process according to the target product based on common knowledge of synthesis.
  • the present invention also provides an application of the pyridazinone derivative of the present invention in the preparation of agonists for agonizing thyroid hormone ⁇ receptor; the pyridazinone compound of formula (I) provided by the present invention shows good Thyroid hormone beta receptor agonist has good liver selectivity, and can be used as a medicine for the treatment and/or prevention of diseases related to this effect.
  • alkyl as used herein means, for example, a branched or unbranched, cyclic or acyclic, saturated or unsaturated (for example, alkenyl or alkynyl) hydrocarbon group, which may be substituted or Can be unsubstituted.
  • the cyclic alkyl group is preferably C 3 to C 6 , and more preferably C 3 to C 6 .
  • the acyclic alkyl group is preferably C 1 to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert Butyl).
  • alkyl as used herein includes, for example, alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or Or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkane Group, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl.
  • aryl as used herein means, for example, a substituted or unsubstituted carbocyclic aromatic group, such as phenyl or naphthyl, or a substituted or unsubstituted heteroaromatic group containing more than one, preferably one heteroatom Group groups, such as pyridyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyrimidinyl, Pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, and benzisothiazole base.
  • saturated or partially saturated cyclic group as used herein means that the saturation in a saturated cyclic group means that the ring does not contain double or triple bonds, and the partial saturation in a partially saturated cyclic group means that the ring contains at least A double bond or triple bond, but not fully unsaturated; for example, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, Substituted or unsubstituted 1,3,2-dioxaphosphoranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted tetrahydrofuran Group, substituted or unsubstituted pyrrolidone group,
  • Alkyl and aryl groups can be substituted or unsubstituted. In the case of substitution, there are usually, for example, 1 to 4 substituents, preferably 2 substituents.
  • Substituents may include, for example: carbon-containing groups such as alkyl groups, aryl groups, aralkyl groups (such as substituted and substituted phenyl groups, substituted and unsubstituted benzyl groups); halogen atoms and halogen-containing groups such as halogenated alkanes Groups (such as trifluoromethyl); oxygen-containing groups such as alcohols (hydroxyl, hydroxyalkyl, aryl (hydroxy) alkyl), ethers (such as alkoxy, aryloxy, alkoxyalkyl, aryloxy Alkyl), aldehydes (such as formaldehyde), ketones (such as alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbon
  • halogen as used herein means fluorine, chlorine, bromine or iodine.
  • the pyridazinone derivative provided by the present invention with the structure represented by formula (I), by selecting a specific modification group, it is found that the pyridazinone derivative provided by the present invention has good performance as a thyroid hormone ⁇ receptor agonist Active, can be used to treat and/prevent diseases caused by thyroid hormone regulation.
  • Step 2 Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (compound 3)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-3-malonic acid methyl Ester (Compound 4)
  • Decompression solvent obtains 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-3-malonic acid methyl Ester (320 mg, 82% yield).
  • Step 4 Preparation of 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-3-malonic acid ( Compound 5)
  • Methyl 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-3-malonate (320mg , 0.740mmol) into the bottle, add MeOH (8mL), 1N NaOH (2mL), react at 50°C for 30 minutes, add water (8mL) to remove methanol by rotary evaporation, extract with ethyl acetate, discard the organic phase, and adjust the pH to 5-6, extract with ethyl acetate, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain 3-((3,5-dichloro-4-((6-chloro-5) -Isopropylpyridazin-3-yl)oxy)phenyl)amino)-3-malonic acid (300 mg, 97% yield).
  • Step 5 3-((3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) -3-malonic acid (Example 1)
  • Step 1 Preparation of (E)-4-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-4- Methyl oxo-2-butenoate (Compound 6)
  • Step 2 Preparation of (E)-4-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) (Phenyl)amino)-4-oxo-2-butenoic acid methyl ester (Compound 7)
  • Step 3 Preparation of (E)-4-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) (Phenyl)amino)-4-oxo-2-butenoic acid (Example 2)
  • Step 1 1-((3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)carbamoyl)cyclopropyl-1- Methyl formate (Compound 8)
  • Step 2 Preparation of 1-((3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino Formyl) cyclopropyl-1-carboxylic acid methyl ester (compound 9)
  • Step 3 Preparation of 1-((3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino Formyl) cyclopropyl-1-methyl carboxylate (Example 3)
  • Step 1 Preparation of ethyl 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)propionate (compound 10 )
  • Step 2 Preparation of 3-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino ) Ethyl propionate (compound 11)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino ) Propionic acid (Example 4)
  • Step 1 Preparation of methyl 3-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)butyrate (Compound 12 )
  • Step 2 Preparation of 3-((3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)butanoic acid (Compound 13)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino ) Butyric acid (Example 5)
  • Step 2 Preparation of 4-(3,5-dichloro-4-((5-isopropyl-6-chloro-1,6-dihydropyridazin-3-yl)oxy)phenoxy)butyl Methyl ester (compound 15)
  • Step 3 Preparation of 4-(3,5-dichloro-4-((5-isopropyl-6-chloro-1,6-dihydropyridazin-3-yl)oxy)phenoxy)butyl Methyl ester (compound 16)
  • Step 4 Preparation of 4-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)butyl Acid (Example 6)
  • Step 1 Preparation of ((3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenoxy)methyl) diethyl phosphate (Compound 17 )
  • Step 1 Preparation of (((3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)oxy)phenoxy (Yl)methyl)diethyl phosphate (Example 7)
  • Step 2 Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)acetonitrile (Compound 18)
  • Step 3 Preparation of 3-((3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy) (Methyl)-1,2,4-oxadiazolin-5(4H)-one (Example 9)
  • Phenyl maleic anhydride (1g, 5.74mmol) and hydrazine sulfate (747mg, 5.74mmol) were put into water (30mL), heated to 120°C, after 6 hours of reaction, a white solid was produced, filtered, the filter cake was washed with water and baked Dry white solid 4-phenyl-1,2-dihydropyridazine-3,6-dione (900mg, 83% yield).
  • Step 4 Preparation of 3-((3,5-Dichloro-4-((6-chloro-5-phenylpyridazin-3-yl)oxy)phenyl)amino)-3-oxopropionate Ester (Compound 24)
  • Step 5 Preparation of 3-((3,5-Dichloro-4-((6-oxo-5-phenyl-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) Methyl-3-oxopropionate (Compound 25)
  • Step 6 Preparation of 3-((3,5-Dichloro-4-((6-oxo-5-phenyl-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) -3-oxopropionic acid (Example 11)
  • Step 1 Preparation of methyl 2-((3,5-dichloro-4-((6-chloro-5-phenylpyridazin-3-yl)oxy)phenyl)amino)-2-oxoacetate (Compound 26)
  • Step 2 Preparation of 3-((3,5-Dichloro-4-((6-oxo-5-phenyl-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) -2-oxoacetic acid (Example 11)
  • Methyl 2-((3,5-dichloro-4-((6-chloro-5-phenylpyridazin-3-yl)oxy)phenyl)amino)-2-oxoacetate (100mg, 0.223mmol) into the bottle, add sodium acetate (100mg, 1.21mmol), acetic acid (2mL), react at 120°C for 6h, rotary evaporate to remove acetic acid, dilute with water, extract with ethyl acetate, combine the organic phases, concentrate in vacuo to remove the solvent.
  • Step 1 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-phenylpyridazin-3-yl)oxy)phenyl)hydrazine (Yl)acetyl)urethane (compound 27)
  • Step 2 Preparation of 2-(3,5-dichloro-4-((5-phenyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3, 5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Example 12)
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-morpholinylpyridazin-3-yl)oxy)phenyl)ylidene Hydrazine) acetyl) ethyl carbamate (Compound 31)
  • reaction solution was added dropwise to ethyl cyanoacetoacetate (46mg , 0.293mmol), pyridine (2.5mL), water (8mL), continue the reaction for 30 minutes, a large amount of solid precipitated out, filtered, washed with water, washed with petroleum ether to obtain (2-cyano-2-(2-( 3,5-Dichloro-4-((6-chloro-5-morpholinylpyridazin-3-yl)oxy)phenyl)hydrazino)acetyl)carbamate (100mg, 69% yield ).
  • Step 4 Preparation of 2-(3,5-dichloro-4-((5-morpholin-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3, 5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Example 13)
  • Step 1 Preparation of ethyl 3-((3,5-dichloro-4-((6-chloro-5-morpholinylpyridazin-3-yl)oxy)phenyl)amino)propionate (compound 32 )
  • Step 2 Preparation of 3-((3,5-dichloro-4-((5-morpholin-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) Ethyl propionate (Compound 33)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((5-morpholin-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino) Propionic acid (Example 14)
  • Step 2 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-4,5-dimethylpyridazin-3-yl)oxy)phenyl ) Hydrazine) Acetyl) ethyl carbamate (Compound 36)
  • Step 3 Preparation of 2-(3,5-dichloro-4-((4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) -3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Example 15)
  • Step 1 Preparation of ethyl 3-((3,5-dichloro-4-((6-chloro-4,5-dimethylpyridazin-3-yl)oxy)phenyl)amino)propionate ( Compound 37)
  • Step 2 Preparation of 3-((3,5-dichloro-4-((4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl )Amino)ethyl propionate (Compound 38)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl )Amino)propionic acid (Example 16)
  • Step 2 Preparation of (2-cyano-2-(2-(3,5-dichloro-4-((4-chlorophthalazin-1-yl)oxy)phenyl)-hydrazino)-acetyl Yl)-carbamoyl ethyl ester (Compound 41)
  • Ethyl cyanoacetoacetate (50mg, 0.32mmol) was dissolved in a solution of pyridine (2.5ml) and water (2.5ml), cooled to 5°C in an ice-water bath, and then the reaction mother liquor prepared above was added dropwise to the system , After the dripping is completed, the solution becomes orange and precipitates solid, and the reaction is kept for 1 hour. Add a small amount of water to the reaction solution, stir, filter with suction, and wash the filter residue with water.
  • Step 3 Preparation of 2-(3,5-dichloro-4-((4-oxy-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo -2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Example 17)
  • reaction system is protected by nitrogen replacement, heated and stirred to increase to 80°C, react for 2 hours, stop heating, filter while hot, add ethyl acetate and water to the filtrate for extraction, combine the organic phases and dry, filter, and remove the solvent under reduced pressure to obtain a residue
  • Step 3 Preparation of (2-cyano-2-(2-(3,5-dibromo-4-((4-chlorophthalazin-1-yl)oxy)phenyl)-hydrazino)-acetyl Yl)-carbamoyl ethyl ester (Compound 45)
  • Ethyl cyanoacetoacetate (39mg, 0.25mmol) was dissolved in a solution of pyridine (2.5ml) and water (2.5ml), cooled to 5°C in an ice-water bath, and then the mother liquid of the diazonium salt prepared above was dropped After adding to the system, the solution turned orange and precipitated solid, and the temperature was kept for 1 hour. Add a small amount of water to the reaction solution, stir, filter with suction, and wash the filter residue with water.
  • Step 4 Preparation of 2-(3,5-dibromo-4-((4-oxy-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo -2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Example 18)
  • Step 1 Preparation of ethyl 3-((3,5-dichloro-4-((4-chlorophthalazin-1-yl)oxy)phenyl)amino)-3-oxopropionate (Compound 46)
  • Step 2 Preparation of 3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)-3-oxo Ethyl propionate (Compound 47)
  • Step 3 Preparation of 3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)-3-oxopropane Acid (Example 19)
  • Step 1 Preparation of ethyl 3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)propionate ( Compound 48)
  • Step 2 Preparation of 3-((3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)propionic acid (Example 20)
  • Step 1 Preparation of ethyl 3-((3,5-dibromo-4-((4-chlorophthalazin-1-yl)oxy)phenyl)amino)-3-oxopropionate (Compound 49)
  • Step 2 Preparation of 3-((3,5-dibromo-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)-3-oxo Ethyl propionate (Compound 50)
  • Step 3 Preparation of 3-((3,5-dibromo-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)-3-oxopropane Acid (Example 21)
  • Step 1 Preparation of ethyl 3-((3,5-dibromo-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)propionate ( Compound 51)
  • Step 2 Preparation of 3-((3,5-dibromo-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)amino)propionic acid (Example twenty two)
  • TR ⁇ 1 human thyroid hormone receptor ⁇ 1 (TR ⁇ 1) and ⁇ 1 (TR ⁇ 1)
  • T 3 3,3',5-triiodo-L-thyroxine
  • the results of transcription activation experiments show that the compounds of the examples of the present invention can achieve agonistic activity on thyroid hormone receptor ⁇ , among which Examples 4, 5, 6, 18 and 19 can selectively agonize thyroid hormone receptor ⁇ .
  • the pyridazinone compound of the present invention has good thyroid hormone beta receptor agonistic activity, and can be used as a medicine for treating or preventing diseases related to the effect.

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Abstract

本发明提供了一种哒嗪酮衍生物及其应用，本发明提供的具有式(I)所示结构哒嗪酮衍生物，通过选择特定的修饰基团，结果发现，本发明提供的哒嗪酮衍生物作为甲状腺激素β受体激动剂具有很好的活性，可用于治疗和/预防由甲状腺激素调节引起的疾病。

Description

一种哒嗪酮衍生物及其应用
本申请要求于2019年05月10日提交中国专利局、申请号为201910391465.7、发明名称为“一种哒嗪酮衍生物及其应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学领域，尤其涉及一种哒嗪酮衍生物及其制备方法和应用。
背景技术
甲状腺激素(TH)对于正常生长和发育以及维持代谢平衡具有关键作用(Paul M Yen，生理学评论(physiological reviews))，81(3)卷：1097-1126页(2001))。TH可促进脂质水解，增加脂肪酸的利用度，从而为机体提供能量，最后导致脂质的减少，降低体重。研究显示，肥胖症患者的TH水平与正常人的相比，发生很大变化。TH主要有两种形式：3,5,3’,5’-四碘-L-甲状腺原氨酸(T4)和3,5,3’,-四碘-L-甲状腺原氨酸(T3)。尽管T4是有甲状腺分泌的主要形式，但T3是生理上更为活跃的形式。T4通过组织特异性脱碘酶被转化为T3，组织特异性脱碘酶存在于所有组织中，但是主要在肝脏和肾脏中。相关研究表明T3或者T3类似物能够对肥胖进行有效治疗，尤其在与低热量的食物同时干预后减肥效果更为明显。因此，控制TH的水平可以有效调节能量平衡。临床上已经观察到，甲状腺功能减退症(甲减)可降低胆固醇的排泄、减少肝脏表面低密度脂蛋白-胆固醇(LDL-C)受体数量，从而使LDL-C分解减少，因此患者常出现总胆固醇和LDL-C水平升高，导致高脂血症、动脉粥样硬化、胰岛素抵抗、非酒精性脂肪性肝病(NAFLD)等代谢综合征。
从病理生理学角度看，在甲状腺机能亢进症中观察到心动过速、心律不齐、心脏衰竭，以及疲劳感、呼吸急促和骨骼肌减少、骨质疏松等现象(生理学评论(Physiology Review),81卷：1097页(2001))。相对地，还观察到对于代谢性疾病如血液中的胆固醇降低和基础代谢增加等治疗有益的现象。反之，在通过垂体障碍和先天性功能障碍等引起的甲状腺功能减退(甲减)中观察到心率下降、血液中胆固醇增加和体重增加。这也是天然在的甲状腺激素存在心脏毒性使其治疗用途受到限制的原因。
从分子生物学角度看，TH的生物活性由核受体——甲状腺激素受体(TRs)介导的(M.A.Lazar，内分泌评论(Endocrine Reviews),14卷:348-399页(1993))。TRs与担当配体-诱导的转录因子的类维生素A受体形成异二聚体。TRs具有配体结合结构域，DNA结合结构域和氨基末端结构域，并通过与NDA相应要素以及与各种核共-活化剂和共-阻遏剂的相互作用而调节基因表达。TRs分别由位于人类染色体17和3上的不同基因α和β编码而来，通过对初级转录物进行选择性剪切后产生不同的 蛋白亚型，每个基因产生两个亚型：α1、α2、β1和β2。TRα1、TRβ1和TRβ2可与T3结合，TRα2不与TH结合。研究显示，甲状腺激素受体亚型在他们对于特殊生理响应的贡献方面可以不同。TRβ1存在于大部分组织中，特别是肝脏。TRα1的分布也比较广泛，并且TH在结合TRα1和TRβ1时活性类似，但是它的分布范围小于TRβ1，研究显示大多数TH对心脏的影响，特别是心律和心率，主要是通过TRα1亚型实现的。
由于TH主要通过受体调控靶器官(肝脏)上的基因表达来维持代谢平衡，包括维持肝脏和脂肪组织的脂质平衡。因此，在避免上述有害事件的同时特别地发挥TH及其类似物的有益方面如胆固醇降低或基础代谢增加，以及在肝脏的特别积累具有临床意义，将打开治疗以下疾病患者的新途径：代谢疾病如肥胖、高脂血症、高胆固醇血症、糖尿病和其他疾病如肝脂肪变性和非酒精性脂肪肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺机能减退、甲状腺癌等。
因此，提供甲状腺激素β受体激动剂用于治疗和/预防由甲状腺激素调节的疾病具有重要意义。
发明内容
有鉴于此，本发明所要解决的技术问题在于提供一种哒嗪酮衍生物及其制备方法和应用，本发明提供的哒嗪酮衍生物对具有良好的甲状腺激素β受体激动活性，可成为治疗或预防与该作用相关的疾病的药物。
与现有技术相比，本发明提供了一种具有式(I)所示结构哒嗪酮衍生物，通过选择特定的修饰基团，实验结果表明，本发明提供的哒嗪酮衍生物作为甲状腺激素β受体激动剂具有很好的活性，可用于治疗和/预防由甲状腺激素调节引起的疾病。
具体实施方式
本发明提供了一种哒嗪酮衍生物，具有式(I)所示结构：
Figure PCTCN2020088905-appb-000001
其中：
X为-CH 2-或-O-；
R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
R 3、R 4独立地选自氢、卤素、C1～C6的烷基、-OR 5、-NR 5R 6、-CONR 5R 6、C6～C10的芳基或C5～C10的杂芳基，且R 3、R 4不同时为氢；其中，R 5和R 6各自独立地选自氢、C1～C15的烷基、C6～C10的芳基或C5～C10的杂芳基，或者R 5和R 6与它们相连的原子一起形成3～7元的饱和环基；
或R 3和R 4与它们相连的碳原子及键一起形成4～7元的饱和环、4～7元的部分饱和的环；
Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)、或式(Y-14)，
Figure PCTCN2020088905-appb-000002
Z选自-O-、-NR 9-或-(CH 2)-O-；
W选自C或SO；
n是1、2或3；
m是0、1、2或3；
R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5-C10的杂芳基甲酰基。
按照本发明，所述R 1优选为Cl、Br、甲基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基，更优选为Cl或Br。
按照本发明，所述R 2优选为Cl、Br、甲基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基，更优选为Cl或Br。
按照本发明，R 3、R 4以及Y的选择优选为：当Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)，优选为式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)时：所述R 3优选为-NR 5R 6、C6～C10的芳基、C5-C10的杂芳基-OR 5或-CONR 5R 6，其中，R 5和R 6各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 5和R 6与它们相连的原子一起形成3～7元的饱和环基，其中环基可任选地含有杂原子N或/和O；其中所述饱和环基、芳环、杂芳环可以是未取代的环或环上的氢原子被1至4个独立地选自以下的基团取代：卤素、烷基、-OR 5、-NR 5R 6、杂芳基或芳基；更优选 的，所述R 3为吡咯烷基、吗啉基、哌嗪基、N-烷基哌嗪基、N,N-二烷基氨基、苯基、苄基、苯乙基、噻吩基、呋喃基、吡啶基、甲氧基、乙氧基、异丙氧基、甲酰胺基、N,N-二烷基甲酰基；最优选为苯基、吡啶基、呋喃基、吡喃基、哌啶基、N-甲基哌啶基、二甲基氨基、异丙基氨基、N-甲基-N-乙基氨基、二异丙基氨基、甲氧基、乙氧基、异丙氧基、N,N-二甲基甲酰基或吗啉基；所述R 4优选为氢、C1～C6的烷基、-NR 5R 6、C6～C50的芳基、-OR 5或-CONR 5R 6，其中，R 5和R 6各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 5和R 6与它们相连的原子一起形成3～7元的饱和环，其中环基可任选地含有N和O的杂原子；其中所述饱和环基、芳环、杂芳环可以是未取代的环或环上的氢原子被1至4个独立地选自以下的基团取代：卤素、烷基、-OR 5、-NR 5R 6、杂芳基或芳基；更优选的，所述R 4为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、吡咯烷基、吗啉基、哌嗪基、N-烷基哌嗪基、N,N-二烷基氨基、苯基、苄基、苯乙基、噻吩基、呋喃基、吡啶基、甲氧基、乙氧基、异丙氧基、甲酰胺基、N,N-二烷基甲酰基。
或所述R 3和R 4与它们相连的碳原子及键一起形成4～7元的部分饱和的环或4～7元的不饱和环，优选的所述R 3和R 4与它们相连的碳原子一起形成苯环、呋喃环、吡咯环、N-甲基吡咯环、环戊烷、环己烷、吗啉环、哌啶环、N-甲基哌啶环、吡喃环、吡啶环、哒嗪环或吡嗪环。
当所述Y选自式(Y-2)、式(Y-3)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)，优选为式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-10)、式(Y-13)或式(Y-14)时，所述R 4为氢或C1～C6的烷基，优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基；且所述R 3为C1～C6的烷基，优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基。
按照本发明，所述Y中的R的取值优选如下：
所述R 7优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、苯基、萘基、蒽基、菲基、吡啶基、呋喃基、吡喃基、咪唑基或吗啉基；所述R 8优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、苯基、萘基、蒽基、菲基、吡啶基、呋喃基、咪唑基、吡喃基或吗啉基；
或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的饱和或部分饱和的环，更优选为形成环丙基、环丁基、环戊基、吖丁啶基或1,3,2-二氧磷杂环己基。
所述R 9优选为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基。
更具体的，
所述哒嗪酮衍生物为式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-6)、式(I-7)、式(I-8)、式(I-9)式(I-10)、式(I-11)、式(I-12)或式(I-13)，
Figure PCTCN2020088905-appb-000003
Figure PCTCN2020088905-appb-000004
其中，X为-CH 2-或-O-；
R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)，
Figure PCTCN2020088905-appb-000005
Z选自-O-、-NR 9-或-(CH 2)-O-；
W选自C或SO；
n是1、2或3；
m是0、1、2或3；
R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5-C10的杂芳基甲酰基。
更具体的，
所述哒嗪酮衍生物为式(I-14)、式(I-15)、式(I-16)、式(I-17)、式(I-18)、式(I-19)、式(I-20)或式(I-21)，
Figure PCTCN2020088905-appb-000006
其中，X为-CH 2-或-O-；
R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
Y选自式(Y-2)、式(Y-3)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)，
Figure PCTCN2020088905-appb-000007
Figure PCTCN2020088905-appb-000008
Z选自-O-、-NR 9-或-(CH 2)-O-；
W选自C或SO；
n是1、2或3；
m是0、1、2或3；
R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5-C10的杂芳基甲酰基。
更具体的，所述哒嗪酮衍生物的具体结构如下。
Figure PCTCN2020088905-appb-000009
Figure PCTCN2020088905-appb-000010
本发明对前述的哒嗪酮衍生物的制备方法没有特殊要求，本领域技术人员可以根据目标产物基于合成的公知常识选择合适的制备工艺。
本发明还提供了一种本发明所述的哒嗪酮衍生物在制备激动甲状腺激素β受体的激动剂中的应用；本发明提供的式(I)的哒嗪酮类化合物显示具有良好的甲状腺激素β受体激动剂作用，并具有良好的肝脏选择性，能够作为与该作用有关的疾病的治疗和/或预防有关的药物。
各术语定义：
应该理解，此处采用的术语目的在于描述具体的实施方案，并非意在限制。此外，尽管类似或者等价于此处描述的任何方法、装置和材料均可用于实施或者测试本发明，但是现在描述的是优选的方法、装置和材料。
此处使用的术语“烷基”表示，例如，支链或非支链的、环状或非环状的、饱和或不饱和的(例如链烯基或者炔基)烃基，其可以被取代也可以是未取代的。其中所述的环状烷基优选为C 3至C 6，更有选为C 3至C 6。其中所述的非环状烷基优选为C 1至C 6，更优选为甲基、乙基、丙基(正丙基或异丙基)、丁基(正丁基、异丁基或叔丁基)。因此，应理解，此处使用的术语“烷基”包括，例如，烷基(支链或非支链的)、取代的烷基(支链或非支链的)、链烯基(支链或非支链的)、取代的链烯基(支链或非支链的)、炔基(支链或非支链的)、取代的炔基(支链或非支链的)、环烷基、取代的环烷基、环烯基、取代的环烯基。
此处使用的术语“芳基”表示，例如，取代或未取代的碳环的芳香族基团，如苯基或萘基，或者取代或未取代的含有一个以上、优选一个杂原子的杂芳香族基团，如吡啶基、吡咯基、呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、恶二唑基、吡唑基、三氮唑基、嘧啶基、哒嗪基、吡嗪基、三嗪基、吲哚基、吲唑基、喹啉基、喹唑啉基、苯并咪唑基、苯并噻唑基、苯并异噁唑基和苯并异噻唑基。
此处使用的术语“饱和或部分饱和的环基”表示，饱和的环基中的饱和是指其环上不含有双键或三键，部分饱和的环基中的部分饱和是指环上至少含有一个双键或三键，但不是全不饱和；例如，取代或未取代的环丙基、取代或未取代的环丁基、取代或未取代的环戊基、取代或未取代的环己基、取代或未取代的1,3,2-二氧磷杂环己基、取代或未取代的吖丙啶基、取代或未取代的吖丁啶基、取代或未取代的吡咯基、取代或未取代的四氢呋喃基、取代或未取代的吡咯啉酮基、取代或未取代的吡咯烷酮基、取代或未取代的哌啶基、取代或未取代的哌嗪基和取代或未取代的吡喃基等。
烷基和芳基可以是取代的或未取代的。在取代的情况下，通常存在例如1到4个取代基，优选2个取代基。取代基可以包括，例如：含碳基团如烷基、芳基、芳烷基(例如取代和为取代的苯基、取代和未取代的苄基)；卤素原子和含卤素的基团如卤代烷基(如三氟甲基)；含氧基团如醇(羟基、羟烷基、芳基(羟基)烷基)、醚(如烷氧基、芳氧基、烷氧基烷基、芳氧基烷基)、醛(如甲醛)、酮(如烷基羰基、烷基羰基烷基、芳基羰基、芳基烷基羰基)、酸(如羧酸、羧基烷基)、酸衍生物如酯(如烷氧基羰基、烷氧基羰基烷基、烷基羰基氧基烷基)、酰胺(如氨基羰基、单-或二-烷基氨基羰基、氨基羰基烷基、单-或二-烷基氨基羰基烷基、芳基氨基羰基)、氨基甲酸酯(如烷氧基羰基氨基、芳氧基羰基氨基、氨基羰基氧基、单-或二-烷基氨基羰基氨基或芳基氨基羰基氨基)；含氮基团如胺(氨基、单-或二-烷基氨基、氨基烷基、单-或二-烷基氨基烷基)、叠氮化物、腈(如氰基、氰基烷基)、硝基；含硫基团如硫醇、硫醚、亚砜和砜(如烷硫基、烷基亚磺酰基、烷基磺酰基、烷硫基烷基、烷基亚磺酰基烷基、烷基磺酰基烷基、芳硫基、芳基亚磺酰基、芳基磺酰基、芳硫基烷基、芳基亚磺酰烷基、芳基磺酰基烷基)；和含有一个以上、优选一个杂原子的杂环基团(如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、恶二唑基、噻二唑基、吖丙啶基、吖丁啶基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、四氢呋喃基、吡喃基、吡喃酮基、吡啶基、吡嗪基、哒嗪基、哌啶基、六氢氮杂卓基、哌嗪基、吗啉基)、硫萘基、苯并呋喃基、异苯并呋喃基、吲哚基、羟基吲哚基、异吲哚基、吲唑基、二氢吲唑基、7-氮杂吲哚基、苯并吡喃基、香豆素基、异香豆素基、喹啉基、异喹啉基、1,5-二氮杂萘基、吡啶并吡啶基、喹唑啉基、苯并噁嗪基、喹喔啉基、苯并二氢吡喃基、异苯并二氢吡喃基、2,3-二氮杂萘基和咔啉基)。
此处使用的术语“卤素”表示，氟、氯、溴或碘。
本发明提供的具有式(I)所示结构哒嗪酮衍生物，通过选择特定的修饰基团，结果发现，本发明提供的哒嗪酮衍生物作为甲状腺激素β受体激动剂具有很好的活性，可用于治疗和/预防由甲状腺激素调节引起的疾病。
下面将结合本发明实施例的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸
Figure PCTCN2020088905-appb-000011
步骤1：制备3,6-二氯-4-异丙基哒嗪(化合物2)
将3,6-二氯哒嗪(45g，0.304mol)，异丁酸(33.45g，0.380mol)，硝酸银(5.138g，0.0304mol)，三氟乙酸(6.932g，0.0608mol)溶于水(270mL)中于70℃搅拌，将过硫酸铵溶于水(180mL)缓慢滴入瓶中。该反应液搅拌20分钟，停止加热，降温至室温。用NaHCO 3水溶液调pH值至9-10。正己烷萃取，合并有机相无水硫酸钠干燥，过滤，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/3],获得3,6-二氯-4-异丙基哒嗪(56g，96％yield)。
LC-MS(m/z)：191.1(M+1)
步骤2：制备3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(化合物3)
将3,6-二氯-4-异丙基哒嗪(25g，13.16mmol)、2,6-二氯-4-氨基苯酚(25.48g，14.47mmol)Cs2CO3(85.07g，26.32mmol)投入DMF(125mL)中，氮气保护下加热至90℃反应6小时，加水稀释，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/2]，获得3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(30g，69％yield)。
LC-MS(m/z)：332.6(M+1)。
步骤3：制备3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸甲酯(化合物4)
3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(300mg，0.901mmol)和DIPEA(174mg,1.355mmol)投入THF(3mL)中，冰浴，然后将氯乙酰乙酸甲酯(150mg、0.992mmol)缓慢滴入瓶中，室温反应20min,加水淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压溶剂获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸甲酯(320mg，82％yield)。
LC-MS(m/z)：432.5(M+1)。
步骤4：制备3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸(化合物5)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸甲酯(320mg，0.740mmol)投入瓶中，加入MeOH(8mL)，1N NaOH(2mL)，50℃反应30分钟，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸(300mg，97％yield)。
LC-MS(m/z)：418.2(M+1)。
步骤5：3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸(实施例1)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-3-丙二酸(300mg，0.719mmol)投入醋酸(10mL)，加入醋酸钠(176mg，2.14mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/1]，获得3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(30mg，10％yield)，LC-MS(m/z)：399.8(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),10.64(s,1H),7.77(s,2H),7.36(s,1H),3.35(s,2H),3.07-3.01(m,1H),1.19(d,J＝7.2Hz,6H).
实施例2
(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸
Figure PCTCN2020088905-appb-000012
步骤1：制备(E)-4-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸甲酯(化合物6)
3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(100mg,0.301mmol)、三乙胺(60mg，0.602mmol)投入二氯甲烷(3mL)中，冰浴，然后将3-氯代羰基丙烯酸甲酯(49mg，0.331mmol)缓慢滴入瓶中，室温反应20分钟,加水淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压除去溶剂获得(E)-4-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸甲酯(140mg，104％yield)。
LC-MS(m/z)：444.5(M+1)。
步骤2：制备(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸甲酯(化合物7)
将(E)-4-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸甲酯(140mg，0.316mmol)投入醋酸(10mL)，加入醋酸钠(140mg，1.627mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/2]，获得(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸甲酯(50mg，37.2％yield)。
LC-MS(m/z)：426.3(M+1)。
步骤3：制备(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸(实施例2)
将(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代丁-2-烯酸甲酯(50mg，00.117mmol)投入瓶中，加入MeOH(8mL)，1N NaOH(2mL),50℃反应30分钟，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调PH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得(E)-4-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-4-氧代-2-丁烯酸(20mg，41.3％yield)。
LC-MS(m/z)：411.9(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),11.05(s,1H),7.92(s,2H),7.35(s,1H),6.72(dd J＝15.6,18.4Hz,2H),3.06-2.99(m,1H),1.17(d,J＝7.2Hz,6H).
实施例3
1-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-羧酸
Figure PCTCN2020088905-appb-000013
步骤1：1-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-甲酸甲酯(化合物8)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(1.0g，3.012mmol)，1,1-环丙基二甲酸单甲酯(492mg,3.331mmol)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)(1.71g,4.518mmol)，N,N-二异丙基乙胺(777mg，1.506mmol)投入二氯甲烷(20mL)中，反应过夜，浓缩除去二氯甲烷,加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，甲醇打浆获得(1-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-甲酸甲酯(800mg，60％yield)。
LC-MS(m/z)：457.9(M+1)。
步骤2：制备1-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-羧酸甲酯(化合物9)
将(1-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-甲酸甲酯(100mg，0.225mmol)投入醋酸(10mL)，加入醋酸钠(100mg，1.116mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/2]，获得(1-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-甲酸甲酯(40mg，42％yield)。
LC-MS(m/z)：440.3(M+1)。
步骤3：制备1-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-羧酸甲酯(实施例3)
将(1-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-甲酸甲酯(40mg，0.094mmol)投入瓶中，加入甲醇(8mL)，1N NaOH(2mL),50℃反应30min，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得1-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基甲酰基)环丙基-1-羧酸甲酯(25mg，64％yield)。
LC-MS(m/z)：425.9(M+1)。
1H NMR(400MHz,DMSO-d 6)δ13.14(s,1H),12.18(s,1H),10.79(s,1H),7.85(s,2H),7.36(s,1H),3.07-3.00(m,1H),1.42(s,4H),1.19(d,J＝7.2Hz,6H).
实施例4
3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸
Figure PCTCN2020088905-appb-000014
步骤1：制备3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物10)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(100mg,0.301mmol)投入丙烯酸甲酯(2mL)中，100℃加一滴三氟乙酸，反应24小时后，加入二氯甲烷(20mL)，减压除去溶剂，然后薄层层析分离[乙酸乙酯/石油醚＝1/3]，获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(60mg，46％yield)。
LC-MS(m/z)：431.9(M+1)。
步骤2：制备3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物11)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(60mg，0.139mmol)投入醋酸(10mL)，加入醋酸钠(60mg，0.731mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(20mg，34％yield)。
LC-MS(m/z)：414.3(M+1)。
步骤3：制备3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(实施例4)
将3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(20mg，0.048mmol)投入瓶中，加入甲醇(8mL)，1N NaOH(2mL),50℃反应30分钟，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(10mg，54％yield)。
LC-MS(m/z)：386.2(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.30(s,1H),12.12(s,1H),7.29(s,1H),6.70(s,2H),6.26(s,1H),3.26(brs,2H),3.09-2.99(m,1H),2.51(dd,J＝6.4Hz,2H),1.18(d,J＝7.2Hz,6H).
实施例5
3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丁酸
Figure PCTCN2020088905-appb-000015
步骤1：制备3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(化合物12)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(500mg,1.506mmol)，溴丁酸甲酯(1.63g,4.518mmol),Et3N(1mL),70℃反应24h，加水稀释，乙酸乙酯萃取两遍， 减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/3]，获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(200mg，30％yield)。
LC-MS(m/z)：447.5(M+1)。
步骤2：制备3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸(化合物13)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(200mg，0.464mmol投入瓶中，加入甲醇(8mL)，1N NaOH(2mL),50℃反应30min，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸(50mg，26％yield)。
LC-MS(m/z)：418.2(M+1)。
步骤3：制备3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丁酸(实施例5)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸(50mg，0.120mmol)投入醋酸(10mL)，加入醋酸钠(50mg，0.609mmol)，100℃反应6h，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丁酸(20mg，41％yield)
LC-MS(m/z)：399.8(M+1)。
1H NMR(400MHz,DMSO-d 6)δ7.95(s,2H),7.81(s,1H),3.89(t,J＝7.2Hz,2H),3.21-3.14(m,2H),2.55(t,J＝8.0Hz,2H),2.11-2.04(m,2H),1.30(d,J＝6.8Hz,6H).
实施例6
4-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)丁酸
Figure PCTCN2020088905-appb-000016
步骤1：制备3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯酚(化合物14)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(5g，15.06mmol)溶于50％硫酸(30mL)中，冰浴，缓慢滴加亚硝酸钠(1.04g，15.03mmol)，反应30分钟，将硫酸铜(35.8g，226.58mmol)溶于水(30mL)滴入反应液中，然后分批加入氧化亚铜(1.43g，15.03mmol),室温反应30分钟，向瓶中加入乙酸乙酯，过滤除去固体，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后柱层层析分离[乙酸乙酯/石油醚＝1/]，获得3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯酚(3.0g，59.8％yield)
LC-MS(m/z)：333.6(M+1)。
步骤2：制备4-(3,5-二氯-4-((5-异丙基-6-氯代-1,6-二氢哒嗪-3-基)氧基)苯氧基)丁酸甲酯(化合物15)
操作：
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯酚(100mg，0.301mmol)，溴丁酸甲酯(181mg，1mmol)，碳酸钾(138mg，1mmol)投入丙酮中回流反应6小时，加水稀释，乙酸乙酯萃取两遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/3]，获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(120mg，96％yield)
LC-MS(m/z)：433.7(M+1)。
步骤3：制备4-(3,5-二氯-4-((5-异丙基-6-氯代-1,6-二氢哒嗪-3-基)氧基)苯氧基)丁酸甲酯(化合物16)
将3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(120mg，0.277mmol)投入醋酸(10mL)，加入醋酸钠(120mg，1.46mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丁酸(20mg，17％yield)
LC-MS(m/z)：415.3(M+1)。
步骤4：制备4-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)丁酸(实施例6)
将3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(20mg，0.048mmol)投入瓶中，加入甲醇(8mL)，1N NaOH(2mL),50℃反应30分钟，加入水(8mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(10mg，52％yield)。
LC-MS(m/z)400.6(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),7.35(s,1H),7.21(s,2H),4.05(t,J＝6.4Hz,2H),3.07-3.00(m,1H),2.36(t,J＝7.2Hz,2H),1.96-1.88(m,2H),1.18(d,J＝6.8Hz,6H).
实施例7
(((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)氧基)苯氧基)甲基)磷酸二乙酯
Figure PCTCN2020088905-appb-000017
步骤1：制备((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯氧基)甲基)磷酸二乙酯(化合物17)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯酚(300mg，0.899mmol)，(二乙氧基磷酰基)甲基4-甲基苯磺酸(347mg，1.08mmol),碳酸铯(586mg,1.80mmol)，60℃反应8小时，加水稀释，乙酸乙酯萃取两遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/1]，获得((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯氧基)甲基)磷酸二乙酯(300mg，92％yield)。
LC-MS(m/z)：483.5(M+1)。
步骤1：制备(((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)氧基)苯氧基)甲基)磷酸二乙酯(实施例7)
将((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯氧基)甲基)磷酸二乙酯(300mg，0.835mmol)投入醋酸(10mL)，加入醋酸钠(172mg，2.506mmol)，100℃反应6h，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丁酸(110mg，69％yield)
LC-MS(m/z)：465.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),7.35(s,1H),7.34(s,2H),4.56(d,J＝10.0Hz,2H),4.15-4.08(m,4H),3.08–3.00(m,1H),1.26(t,J＝7.2Hz,6H),1.18(d,J＝6.8Hz,6H).
实施例8
(((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)氧基)苯氧基)甲基)磷酸
Figure PCTCN2020088905-appb-000018
将(((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)氧基)苯氧基)甲基)磷酸二乙酯(100mg,0.215mmol)溶于二氯甲烷(2mL)中，冰浴下滴加三甲甲硅烷基溴化物(658mg，4.310mmol)，室温搅拌过夜，真空浓缩除去溶剂，用乙腈-水(1:1.5mL)处理残留物,真空浓缩，获得(((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)氧基)苯氧基)甲基)磷酸(50mg，56％yield)
LC-MS(m/z)：409.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),7.35(s,1H),7.28(s,2H),4.21(d,J＝10.0Hz,2H),3.07-3.00(m,1H),1.18(d,J＝6.8Hz,6H).
实施例9
3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)甲基)-1,2,4-噁二唑林-5(4H)-酮
Figure PCTCN2020088905-appb-000019
步骤1：制备2-(3,5-二氯-4-((6-氯-5-异丙基-3-基)氧基)苯氧基)乙腈(化合物18)
将3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯酚(500mg，1.506mmol)，溴乙腈(271mg，2.259mmol),碳酸铯(1.468g，4.518mmol),60℃反应8小时，加水稀释，乙酸乙酯萃取两遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/3]，获得3-((3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯基)氨基)丁酸甲酯(120mg，22％yield)。
LC-MS(m/z)：372.3(M+1)。
步骤2：制备2-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)乙腈(化合物18)
将2-(3,5-二氯-4-((6-氯-5-异丙基-3-基)氧基)苯氧基)乙腈(120mg，0.323mmol)投入醋酸(10mL)，加入醋酸钠(80mg，0.967mmol)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，水洗一遍，减压除去溶剂得到残留物，然后薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得2-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)乙腈(70mg，61％yield)。
LC-MS(m/z)：353.9(M+1)。
步骤3：制备3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)甲基)-1,2,4-噁二唑林-5(4H)-酮(实施例9)
将2-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)乙腈(70mg，0.198mmol),盐酸羟胺(26mg，0.376mmol),碳酸氢钠(42mg，0.5mmol)溶于甲醇中(2mL),加热至70℃搅拌2分钟。加水稀释，乙酸乙酯萃取，合并浓缩有机相。然后将所得残留物溶于二氯甲烷中并缓慢滴加N,N'-羰基二咪唑(38mg,0.851mmol)，滴毕，继续搅拌30分钟。反应液用乙酸乙酯萃取真空浓缩有机相，薄层层析(二氯甲烷/MeOH＝12/1)分离，获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯氧基)甲基)-1,2,4-噁二唑林-5(4H)-酮(11mg,13％yield)。
LC-MS(m/z)：413.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),12.16(s,1H),7.36(s,3H),5.18(s,2H),3.07-3.01(m,1H),1.19(d,J＝6.8Hz,6H).
实施例10
3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸
Figure PCTCN2020088905-appb-000020
步骤1：制备4-苯基-1,2-二氢哒嗪-3,6-二酮(化合物21)
将苯基顺酐(1g，5.74mmol),硫酸肼(747mg，5.74mmol)投入水(30mL)中，加热到120℃,反应6小时后，有白色固体产生，过滤，滤饼用水洗涤，烘干获得白色固体4-苯基-1,2-二氢哒嗪-3,6-二酮(900mg，83％yield)。
LC-MS(m/z)：188.9(M+1)。
步骤2：制备3,6-二氯-4-苯基哒嗪(化合物22)
在单口瓶中投入4-苯基-1,2-二氢哒嗪-3,6-二酮(900mg，4.78mmol)，加入三氯氧磷4.5mL，85℃反应6小时，将反应液缓慢加入50mL水中，析出固体，过滤，滤饼用水洗涤，烘干获得白色固体3,6-二氯-4-苯基哒嗪(850mg，79％yield)
LC-MS(m/z)：225.1(M+1)。
步骤3：制备3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯胺(化合物23)
将3,6-二氯-4-苯基哒嗪(850mg，3.81mmol)，2,6-二氯-4-氨基苯酚(739mg，4.19mmol)，无水碳酸钾(1.04g，7.62mmol)，碘化亚铜(359mg，1.90mmol)投入二甲基亚砜(5mL)中，氮气保护，90℃反应6小时。向反应体系中加入乙酸乙酯(50mlL)和水(50mL)，摇匀，过滤分层，水相用乙酸乙酯萃取，合并浓缩有机相，然后柱层析分离[乙酸乙酯/石油醚＝1/1]，获得白色固体3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯胺(360mg，25％yield)。
LC-MS(m/z)：366.2(M+1)。
步骤4：制备3-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(化合物24)
将3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯胺(70mg，0.192mmol)投入瓶中，加入二氯甲烷(3mL)，三乙胺(58mg，0.576mmol),冰浴条件下滴加氯乙酰乙酸甲酯(35mg，1.09mmol)，室温反应20分钟，反应液加水淬灭，分层，水相用二氯甲烷萃取，真空浓缩有机相，获得3-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(75mg，84％yield)。
LC-MS(m/z)：466.7(M+1)。
步骤5：制备3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(化合物25)
将3-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(75mg，0.161mmol)投入瓶中，加入醋酸钠(75mg，0.914mmol)，醋酸(2mL),100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，合并有机相，真空浓缩除去溶剂，薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(20mg，27％yield)。
LC-MS(m/z)：448.1(M+1)。
步骤6：制备3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸(实施例11)
将3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-3-氧代丙酸甲酯(20mg，0.044mmol)投入瓶中，加入甲醇(4mL)，1N NaOH(1mL),50℃反应30分钟，加入水(4mL)旋蒸除去甲醇，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤，减压除去溶剂获得3-((3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(7mg，36％yield)。
LC-MS(m/z)456.1(M+Na)
1H NMR(400MHz,DMSO-d 6)δ12.46(s,1H),10.53(s,1H),7.99–7.91(m,2H),7.81(s,1H),7.79(s,2H),7.53–7.45(m,3H),3.39(s,2H).
实施例11
3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸
Figure PCTCN2020088905-appb-000021
步骤1：制备2-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸甲酯(化合物26)
将3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯胺(100mg，0.274mmol)投入瓶中，加入二氯甲烷(3mL)，三乙胺(61mg，0.548mmol)，冰浴条件下滴加草酰氯单甲酯(50mg，0.328mmol)，室温反应20min，反应液加水淬灭，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩有机相，获得2-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸甲酯(100mg，81％yield)。
LC-MS(m/z)：452.5(M+1)
步骤2：制备3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸(实施例11)
将2-((3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸甲酯(100mg，0.223mmol)投入瓶中，加入醋酸钠(100mg，1.21mmol)，醋酸(2mL),120℃反应6h，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，合并有机相，真空浓缩除去溶剂，薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得3-((3,5-二氯-4-((6-氧代-5-苯基-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)-2-氧代乙酸(20mg，21％yield)。
LC-MS(m/z)：420.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.44(s,1H),10.60(s,1H),8.09(s,2H),7.95-7.92(m,2H),7.81(s,1H),7.50-7.46(m,3H).
实施例12
2-(3,5-二氯-4-((5-苯基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2020088905-appb-000022
步骤1：制备(2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(化合物27)
将3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯胺(100mg，0.274mmol)投入瓶中，加入盐酸(2.5mL)，水(5mL),冰浴条件下滴加亚硝酸钠(溶于0.2ml水中)(23mg，0.342mmol)，反应30分钟，LC-MS监控反应完全，冰浴条件下，将反应液加入氰基乙酰乙酸乙酯(47mg，0.301mmol)，吡啶(5mL)，水(8mL)中，反应30分钟，获得(2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(100mg，68％yield)。
LC-MS(m/z)：533.1(M+1)。
步骤2：制备2-(3,5-二氯-4-((5-苯基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(实施例12)
将(2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-苯基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(100mg，0.187mmol)投入瓶中，加入醋酸钠(100mg，1.22mmol)，醋酸(2mL)，120℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，合并有机相，真空浓缩除去溶剂，薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得2-(3,5-二氯-4-((5-苯基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(10mg，11％yield)。
LC-MS(m/z)469.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.48(s,1H),7.97-7.95(m,2H),7.88(s,1H),7.80(s,2H),7.53–7.44(m,3H).
实施例13
2-(3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2020088905-appb-000023
步骤1：制备4-(3,6-二氯哒嗪-4-基)吗啉(化合物29)
将3,4,6-三氯哌嗪(500mg,1.506mmol)，吡啶1.63g，4.518mmol),二异丙基乙胺(1mL)投入四氢呋喃(10mL)中，70℃反应6小时，加水稀释，乙酸乙酯萃取两遍，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/3]，获得4-(3,6-二氯哒嗪-4-基)吗啉(300mg，30％yield)。
LC-MS(m/z)：234.1(M+1)。
步骤2：制备3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯胺(化合物30)
将4-(3,6-二氯哒嗪-4-基)吗啉(300mg，1.287mmol)、2,6-二氯-4-氨基苯酚(117mg，1.544mmol)和无水碳酸铯(836mg，2.574mmol)投入N,N-二甲基甲酰胺(3mL)中，氮气保护，加热至90℃反应6小时，加水稀释，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/2]，获得3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯胺(200mg，41％yield)。
LC-MS(m/z)：375.2(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(化合物31)
将制备3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯胺(100mg，0.267mmol)投入瓶中，加盐酸(2.5mL)，水(5mL)，冰浴条件下滴加亚硝酸钠(溶于0.2ml水中)(22mg，0.334mmol)，继续反应30min，冰浴条件下，将反应液滴加入氰基乙酰乙酸乙酯(46mg，0.293mmol)，吡啶(2.5mL)，水(8mL)的混合液中，继续反应30分钟，析出大量固体，过滤，水洗，石油醚洗，获得(2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(100mg，69％yield)。
LC-MS(m/z)：542.3(M+1)。
步骤4：制备2-(3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(实施例13)
将2-氰基-2-(2-(3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(100mg，0.184mmol)投入瓶中，加入醋酸钠(100mg，1.22mmol)，醋酸(5mL),120℃反应6小时，旋蒸除去醋酸，加水(30mL)稀释，析出固体，过滤，滤饼用醋酸：水＝1:1洗涤，薄层层析分离[乙酸乙酯/石油醚＝1/1]，获得2-(3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(10mg，11％yield)。
LC-MS(m/z)：478.6(M+1)。
1H NMR(400MHz,DMSO-d 6)δ11.76(s,1H),7.78(s,2H),6.12(s,1H),3.77-3.74(m,4H),3.38-3.36(m,4H).
实施例14
3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸
Figure PCTCN2020088905-appb-000024
步骤1：制备3-((3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物32)
将3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯胺(100mg，0.267mmol)投入丙烯酸甲酯(2mL)中，100℃加一滴三氟乙酸，反应24小时后，加入二氯甲烷(20mL)，浓缩溶剂，薄层层析分离[乙酸乙酯/石油醚＝1/3]，获得3-((3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(75mg，69％yield)。
LC-MS(m/z)475.2(M+1)
步骤2：制备3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物33)
将3-((3,5-二氯-4-((6-氯-5-吗啉基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(75mg，0.158mmol)投入瓶中，加入醋酸钠(70mg，0.853mmol)，醋酸(3mL)，100℃反应6小时，旋蒸除去醋酸，加水稀释，乙酸乙酯萃取，浓缩有机相后,薄层层析分离，获得3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(10mg，13％yield)。
LC-MS(m/z)：457.3(M+1)。
步骤3：制备3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(实施例14)
将3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(10mg，0.022mmol)投入瓶中，加入甲醇(4mL)，1N NaOH(1mL)，50℃反应30分钟，LC-MS监控反应完全，旋蒸除去甲醇，加水稀释，乙酸乙酯萃取，丢弃有机相，水相调pH至5-6，乙酸乙酯萃取，水洗一遍，饱和食盐水洗一遍，真空浓缩，薄层层析分离，获得3-((3,5-二氯-4-((5-吗啉-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(2mg，22％yield)。
LC-MS(m/z)：428.9(M+1)。
实施例15
2-(3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2020088905-appb-000025
步骤1：制备3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯胺(化合物35)
将3,6-二氯-4,5-二甲基哒嗪(1g，5.71mmol)、2,6-二氯-4-氨基苯酚(1.11g，6.28mmol)无水碳酸铯(3.71g，11.42mmol)投入N,N-二甲基甲酰胺(10mL)中，氮气保护，加热至90℃反应6小时，加水稀释，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压除去溶剂得到残留物，然后柱层析分离[乙酸乙酯/石油醚＝1/2]，获得3,5-二氯-4-((6-氯-5-异丙基哒嗪-3-基)氧基)苯胺(300mg，16％yield)。
LC-MS(m/z)：318.6(M+1)。
步骤2：制备(2-氰基-2-(2-(3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(化合物36)
将3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯胺(100mg，0.316mmol)投入瓶中，加入盐酸(2.5mL)，水(5mL)，冰浴条件下滴加亚硝酸钠(溶于0.2ml水中)(27mg，0.348mmol)，反应30分钟，冰浴条件下，将反应液加入氰基乙酰乙酸乙酯(54mg，0.347mmol)，吡啶(2.5mL)，水8mL)体系中，反应30分钟，析出大量固体，过滤，水洗，石油醚洗，获得(2-氰基-2-(2-(3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(53mg，34％yield)。
LC-MS(m/z)：485.3(M+1)。
步骤3：制备2-(3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(实施例15)
将(2-氰基-2-(2-(3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)亚肼基)乙酰基)氨基甲酸乙酯(53mg，0.109mmol)投入瓶中，加入醋酸钠(53mg，0.547mmol)，醋酸(3mL),120℃反应6小时，旋蒸除去醋酸，加水(30mL)稀释，析出固体，过滤，滤饼用醋酸：水＝1:1洗涤，薄层层析分离，获得2-(3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(10mg，21％yield)。
LC-MS(m/z)：20.8(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.12(s,1H),7.78(s,2H),2.29(s,3H),2.11(s,3H).
实施例16
3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸
Figure PCTCN2020088905-appb-000026
步骤1：制备3-((3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物37)
将3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯胺(100mg，0.316mmol)投入丙烯酸甲酯(2mL)中，100℃加一滴三氟乙酸，4小时后，加入二氯甲烷(20mL)，直接浓缩溶剂，薄层层析分离，获得3-((3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(54mg，40％yield)。
LC-MS(m/z)：418.2(M+1)。
步骤2：制备3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(化合物38)
将3-((3,5-二氯-4-((6-氯-4,5-二甲基哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(54mg，0.129mmol)投入瓶中，加入醋酸钠(60mg，0.647mmol)，醋酸(3mL),120℃反应6小时，旋蒸除去醋酸，加水(30mL)稀释，乙酸乙酯萃取，浓缩有机相，薄层层析分离，获得3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(20mg，23％yield)。
LC-MS(m/z)：400.2(M+1)。
步骤3：制备3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(实施例16)
将3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸乙酯(20mg，0.040mmol)投入瓶中，加入甲醇(8mL)，1N NaOH(2mL)，50℃反应30分钟，旋蒸除去甲醇，乙酸乙酯萃取，水相调pH至5-6，析出固体，过滤，水洗获得3-((3,5-二氯-4-((4,5-二甲基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)氨基)丙酸(10mg，67％yield)。LC-MS(m/z)：371.9(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.00(s,1H),6.69(s,2H),3.24(t,J＝6.6Hz,2H),2.45(t,J＝6.6Hz,1H),2.23(s,3H),2.08(s,3H).
实施例17
2-(3,5-二氯-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2020088905-appb-000027
步骤1：制备3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(化合物40)
将4-氨基-2,6-二氯苯酚(187mg，1.05mmol)和1,4-二氯酞嗪(199mg，1mmol)溶于乙腈(5ml)中，再加入碳酸铯(815mg，2.5mmol)，加料完毕，加热搅拌升温至90℃，反应3小时，停止加热，趁热过滤，滤液减压除去溶剂得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/2)，得3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(243mg，71.1％yield)。
LC-MS(m/z)：341.6(M+1)。
步骤2：制备(2-氰基-2-(2-(3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(化合物41)
将3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(100mg，0.3mmol)溶于盐酸(2.5ml)和水(2.5ml)的溶液中，冰水浴冷却降温至5℃，再滴加入亚硝酸钠(25mg，0.36mmol)的水溶液，保温反应30分钟，制得反应母液。将氰基乙酰乙酸乙酯(50mg，0.32mmol)溶于吡啶(2.5ml)和水(2.5ml)的溶液中，冰水浴冷却降温至5℃，然后将上述制得的反应母液滴加入体系中，滴加完毕，溶液变成橙色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到(2-氰基-2-(2-(3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(78mg，51.2％yield)。
LC-MS(m/z)：508.7(M+1)。
步骤3：制备2-(3,5-二氯-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(实施例17)
室温下，将(2-氰基-2-(2-(3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(78mg，0.15mmol)溶于5ml乙酸中，再加入醋酸钠(123mg，1.5mmol)，升温至100℃搅拌反应6小时，停止加热。冷却至室温，加入冰水，碳酸钠调PH至8，加入乙酸乙酯萃取，有机相再用饱和氯化钠饱和溶液洗涤，合并有机相干燥，过滤，减压除去溶剂得到2-(3,5-二氯-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(11mg，16.3％yield)。
LC-MS(m/z)：444.2(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.01(s,1H),8.31(d,J＝8.0Hz,1H),8.27(d,J＝8.0Hz,1H),8.08(t,J＝7.6Hz,1H),8.02(t,J＝7.6Hz,1H),7.82(s,2H).
实施例18
2-(3,5-二溴-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈
Figure PCTCN2020088905-appb-000028
步骤1：制备4-氨基-2,6-二溴苯酚(化合物43)
将4-硝基-2,6-二溴苯酚(2.97g，10mmol)溶于乙醇(15ml)和水(3ml)中，再加入乙酸(1ml)。然后加热搅拌升温至80℃，分批加入铁粉(1.68g，30mmol)。加料完毕，该反应液继续保温反应30分钟，停止加热，趁热过滤，滤液减压浓缩，然后向浓缩残留物中加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)，获得4-氨基-2,6-二溴苯酚(2.52g，94.4％yield)。
LC-MS(m/z)：267.9(M+1)。
步骤2：制备3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺(化合物44)
将4-氨基-2,6-二溴苯酚(280mg，1.05mmol)和1,4-二氯酞嗪(199mg，1mmol)溶于N,N-二甲基甲酰胺(5ml)中，再加入碳酸钾(345mg，2.5mmol)和碘化亚铜(90mg，0.5mmol)。加料完毕，反应体系氮气置换保护，加热搅拌升温至80℃，反应2小时，停止加热，趁热过滤，向滤液加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/2)，获得3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺(247mg，57.5％yield)。
LC-MS(m/z)：430.5(M+1)。
步骤3：制备(2-氰基-2-(2-(3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(化合物45)
将3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺(100mg，0.24mmol)溶于盐酸(2.5ml)和水(2.5ml)的溶液中，冰水浴冷却降温至5℃，再滴加入亚硝酸钠(20mg，0.29mmol)的水溶液，保温反应30分钟，制得反应母液。将氰基乙酰乙酸乙酯(39mg，0.25mmol)溶于吡啶(2.5ml)和水(2.5ml)的溶液中，冰水浴冷却降温至5℃，然后将上述制得的重氮盐反应母液滴加入体系中，滴加完毕，溶液变成橙色析出固体，继续保温反应1小时。向反应液中加入少量的水，搅拌，抽滤，滤渣用水洗涤。烘干固体，得到(2-氰基-2-(2-(3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(74mg，53.9％yield)。
LC-MS(m/z)：597.6(M+1)。
步骤4：制备2-(3,5-二溴-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(实施例18)
室温下，将(2-氰基-2-(2-(3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)-亚肼基)-乙酰基)-氨基甲酰乙酯(74mg，0.12mmol)溶于5ml乙酸中，再加入醋酸钠(98mg，1.2mmol)，升温至100℃搅拌反应6小时，停止加热。冷却至室温，加入冰水，碳酸钠调PH至8，加入乙酸乙酯萃取，有机相再用饱和氯化钠饱和溶液洗涤，合并有机相干燥，过滤，减压除去溶剂，柱层析分离(甲醇/二氯甲烷＝1/20)，获得2-(3,5-二溴-4-((4-氧基-3,4-二氢酞嗪-1-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(16mg，25.1％yield)。
LC-MS(m/z)：533.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.03(s,1H),8.32(d,J＝8.0Hz,1H),8.26(d,J＝8.0Hz,1H),8.10(t,J＝7.6Hz,1H),8.03(t,J＝7.6Hz,1H),7.96(s,2H).
实施例19
3-((3,5-二氯-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸
Figure PCTCN2020088905-appb-000029
步骤1：制备3-((3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(化合物46)
将3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(68mg，0.2mmol)溶于四氢呋喃(5ml)中，再加入N,N-二异丙基乙胺(78mg，0.6mmol)。然后冰水浴降温至5℃，再加入氯甲酰乙酸乙酯(45mg，0.3mmol)。加料完毕，升温至室温搅拌反应1小时。原料反应完全，加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得3-((3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(73mg，80.4％yield)。
LC-MS(m/z)：454.7(M+1)。
步骤2：制备3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(化合物47)
室温下，将3-((3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(73mg，0.17mmol)溶于乙酸(5ml)中，再加入醋酸钠(41mg，0.5mmol)，升温至100℃搅拌反应6小时，停止加热。冷却至室温，加入冰水，碳酸钠调pH至8，加入乙酸乙酯萃取，有机相再用饱和氯化钠饱和溶液洗涤，合并有机相干燥，过滤，减压除去溶剂得到残留物，柱层析分离(乙酸乙酯/石油醚＝2/1)，获得3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(36mg，48.7％yield)。
LC-MS(m/z)：436.2(M+1)。
步骤3：制备3-((3,5-二氯-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸(实施例19)
将3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(36mg，0.08mmol)溶于甲醇(3ml)中，再加入1mol/L的氢氧化钠水溶液(1ml)，升温至80℃搅拌反应2小时。停止加热，减压浓缩蒸出甲醇，加入水和乙酸乙酯萃取，取水层。再用1mol/L的盐酸调PH至4，析出白色固体，过滤获得3-((3,5-二氯-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸(19mg，57.5％yield)。
LC-MS(m/z)：408.2(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.77(s,1H),11.98(s,1H),10.54(s,1H),8.30(d,J＝8.0Hz,1H),8.23(d,J＝8.0Hz,1H),8.07(t,J＝7.6Hz,1H),8.01(t,J＝7.6Hz,1H),7.81(s,2H),3.40(s,2H).
实施例20
3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸
Figure PCTCN2020088905-appb-000030
步骤1：制备3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(化合物48)
将3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(68mg，0.2mmol)溶于丙烯酸乙酯(5ml)，加入1滴三氟乙酸，然后升温至110℃搅拌反应25小时，停止加热。加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，柱层析分离(乙酸乙酯/石油醚＝1/3)。得3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(35mg，41.4％yield)。
LC-MS(m/z)：423.3(M+1)。
步骤2：制备3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸(实施例20)
将3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(35mg，0.08mmol)溶于甲醇(3ml)中，再加入1mol/L的氢氧化钠水溶液(1ml)，升温至80℃搅拌反应2小时。停止加热，减压浓缩蒸出甲醇，加入水和乙酸乙酯萃取，取水层。再用1mol/L的盐酸调PH至4，析出白色固体，过滤，用水洗涤滤饼，获得3-((3,5-二氯-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸(13mg，41.3％yield)。
LC-MS(m/z)：395.2(M+1)。
实施例21
3-((3,5-二溴-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸
Figure PCTCN2020088905-appb-000031
步骤1：制备3-((3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(化合物49)
将3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺(73mg，0.17mmol)溶于四氢呋喃(5ml)中，再加入N,N-二异丙基乙胺(65mg，0.5mmol)。然后冰水浴降温至5℃，再加入氯甲酰乙酸乙酯(38mg，0.25mmol)。加料完毕，升温至室温搅拌反应1小时。原料反应完全，加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，最后柱层析分离(乙酸乙酯/石油醚＝1/3)。得3-((3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(75mg，81.1％yield)。
LC-MS(m/z)：544.6(M+1)。
步骤2：制备3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(化合物50)
室温下，将3-((3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯
(75mg，0.14mmol)溶于乙酸(5ml)中，再加入醋酸钠(41mg，0.5mmol)，升温至100℃搅拌反应6小时，停止加热。冷却至室温，加入冰水，碳酸钠调PH至8，加入乙酸乙酯萃取，有机相再用饱和氯化钠饱和溶液洗涤，合并有机相干燥，过滤，减压除去溶剂得到残留物，柱层析分离(乙酸乙酯/石油醚＝2/1)，得3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(41mg，55.7％yield)。
LC-MS(m/z)：526.2(M+1)。
步骤3：制备3-((3,5-二溴-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸(实施例21)
将3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸乙酯(41mg，0.08mmol)溶于甲醇(3ml)中，再加入1mol/L的氢氧化钠水溶液(1ml)，升温至80℃搅拌反应2小时。停止加热，减压浓缩蒸出甲醇，加入水和乙酸乙酯萃取，取水层。再用1mol/L的盐酸调pH至4，过滤获得3-((3,5-二溴-4-((4-氧-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)-3-氧代丙酸(23mg，57.7％yield)。
LC-MS(m/z)：498.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.76(s,1H),11.98(s,1H),10.51(s,1H),8.30(d,J＝8.0Hz,1H),8.23(d,J＝8.0Hz,1H),8.07(t,J＝7.6Hz,1H),8.01(t,J＝7.6Hz,1H),7.97(s,2H),3.39(s,2H).
实施例22
3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸
Figure PCTCN2020088905-appb-000032
步骤1：制备3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(化合物51)
将3,5-二溴-4-((4-氯酞嗪-1-基)氧基)苯胺(73mg，0.17mmol)溶于丙烯酸乙酯(5ml)，加入1滴三氟乙酸，然后升温至110℃搅拌反应25小时，停止加热。加入乙酸乙酯和水萃取，合并有机相干燥，过滤，减压除去溶剂得到残留物，柱层析分离(乙酸乙酯/石油醚＝1/3)。得3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(32mg，36.8％yield)。
LC-MS(m/z)：512.1(M+1)。
步骤2：制备3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸(实施例22)
将3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸乙酯(32mg，0.06mmol)溶于甲醇(3ml)中，再加入1mol/L的氢氧化钠水溶液(1ml)，升温至80℃搅拌反应2小时。停止加热，减压浓缩蒸出甲醇，加入水和乙酸乙酯萃取，取水层。再用1mol/L的盐酸调pH至4，过滤得3-((3,5-二溴-4-((4-氧代-3,4-二氢酞嗪-1-基)氧基)苯基)氨基)丙酸(16mg，55.2％yield)。
LC-MS(m/z)：484.1(M+1)。
1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.31(d,J＝8.0Hz,1H),8.19(d,J＝8.0Hz,1H),8.07-7.98(m,2H),6.89(s,2H),5.61(brs,2H),4.09(t,J＝7.2Hz,2H).
实施例23
人类甲状腺激素受体α1(TRα1)和β1(TRβ1)的转录活化实验
使用X-tremeGENE HP DNA Transfection Reagent(由Roche制造)将来自人体肝脏的细胞克隆的TRα1或TRβ1的pcDNA3.1载体(由Invitrogen制造)和具有甲状腺激素响应序列的萤火虫荧光素酶载体pTA-TRE-Luc(由Promega制造)转染至达尔伯克氏伊格尔培养基(Dulbecco’s modified Eagle medium，DMEM)中培养的CV-1细胞中。转染16小时后，添加用二甲亚砜溶液稀释的化合物，并测量24小时后荧光素酶的活性。
使用3,3’,5-三碘代-L-甲状腺素(T 3)作为阳性对照，所述化合物在TRα1和TRβ1上的转录活化作用通过相对于T 3的最大荧光素酶活性值为100的各EC 50值和最大荧光素酶的活性值示出。结果示于下表1中。
表1
Figure PCTCN2020088905-appb-000033
Figure PCTCN2020088905-appb-000034
表中，选择性(TRα/TRβ)表示为：
A：5<(TRα/TRβ)
B：2<(TRα/TRβ)<5
C：2>(TRα/TRβ)
转录活化实验结果表明，本发明实施例化合物能实现对甲状腺激素受体β的激动活性，其中是实施例4、5、6、18和19能选择性地激动甲状腺激素受体β。
产业上的可应用性
本发明的哒嗪酮类化合物具有良好的甲状腺激素β受体激动活性，可成为治疗或预防与该作用相关的疾病的药物。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 一种哒嗪酮衍生物，具有式(I)所示结构：
    Figure PCTCN2020088905-appb-100001
    其中：
    X为-CH 2-或-O-；
    R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
    R 3、R 4独立地选自氢、卤素、C1～C6的烷基、-OR 5、-NR 5R 6、-CONR 5R 6、C6～C10的芳基或C5～C10的杂芳基，且R 3、R 4不同时为氢；其中，R 5和R 6各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5～C10的杂芳基，或者R 5和R 6与它们相连的原子一起形成3～7元的饱和环基；
    或R 3和R 4与它们相连的碳原子及键一起形成4～7元的饱和环、4～7元的部分饱和的环或4～7元的不饱和环；
    Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)、或式(Y-14)，
    Figure PCTCN2020088905-appb-100002
    Z选自-O-、-NR 9-或-(CH 2)-O-；
    W选自C或SO；
    n是1、2或3；
    m是0、1、2或3；
    R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
    R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5～C10的杂芳基甲酰基。
  2. 根据权利要求1所述的哒嗪酮衍生物，其特征在于，所述Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)时，所述R 3为-NR 5R 6、C6～C10的芳基、C5-C10的杂芳基、-OR 5或-CONR 5R 6，所述R 4为氢、C1～C6的烷基、-NR 5R 6、C6～C10的芳基、C5～C10的杂芳基、-OR 5或-CONR 5R 6；
    或者所述R 3和所述R 4与它们相连的碳原子一起形成C6～C10的芳环、C5～C10的杂芳环或C5～C8的环烷基、吗啉环、哌啶环、N-甲基哌啶环或吡喃环。
  3. 根据权利要求2所述的哒嗪酮衍生物，其特征在于，所述R 3为苯基、吡啶基、呋喃基、吡喃基、哌啶基、N-甲基哌啶基、二甲基氨基、异丙基氨基、N-甲基-N-乙基氨基、二异丙基氨基、甲氧基、乙氧基、异丙氧基、N,N-二甲基甲酰基或吗啉基；
    所述R 4为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、苯基、吡啶基、呋喃基、吡喃基或吗啉基。
  4. 根据权利要求2所述的哒嗪酮衍生物，其特征在于，所述R 3和R 4与它们相连的碳原子一起形成苯环、呋喃环、吡咯环、N-甲基吡咯环、环戊烷、环己烷、吗啉环、哌啶环、N-甲基哌啶环、吡喃环、吡啶环、哒嗪环或吡嗪环。
  5. 根据权利要求2所述的哒嗪酮衍生物，其特征在于，所述哒嗪酮衍生物为式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-6)、式(I-7)、式(I-8)、式(I-9)式(I-10)、式(I-11)、式(I-12)或式(I-13)，
    Figure PCTCN2020088905-appb-100003
    其中，X为-CH 2-或-O-；
    R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
    Y选自式(Y-1)、式(Y-2)、式(Y-3)、式(Y-4)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)、或式(Y-14)，
    Figure PCTCN2020088905-appb-100004
    Z选自-O-、-NR 9-或-(CH 2)-O-；
    W选自C或SO；
    n是1、2或3；
    m是0、1、2或3；
    R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
    R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5-C10的杂芳基甲酰基。
  6. 根据权利要求1所述的哒嗪酮衍生物，其特征在于，所述Y选自式(Y-2)、式(Y-3)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)时，所述R 4为氢或C1～C6的烷基，且R 3为C1～C6的烷基。
  7. 根据权利要求6所述的哒嗪酮衍生物，其特征在于，所述R 4为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或正己基；
    所述R 3为甲基、乙基、正丙基、环丙基、异丙基、正丁基、环丁基、异丁基、叔丁基、正戊基、环戊基、异戊基或正己基。
  8. 根据权利要求6所述的哒嗪酮衍生物，其特征在于，所述哒嗪酮衍生物为式(I-14)、式(I-15)、式(I-16)、式(I-17)、式(I-18)、式(I-19)、式(I-20)或式(I-21)，
    Figure PCTCN2020088905-appb-100005
    Figure PCTCN2020088905-appb-100006
    其中，X为-CH 2-或-O-；
    R 1、R 2独立地选自Cl、Br或C1～C6的烷基；
    Y选自式(Y-2)、式(Y-3)、式(Y-5)、式(Y-6)、式(Y-7)、式(Y-8)、式(Y-9)、式(Y-10)、式(Y-11)、式(Y-12)、式(Y-13)或式(Y-14)，
    Figure PCTCN2020088905-appb-100007
    Z选自-O-、-NR 9-或-(CH 2)-O-；
    W选自C或SO；
    n是1、2或3；
    m是0、1、2或3；
    R 7和R 8各自独立地选自氢、C1～C6的烷基、C6～C10的芳基或C5-C10的杂芳基，或者R 7和R 8与它们相连的原子一起形成3～6元的饱和环或3～6元的部分饱和的环；
    R 9选自氢、C1～C6的烷基、C1～C6的烷基甲酰基、C6～C10的芳基甲酰基或C5-C10的杂芳基甲酰基。
  9. 根据权利要求1所述的哒嗪酮衍生物，其特征在于，所述哒嗪酮衍生物的具体结构如下。
    Figure PCTCN2020088905-appb-100008
  10. 一种权利要求1～9任意一项所述的哒嗪酮衍生物在制备激动甲状腺激素β受体的激动剂中的应用。
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