WO2021057791A1 - 一种作为甲状腺激素Beta受体激动剂的化合物及其用途 - Google Patents

一种作为甲状腺激素Beta受体激动剂的化合物及其用途 Download PDF

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WO2021057791A1
WO2021057791A1 PCT/CN2020/117131 CN2020117131W WO2021057791A1 WO 2021057791 A1 WO2021057791 A1 WO 2021057791A1 CN 2020117131 W CN2020117131 W CN 2020117131W WO 2021057791 A1 WO2021057791 A1 WO 2021057791A1
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alkyl
group
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dichloro
cooh
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PCT/CN2020/117131
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French (fr)
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顾峥
黎健豪
邓新山
李峥
陈道乾
邓建超
吕爱贞
刘建余
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广东东阳光药业有限公司
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Priority to JP2022518790A priority Critical patent/JP2022549009A/ja
Priority to EP20869854.8A priority patent/EP4036090A4/en
Priority to US17/763,578 priority patent/US20220411400A1/en
Publication of WO2021057791A1 publication Critical patent/WO2021057791A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a compound as a thyroid hormone Beta receptor agonist and its use, and further relates to a pharmaceutical composition containing the compound.
  • the present invention further relates to the use of the compound and the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of diseases mediated by activated thyroid hormone beta receptors, in particular to the preparation for the treatment of non-alcoholic fatty liver disease Use in medicines.
  • Thyroid hormone plays an extremely important role in growth, differentiation, development and maintenance of metabolic balance. Thyroid hormones are synthesized by the thyroid gland and secreted into the circulatory system in two main forms: triiodothyronine (T3) and tetraiodothyronine (T4). Although T4 is the main form secreted by the thyroid, 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 liver and kidney.
  • TR thyroid hormone receptor
  • TR belongs to the nuclear receptor superfamily. It is a transcription factor induced by ligand T3 and plays a central role in mediating the action of ligand T3.
  • TR is mainly located in the nucleus and forms a heterodimer with the retinoic X receptor (RXR) and other nuclear receptors and binds to the thyroid hormone response element (TRE) in the promoter region of the target gene. , Thereby regulating gene transcription.
  • TR ⁇ and TR ⁇ There are two subtypes of TR: TR ⁇ and TR ⁇ . TR ⁇ can be divided into TR ⁇ 1 and TR ⁇ 2, and TR ⁇ can be divided into TR ⁇ 1 and TR ⁇ 2.
  • TR ⁇ mainly regulates heart rate, and TR ⁇ plays a key role in controlling liver cholesterol metabolism and inhibiting the release of thyroid-stimulating hormone (TSH), which may be related to the high expression of TR ⁇ in the liver and pituitary gland.
  • TSH thyroid-stimulating hormone
  • thyroid hormone has certain therapeutic benefits (Paul M. Yen et al. Physiological Reviews, Vol. 81(3): pp. 1097-1126 (2001); Paul Webb et. al. Expert Opin. Investig. Drugs, Vol. 13(5): pp.489-500(2004)).
  • thyroid hormones can increase metabolic rate, oxygen consumption, and calorie production, thereby reducing weight. Reducing body weight will improve obesity-related comorbidities and have a beneficial effect on obese patients, and may also have a beneficial effect on blood sugar control in obese patients with type 2 diabetes.
  • Thyroid hormones can also reduce serum low-density lipoprotein (LDL) (Eugene Morkin et al. Journal of Molecular and Cellular Cardiology, Vol. 37: pp. 1137-1146 (2004)). It has been found that hyperthyroidism is associated with low total serum cholesterol, which is due to thyroid hormones increasing liver LDL receptor expression and stimulating the metabolism of cholesterol to bile acids (JJ. Abrams et. al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). Hypothyroidism is related to hypercholesterolemia, and there have been reports that thyroid hormone replacement therapy reduces total cholesterol (M. Aviram et. al. Clin. Biochem., Vol. 15: pp.
  • LDL serum low-density lipoprotein
  • thyroid hormones have been shown to have the beneficial effects of increasing HDL cholesterol and increasing the expression of apo A-1 (one of the major apoproteins of HDL) to increase the conversion rate of LDL to HDL (Gene C. Ness et.al.Biochemical Pharmacology,Vol.56:pp.121-129(1998); GJ.Grover et.al.Endocrinology,Vol.145:pp.1656-1661(2004); GJ.Grover et.al.Proc . Natl. Acad. Sci. USA, Vol. 100: pp.
  • non-alcoholic fatty liver disease is also closely related to thyroid hormones.
  • NAFLD non-alcoholic fatty liver disease
  • studies have shown that the formation of fatty liver in rats is induced by choline-methionine deficiency diet, and the reversal of fatty liver can be observed after feeding T3 (Perra A, et al. Faseb, 2008, 22(8):2981).
  • thyroid hormone analogs such as thyroid hormone beta receptor agonists
  • hyperthyroidism especially side effects related to cardiovascular toxicity
  • cardiovascular disease especially side effects related to cardiovascular toxicity
  • hypothyroidism thyroid cancer
  • thyroid disease and related conditions and diseases.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone ⁇ receptors.
  • Such compounds and their compositions can be prepared for the prevention, treatment or alleviation of patients with non-alcoholic fatty liver disease, atherosclerosis, Coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer drug.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, or solvate of a compound represented by formula (I) , Metabolites, pharmaceutically acceptable salts or their prodrugs,
  • Each R a, R b, R c , R d and R e are independently H, deuterium, F, Cl, Br, I , -CN, -NO 2, -COOH, -OH, -NH 2, -SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy;
  • R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, C 1- 6 alkyl amino C 1-6 alkyl group or a cyano group;
  • E 1 is N, CH or CR z , where R z is deuterium , F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, 3-8 atoms heterocyclyl, (heterocyclyl 3-8 atoms) C 1- 6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, Heteroaryl group consisting of 5-10 atoms or (heter
  • E 2 is CR 2 ;
  • E 3 is N or CR 3 ;
  • R 2 and R 3 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 haloalkoxy, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3 -8 cycloalkyl C 1-6 alkyl, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, 5-10 heteroaryl or (5-10 heteroaryl) C 1-6 alkyl;
  • R 5 is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, C 6- 10 aryl groups or heteroaryl groups composed of 5-6 atoms.
  • R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.
  • each R a, R b, R c , R d and R e are independently H, deuterium, F, Cl, Br, I , -CN, -NO 2, -COOH, -OH, - NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 or trifluoromethyl Oxy.
  • R z is deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, N-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, C 2 -4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-3 alkyl, 5-6 Heterocyclic group consisting of atoms, (heterocyclic group consisting of 5-6 atoms) C 1-3 alkyl, phenyl, phenylmethyl, phenylethyl, pyridyl,
  • R 2 and R 3 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl Group, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-3 alkyl, 5- 6-atom heterocyclic group, (5-6 atom heterocyclic group) C 1-3 alkyl, phenyl, phenylmethyl, phenylethyl, pyridyl, pyrimidinyl, pyrida
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention, and optionally, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or Any combination of them.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used for stimulating thyroid hormone receptor; or for preventing, treating or alleviating A disease mediated by activation of thyroid hormone receptors.
  • the thyroid hormone receptor of the present invention is a thyroid hormone beta receptor.
  • the diseases mediated by activation of thyroid hormone receptors of the present invention are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, and hyperlipidemia.
  • the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, cryptogenic liver cirrhosis, or primary liver cancer.
  • the metabolic disorder described in the present invention is a lipid metabolism disorder or a glucose metabolism disorder.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone beta receptors and a preparation method thereof, a pharmaceutical composition containing the compound and uses thereof.
  • the articles “a”, “an” and “said” used herein are intended to include “at least one” or “one or more.” Therefore, the articles used herein refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, that is, more than one component may be considered to be adopted or used in the embodiment of the described embodiment.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • a class of compounds can be used interchangeably.
  • the term “optional”, “optional” or “optional” means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs, and the event in which the event does not occur Or the condition of the situation.
  • an optional substituent group can be substituted at each substitutable position of the group.
  • substituents When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
  • C 1-6 alkyl specifically refers to independently disclosed C 1 alkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl
  • C 3-8 cycloalkyl especially refers to independently disclosed C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl and C 8 Cycloalkyl
  • 5-8 atom heteroaryl group refers to a 5-atom heteroaryl group, 6-atom heteroaryl group, 7-atom heteroaryl group and 8 ring atoms Heteroaryl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl or “alkyl group” refers to a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group may optionally be One or more substituents described in the present invention are substituted.
  • the alkyl group contains 1-10 carbon atoms, that is, C 1-10 alkyl; in some embodiments, the alkyl group contains 1-8 carbon atoms, that is, C 1-8 alkane In some embodiments, the alkyl group contains 1-6 carbon atoms, that is, C 1-6 alkyl; in some embodiments, the alkyl group contains 1-4 carbon atoms, that is, C 1- 4 alkyl; in some embodiments, the alkyl group contains 1-3 carbon atoms, that is, C 1-3 alkyl; in some embodiments, the alkyl group contains 1-2 carbon atoms, that is, C 1- 2 Alkyl.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which at least one site of unsaturation is a carbon-carbon sp 2 double bond, wherein the alkenyl group can be any Optionally substituted by one or more substituents described in the present invention, including the positioning of "cis” and “trans”, or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms, ie C 2-8 alkenyl; in some embodiments, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 alkenyl Group; In some embodiments, the alkenyl group contains 2-4 carbon atoms, ie C 2-4 alkenyl.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which at least one unsaturation site is a carbon-carbon sp triple bond, wherein the alkynyl group may optionally Ground is substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms, ie C 2-8 alkynyl; in some embodiments, the alkynyl group contains 2-6 carbon atoms, ie C 2-6 alkyne In some embodiments, an alkynyl group contains 2-4 carbon atoms, ie, C 2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ CH-CH 3 ), propargyl (-CH 2 C ⁇ CH), 1-butynyl Alkynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and so on.
  • alkoxy refers to an alkyl group connected to the rest of the molecule through an oxygen atom, that is, -O-alkyl, where the alkyl group has the meaning as described in the present invention, wherein the alkoxy group Groups can be optionally substituted with one or more substituents described in this invention.
  • the alkoxy group contains 1-8 carbon atoms, that is, C 1-8 alkoxy; in some embodiments, the alkoxy group contains 1-6 carbon atoms, that is, C 1 -6 alkoxy; in some embodiments, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 alkoxy; in some embodiments, the alkoxy group contains 1-3 The carbon atom is a C 1-3 alkoxy group; in some embodiments, the alkoxy group contains 1-2 carbon atoms, which is a C 1-2 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), n-propyloxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), isopropyloxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-isopropyloxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 3
  • alkylamino includes “N-alkylamino” and “N,N-dialkylamino”, which means that the amino group is independently substituted with one or two alkyl groups, and the alkyl group has the nature The definition of the invention. Wherein, the alkylamino group may be optionally substituted by one or more substituents described in the present invention.
  • the alkylamino group is an alkylamino group with one or two C 1-6 alkyl groups attached to the nitrogen atom, that is, C 1-6 alkylamino; in some embodiments, the alkylamino group is one or two An alkylamino group in which a C 1-4 alkyl group is attached to the nitrogen atom, that is, a C 1-4 alkylamino group; in some embodiments, the alkylamino group is one or two C 1-2 alkyl groups attached to the nitrogen atom The alkylamino group, that is, C 1-2 alkylamino.
  • alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), dimethylamino (N,N-dimethylamino), diethylamino (N, N-diethylamino), n-propylamino (N-n-propylamino), isopropylamino (N-isopropylamino), tert-butylamino (N-tert-butylamino) and so on.
  • alkylthio refers to an alkyl group connected to the rest of the molecule through a sulfur atom, that is, -S-alkyl, wherein the alkyl group has the meaning as described in the present invention, wherein the alkylthio group Groups can be optionally substituted with one or more substituents described in this invention.
  • the alkylthio group contains 1-8 carbon atoms, that is, C 1-8 alkylthio; in some embodiments, the alkylthio group contains 1-6 carbon atoms, that is, C 1 -6 alkylthio; in some embodiments, the alkylthio group contains 1-4 carbon atoms, that is, C 1-4 alkylthio; in some embodiments, the alkylthio group contains 1-3 The carbon atom is a C 1-3 alkylthio group; in some embodiments, the alkylthio group contains 1-2 carbon atoms, which is a C 1-2 alkylthio group. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described in the present invention.
  • the haloalkyl group contains 1-10 carbon atoms, that is, C 1-10 haloalkyl; in some embodiments, the haloalkyl group contains 1-8 carbon atoms, that is, C 1-8 haloalkyl
  • the haloalkyl group contains 1-6 carbon atoms, that is, C 1-6 haloalkyl; in some embodiments, the haloalkyl group contains 1-4 carbon atoms, that is, C 1- 4 haloalkyl; in some embodiments, the haloalkyl group contains 1-3 carbon atoms, that is, C 1-3 haloalkyl; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, that is C 1-2 halo
  • haloalkyl groups include, but are not limited to, fluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), fluoroethyl (-CHFCH 3 ,- CH 2 CH 2 F), difluoroethyl (-CF 2 CH 3 , -CFHCFH 2 , -CH 2 CHF 2 ), perfluoroethyl, fluoropropyl (-CHFCH 2 CH 3 , -CH 2 CHFCH 3 , -CH 2 CH 2 CH 2 F), difluoropropyl (-CF 2 CH 2 CH 3 , -CFHCFHCH 3 , -CH 2 CH 2 CHF 2 , -CH 2 CF 2 CH 3 , -CH 2 CHFCH 2 F) , Trifluoropropyl, 1,1-dichloroethyl, 1,2-dichloropropyl, etc.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen substituents, wherein the halogenated alkoxy group may be optionally substituted with one or more substituents described in the present invention .
  • the haloalkoxy group contains 1-10 carbon atoms, that is, C 1-10 haloalkoxy; in some embodiments, the haloalkoxy group contains 1-8 carbon atoms, that is, C 1 -8 haloalkoxy; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, that is, C 1-6 haloalkoxy; in some embodiments, the haloalkoxy group contains 1-4 A carbon atom, a C 1-4 haloalkoxy group; in some embodiments, a haloalkoxy group contains 1-3 carbon atoms, a C 1-3 haloalkoxy group; in some embodiments, a haloalkyl group Contain 1-2 carbon atom
  • hydroxyalkyl refers to an alkyl group substituted by one or more hydroxy groups (-OH), and the alkyl group has the meaning described in the present invention, wherein the hydroxyalkyl group may be optionally substituted by one or Multiple substituents described in this invention are substituted.
  • the hydroxyalkyl group described in the present invention refers to a C 1-6 alkyl group substituted by one or more hydroxy groups (-OH), that is, a hydroxy C 1-6 alkyl group; in some In embodiments, a hydroxyalkyl group refers to a C 1-4 alkyl group substituted with one or more hydroxyl groups (-OH), that is, a hydroxy C 1-4 alkyl group; in some embodiments, a hydroxyalkyl group The group refers to a C 1-2 alkyl group substituted with one or more hydroxy groups (-OH), that is, a hydroxy C 1-2 alkyl group.
  • hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH 2 OH), hydroxyethyl (e.g., 2-hydroxyethyl), hydroxy n-propyl (e.g., -CH 2 CH 2 CH 2 OH), etc.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups (-NH 2 ).
  • the alkyl group has the meaning described in the present invention, wherein the aminoalkyl group may optionally be substituted by one Or multiple substituents described in the present invention.
  • the aminoalkyl group described in the present invention refers to a C 1-6 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-6 alkyl group;
  • an aminoalkyl group refers to a C 1-4 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-4 alkyl group;
  • an amino group The alkyl group refers to a C 1-2 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-2 alkyl group.
  • aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), diaminomethyl (-CH(NH 2 ) 2 ), aminoethyl (e.g., 2-aminoethyl) , Amino n-propyl (for example, -CH 2 CH 2 CH 2 NH 2 ), and so on.
  • cyanoalkyl refers to an alkyl group substituted with one or more cyano groups (-CN), and the alkyl group has the meaning described in the present invention, wherein the cyanoalkyl group may optionally It is substituted by one or more substituents described in the present invention.
  • the cyanoalkyl group of the present invention refers to a C 1-6 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-6 alkyl group
  • a cyanoalkyl group refers to a C 1-4 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-4 alkyl group
  • the cyanoalkyl group refers to a C 1-2 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-2 alkyl group.
  • cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH 2 CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
  • carboxyalkyl refers to an alkyl group substituted with one or more carboxyl groups (-COOH), and the alkyl group has the meaning described in the present invention, wherein the carboxyalkyl group may optionally be substituted by one or Multiple substituents described in this invention are substituted.
  • the carboxyalkyl group of the present invention refers to a C 1-6 alkyl group substituted by one or more carboxy groups (-COOH), that is, a carboxy C 1-6 alkyl group; in some In embodiments, a carboxyalkyl group refers to a C 1-4 alkyl group substituted with one or more carboxy groups (-COOH), that is, a carboxy C 1-4 alkyl group; in some embodiments, a carboxyalkyl group The group refers to a C 1-2 alkyl group substituted with one or more carboxy groups (-COOH), that is, a carboxy C 1-2 alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and the like.
  • cycloalkyl refers to a monovalent or multivalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms, wherein the cycloalkyl group is optionally selected by the present invention The described substituents are substituted.
  • the cycloalkyl group is a ring system containing 3-10 ring carbon atoms, that is, a C 3-10 cycloalkyl group; in some embodiments, the cycloalkyl group is a ring system containing 3-8 ring carbon atoms.
  • the ring system is a C 3-8 cycloalkyl group; in some embodiments, the cycloalkyl group is a ring system containing 3-6 ring carbon atoms, that is, a C 3-6 cycloalkyl group.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Carbocyclyl refers to a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-14 ring carbon atoms.
  • the terms “carbocyclic”, “carbocyclic” or “carbocyclic” are used interchangeably herein.
  • the number of ring carbon atoms of the carbocyclic ring is 3-12, ie, C 3-12 carbocyclyl; in some embodiments, the number of ring carbon atoms of the carbocyclic ring is 3-10, ie C 3-10 carbocyclic group; in some embodiments, the number of carbocyclic ring carbon atoms is 3-8, that is, C 3-8 carbocyclic group; in some embodiments, the number of carbocyclic ring carbon atoms The number is 3-6, ie C 3-6 carbocyclyl; in some embodiments, the number of ring carbon atoms of the carbocyclic ring is 5-6, ie C 5-6 carbocyclyl; in some embodiments , The number of ring carbon atoms of the carbocyclic ring is 5-8, that is, C 5-8 carbocyclic group.
  • the number of ring carbon atoms of the carbocyclic ring is 6-8, that is, C6-8 carbocyclyl.
  • carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.3.1] Nonyl, bicyclo[3.2.3] Nonyl, etc.
  • heterocyclyl refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 atoms, in which at least one ring atom is selected from nitrogen, sulfur, oxygen and phosphorus Heteroatoms such as atoms, wherein the heterocyclic group is non-aromatic and does not contain any aromatic ring, and the heterocyclic group may be optionally substituted by one or more substituents described in the present invention .
  • heterocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems.
  • Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups and spiro bicyclic heterocyclic groups.
  • heterocyclyl and “heterocycle” are used interchangeably herein.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the phosphorus atom of the ring may optionally be oxidized to form a P-oxygen compound.
  • the heterocyclic group is a ring system composed of 3-10 atoms, that is, a heterocyclic group composed of 3-10 atoms; in some embodiments, a heterocyclic group is a ring composed of 5-10 atoms.
  • a heterocyclic group is a ring system consisting of 5-8 atoms, that is, a heterocyclic group consisting of 5-8 atoms; in some embodiments
  • a heterocyclic group is a ring system composed of 6-8 atoms, that is, a heterocyclic group composed of 6-8 atoms; in some embodiments, a heterocyclic group is a ring system composed of 5-6 atoms, that is, 5 -6-atom heterocyclic group; in some embodiments, the heterocyclic group is a 3-6-atom ring system, that is, a 3-6-atom heterocyclic group; in some embodiments, the heterocyclic group A group is a system composed of 3 ring atoms; in some embodiments, a heterocyclic group is a ring system composed of 4 atoms; in other embodiments, a heterocyclic group is a ring system composed of 5 atoms; in
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydrofuryl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetra Hydrothienyl, dihydrothienyl, tetrahydropyridyl, dihydropyridyl (for example, 1,2-dihydropyridyl, 1,4-dihydropyridyl), tetrahydropyrimidinyl, dihydropyrimidinyl, Tetrahydropyrazinyl, dihydropyrazinyl,
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. 1] Sinki, etc.
  • m typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is m.
  • piperidinyl is a 6-atom heterocyclic group
  • furyl is a 5-atom heteroaryl group.
  • heteroaryl group consisting of 5-8 atoms refers to a heteroaryl group consisting of 5, 6, 7, or 8 atoms.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring system containing 6-14 ring atoms, wherein each ring contains 3-7 ring atoms.
  • the aryl group contains a carbocyclic ring system of 6-12 ring atoms, that is, a C 6-12 aryl group.
  • the aryl group contains a carbocyclic ring system of 6-10 ring atoms, that is, a C 6-10 aryl group.
  • the aryl group may be optionally substituted by one or more substituents described in the present invention.
  • aryl can be used interchangeably with the terms “aromatic ring” or "aromatic ring”.
  • aryl groups include, but are not limited to, phenyl, indenyl, naphthyl and anthracenyl, and the like.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic aromatic system containing 5-14 ring atoms, wherein at least one ring contains one or more heteroatoms, each of which The ring contains 5-7 ring atoms, and at least one of the ring systems is aromatic.
  • the heteroaryl group may be optionally substituted by one or more substituents described in the present invention.
  • the heteroaryl group can be connected to the rest of the molecule (such as the main structure in the general formula) through any reasonable position (which can be C in CH or N in NH).
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-8 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, The heteroaryl group is a heteroaryl group consisting of 5-7 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, P, and N; in some embodiments, the heteroaryl group contains 1 , 2, 3 or 4 heteroaryl groups consisting of 5-6 atoms independently selected from O, S, P and N heteroatoms; in some embodiments, the heteroaryl group contains 1, 2, 3 or 4 A heteroaryl group consisting of 5 atoms independently selected from O, S, P and N heteroatoms; in some embodiments, the heteroaryl group includes 1, 2, 3 or 4 independently selected from O, S, Heteroaryl group consisting of 6 atoms of P and N heteroatoms.
  • heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl (2-furyl, 3-furyl), imidazolyl (N-imidazolyl, 2-imidazolyl) , 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (2-oxazolyl, 4 -Oxazolyl, 5-oxazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), Pyrimidyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • cycloalkylalkyl refers to cycloalkyl, heterocyclyl, aryl and heteroaryl, respectively, and each independently Connected to the rest of the molecule through an alkyl group, the cycloalkyl, heterocyclyl, aryl, heteroaryl and alkyl groups respectively have the meanings described in the present invention; such examples include, but are not limited to, cyclopropyl Pyridylmethyl, morpholinylmethyl, piperidinylmethyl, tetrahydrofuranylmethyl, phenylmethyl (ie, benzyl), phenylethyl, pyridylmethyl, pyridylethyl, or pyrimidinylmethyl Base and so on.
  • heteroatom refers to O, S, N, P, and Si, including S, N, and P in any oxidation state; primary, secondary, and tertiary amines and quaternary ammonium salt forms; or on the nitrogen atom in the heterocycle hydrogen substituted form, e.g., N (N 3,4- dihydro -2H- as pyrrolyl), NH (as in pyrrolidinyl NH) or NR T (as in N- substituted pyrrolidinyl NR T , R T is a substituent on N).
  • halogen refers to F, Cl, Br or I.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • deuterium refers to deuterium, i.e., 2 H.
  • protecting group refers to a substituent group used to block or protect specific functionalities when other functional groups in the compound react.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to the substituent of the hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, and p-methoxy. Benzyl and silyl, etc.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • LG refers to an atom or functional group that is detached from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group.
  • Common leaving groups include, but are not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, or hydroxyl groups.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated with it.
  • pharmaceutically acceptable in the present invention refers to those approved by the federal regulatory agency or the national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, especially humans.
  • carrier includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (such as antibacterial agents, antifungal agents), isotonic agents, salts, drug stabilizers, binders, excipients Forms, dispersants, lubricants, sweeteners, flavors, colorants, or combinations thereof, these carriers are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990 , pp. 1289-1329). Except for the incompatibility of any conventional carrier with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.
  • pharmaceutical composition means a mixture of one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable Carriers, excipients, diluents, adhesives, fillers and other excipients, as well as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerosis agents or Additional therapeutic agents such as lipid-lowering agents.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs you can refer to the following documents: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ASC Symposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51,2328- 2345.
  • the term "metabolite” refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known to us in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19.
  • solvate refers to an association formed by one or more solvent molecules with the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), where, for example, in an inert solvent, such as methylene chloride, the amine compound is combined with
  • any asymmetric atom (e.g., carbon, etc.) of the compound of the present invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration .
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the substituents on the atoms with unsaturated double bonds may exist in the form of cis-(Z)- or trans-(E)-.
  • the compounds of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers, or in the form of mixtures thereof,
  • they are substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
  • Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on the physical and chemical differences of the components, for example, by chromatography and/or analysis. Step crystallization for separation.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis (e.g. Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • the present invention also includes isotopically-labeled compounds of the present invention, which are the same as those described in the present invention except for the fact that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the natural common atomic mass or mass number.
  • Exemplary isotopes that can also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.
  • the compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are all included in the scope of the present invention.
  • Isotope-labeled compounds of the present invention such as radioisotopes, such as 3 H and 14 C, incorporated into the compounds of the present invention can be used for drug and/or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred.
  • substitution with larger mass isotopes, such as deuterium, or 2 H can provide some therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.
  • stereochemistry definitions and conventions used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry” of Organic Compounds", the definitions and conventions recorded in John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomeric forms. It is expected that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and their mixtures such as racemic mixtures, It is also included in the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule in terms of the chiral center (or multiple chiral centers) in the molecule.
  • the prefixes d and l or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (–) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory. In terms of a given chemical structure, these stereoisomers are the same except that these stereoisomers are mirror images of each other.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of said isomers is usually referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate. When there is no stereoselectivity or stereospecificity in a chemical reaction or method, the racemic mixture or racemate may occur Spin body.
  • the compounds of the present invention may exist in the form of one of the possible isomers or their mixtures, for example, as pure optical isomers, or as a mixture of isomers, such as racemic and non- Enantiomer mixture, which depends on the number of asymmetric carbon atoms.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.
  • the structure described in the present invention also includes all isomers (e.g., enantiomers, diastereomers, atropisomers and geometric (or conformation)) forms of this structure; for example, The R and S configurations of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers and enantiomeric mixtures, diastereomer mixtures, and geometric isomer (or conformational isomer) mixtures of the compounds of the present invention are all within the scope of the present invention.
  • isomers e.g., enantiomers, diastereomers, atropisomers and geometric (or conformation)
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • subject and patient used in the present invention are used interchangeably.
  • the terms “subject” and “patient” refer to animals (for example, birds or mammals such as chickens, quails, or turkeys), especially “mammals” including non-primates (for example, cattle, pigs, etc.) , Horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans.
  • the subject is a non-human animal, such as a domestic animal (e.g., horse, cow, pig, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit).
  • "patient” refers to a human being.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • treating any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone beta receptors, which are used for preparing and treating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, and hyperlipidemia.
  • the present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds and pharmaceutical compositions to prepare drugs for treating the above-mentioned diseases in mammals, especially humans.
  • the compound of the present invention Compared with existing similar compounds, the compound of the present invention not only has good pharmacological activity and selectivity, but also has excellent in vivo metabolic kinetic properties and in vivo pharmacodynamic properties.
  • the preparation method of the compound of the present invention is simple and easy to implement, the process method is stable, and it is suitable for industrial production. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, or solvate of a compound represented by formula (I) , Metabolites, pharmaceutically acceptable salts or their prodrugs,
  • L, W, Y, M, E 1 , E 2 , E 3 , R 1 , R 3a , R 3b , R 3c and R 3d have the definitions as described in the present invention.
  • each R a, R b, R c , R d and R e are independently H, deuterium, F, Cl, Br, I , -CN, -NO 2, -COOH, -OH, - NH 2 , -SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy.
  • R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or cyano C 1-6 alkyl.
  • E 1 is N, CH, or CR z , where R z has the definition described in the present invention.
  • E 2 is N or CR 2 , wherein said R 2 has the definition described in the present invention.
  • E 2 is CR 2 , wherein said R 2 has the definition described in the present invention.
  • E 3 is N or CR 3 , wherein said R 3 has the definition described in the present invention.
  • R z is deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkyl C 1-6 alkyl, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-6 alkyl, C 6-10 aryl, C 6- 10 aryl C 1-6 alkyl, 5-10 heteroaryl or (5-10 heteroaryl) C 1-6 alkyl.
  • R 2 and R 3 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, 3-8 heterocyclic group, (3-8 heterocyclic group) C 1-6 alkyl, C 6 -10 aryl, C 6-10 aryl, C 1-6 alkyl, 5-10 heteroaryl or (5-10 heteroaryl) C 1-6 alkyl.
  • R 5 is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 atom hetero Cyclic group, C 6-10 aryl group or heteroaryl group consisting of 5-6 atoms.
  • R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or cyano C 1-4 alkyl.
  • R 3a , R 3b , R 3c and R 3d are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , Trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.
  • each R a, R b, R c , R d and R e are independently H, deuterium, F, Cl, Br, I , -CN, -NO 2, -COOH, -OH, - NH 2 , -SH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy.
  • each R a, R b, R c , R d and R e are independently H, deuterium, F, Cl, Br, I , -CN, -NO 2, -COOH, -OH, - NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 or trifluoromethyl Oxy.
  • R z is deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl C 1-3 alkyl, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-3 alkyl, C 6-10 aryl, C 6- 10 aryl C 1-3 alkyl group, 5-6 atom heteroaryl group or (5-6 atom heteroaryl group) C 1-3 alkyl group.
  • R z is deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, methyl, ethyl, n-propyl, isopropyl, N-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, C 2 -4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-3 alkyl, 5-6 Heterocyclic group consisting of atoms, (heterocyclic group consisting of 5-6 atoms) C 1-3 alkyl, phenyl, phenylmethyl, phenylethyl, pyridyl,
  • R 2 and R 3 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy C 1-4 alkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-3 alkyl, C 6 -10 aryl, C 6-10 aryl, C 1-3 alkyl, 5-6 heteroaryl or (5-6 heteroaryl) C 1-3 alkyl.
  • R 2 and R 3 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -NH 2 , -SH, methyl, ethyl, N-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, n-propoxy , Isopropoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1- 3 Alkyl groups, heterocyclic groups composed of 5-6 atoms, (heterocyclic groups composed of 5-6 atoms) C 1-3 alkyl, phenyl, phenylmethyl, phenylethyl, pyridy
  • R 5 is H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 atoms of hetero Cyclic group, C 6-10 aryl group or heteroaryl group consisting of 5-6 atoms.
  • the present invention relates to one of the following structures, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or these Prodrugs,
  • the present invention relates to a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention optionally, further comprises any one of pharmaceutically acceptable carriers, excipients, adjuvants, vehicles, or any combination thereof.
  • the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicine, wherein the medicine is used for stimulating thyroid hormone receptor; or for preventing, treating or alleviating Diseases regulated by stimulating thyroid hormones.
  • the present invention relates to a method of using the compound or pharmaceutical composition of the present invention to agonize thyroid hormone receptors, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the method is to administer an effective therapeutic amount of the compound or the pharmaceutical composition to an individual in need.
  • the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at certain time intervals.
  • the present invention relates to the use of the compound or pharmaceutical composition of the present invention for agonizing thyroid hormone receptors, or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the diseases mediated by thyroid receptors of the present invention are diseases mediated by activation of thyroid receptors.
  • the thyroid hormone receptor of the present invention is a thyroid hormone beta receptor.
  • the diseases regulated by thyroid hormone receptor agonists of the present invention are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, Hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, type 1A glycogen storage disease, hypothyroidism, or thyroid cancer.
  • the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, cryptogenic liver cirrhosis, or primary liver cancer.
  • the metabolic disorder described in the present invention comprises a lipid metabolism disorder or a glucose metabolism disorder.
  • the dosage of the compound or pharmaceutical composition required to implement the effects of treatment, prevention, or delay usually depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by the attending physician.
  • the specific situation is determined. For example, when the compound or pharmaceutical composition provided by the present invention is administered via an intravenous route, the administration may be performed once a week or even at longer intervals.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated with it.
  • the compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and can be used for preparing and/or purifying the compounds of the present invention and/or for isolating the compounds of the present invention
  • the intermediates of the enantiomers are not necessarily pharmaceutically acceptable salts, and can be used for preparing and/or purifying the compounds of the present invention and/or for isolating the compounds of the present invention.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.
  • the present invention relates to a pharmaceutical composition, which includes the compound of the present invention or the compound of the structure shown in the examples, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, and solvates , Metabolites and pharmaceutically acceptable salts or their prodrugs.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof, and optionally, other therapeutic and/or preventive components.
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant or vehicle.
  • the amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably activate the thyroid hormone beta receptor in a biological specimen or a patient.
  • the pharmaceutically acceptable carrier may contain inert ingredients that do not excessively inhibit the biological activity of the compound.
  • the pharmaceutically acceptable carrier should be biocompatible, such as non-toxic, non-inflammatory, non-immunogenic or without other adverse reactions or side effects once administered to the patient. Standard pharmaceutical technology can be used.
  • the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, as used in the present invention, including Suitable for the specific target dosage form, any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant ,and so on.
  • a pharmaceutically acceptable carrier including Suitable for the specific target dosage form, any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant ,and so on.
  • Remington The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J.
  • substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80 , Phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g.
  • oils e.g. peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil
  • ethylene glycol e.g. propylene glycol or poly Ethylene glycol
  • esters e.g. ethyl oleate and ethyl laurate
  • agar e.g.
  • magnesium hydroxide and aluminum hydroxide examples include alginic acid, pyrogen-free water, isotonic saline, Ringer's solution (Ringer'ssolution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, anti-sticking agents, coating agents, Sweetening and flavoring agents, preservatives and antioxidants may also be present in the composition.
  • the pharmaceutical composition of the present invention can be administered directly or in the form of a pharmaceutical composition or drug with a suitable carrier or excipient, which is well known in the art.
  • the treatment method of the present invention may comprise administering an effective compound of the present invention to an individual in need.
  • the individual is a mammalian individual, and in other embodiments, the individual is a human individual.
  • the effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by conventional method tests, and the most effective and convenient route of administration and the most suitable formulation can also be determined by conventional tests.
  • the compound or composition of the present invention can be administered by any suitable means, according to the severity of the disease, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) or Nasal sprays and the like administer the above-mentioned compounds and pharmaceutically acceptable compositions to humans or other animals.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cotton seed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof.
  • oral compositions may also include adjuvants such as we
  • Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • water, Ringer's solution, and isotonic sodium chloride solution can be used.
  • sterile non-volatile oils are conventionally used.
  • any odorless fixed oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as octadecenoic acid, are used in the preparation of injections.
  • the sterilant can be dissolved or dispersed in sterile water or other sterile injectable medium before use is sterilized for the injectable preparation.
  • the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal shape.
  • delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle.
  • An injectable storage form is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The release rate of the compound can be controlled according to the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • composition for rectal or vaginal administration is particularly a suppository prepared by mixing the compound of the present invention and a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax.
  • a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax.
  • the carrier is solid at ambient temperature but liquid at body temperature, and therefore melts in the rectum or vaginal cavity and releases the active compound.
  • Oral solid dosage forms include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agent, such as starch, lactose, sucrose , Glucose, mannitol and silicic acid; b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerin; d) disintegrants , Such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution blockers, such as paraffin wax; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting Agents such as cetyl alcohol and gly
  • excipients such as lactose or toffee and macromolecular polyethylene glycols
  • solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably in a certain part of the intestinal tract.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the active compound may also be in a microencapsulated form with one or more of the above-mentioned excipients.
  • the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch.
  • inert diluents such as sucrose, lactose or starch.
  • dosage forms may also contain additional substances in addition to inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the topical or transdermal application dosage forms of the compound of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of the present invention.
  • the present invention contemplates the use of a skin patch that has the added advantage of providing controlled delivery of the compound to the body.
  • This dosage form can be made by dissolving or dispersing the compound in an appropriate medium.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • composition of the present invention can also be administered orally, parenterally, locally, rectum, nasal, oral cavity, vagina via inhalation spray, or via implanted kit.
  • parenteral as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally or intravenously.
  • the sterile injectable form of the composition of the present invention may be a water or oil suspension. These suspensions can be prepared following techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example, a solution in 1,3-butanediol.
  • water, Ringer's solution and isotonic sodium chloride solution can be used.
  • sterile non-volatile oils are conventionally used. For this purpose, any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides.
  • oils such as olive oil or castor oil, in particular in polyoxyethylated form
  • fatty acids such as octadecenoic acid and its glyceride derivatives
  • oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions).
  • surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.
  • the pharmaceutical composition of the present invention can be taken orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.
  • commonly used carriers include, but are not limited to, lactose and starch.
  • Lubricants such as magnesium stearate are usually added.
  • useful diluents include lactose and dried corn starch.
  • the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal use.
  • These pharmaceutical compositions can be prepared by mixing reagents and non-irritating excipients, including but not limited to cocoa butter, beeswax, and polyethylene glycol.
  • the pharmaceutical composition of the present invention can also be applied locally. It is easy to prepare a suitable topical formulation for each of these areas or organs.
  • Rectal suppository preparations (see above) or suitable enema preparations can be used to achieve local drip administration to the lower intestinal tract.
  • a topical skin patch can also be used.
  • the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.
  • Carriers suitable for topical instillation of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water .
  • the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or especially a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride.
  • the pharmaceutical composition can be formulated as an ointment, such as petrolatum.
  • the pharmaceutical composition can also be administered via nasal vaporized spray or inhalation.
  • This composition is prepared according to well-known techniques in the pharmaceutical field and prepared into salt water by using benzyl alcohol and other suitable preservatives, absorption promoters that improve bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants Solution.
  • the compound or pharmaceutical composition provided by the present invention can be used to prepare drugs that stimulate thyroid hormone receptors, or to prepare drugs for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the compound or pharmaceutical composition provided by the present invention can be used to stimulate thyroid hormone receptor, or to prevent, treat or alleviate diseases regulated by thyroid hormone receptor.
  • the present invention provides a method for stimulating thyroid hormone receptor, or a method for preventing, treating or alleviating diseases regulated by thyroid hormone receptor, the method comprising administering a therapeutically effective amount of the above-mentioned compound to a patient in need of treatment Or its pharmaceutical composition.
  • the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at certain time intervals.
  • the disease regulated by the thyroid hormone receptor in the present invention is a disease mediated by the activation of the thyroid hormone receptor.
  • the thyroid hormone receptor of the present invention is thyroid hormone ⁇ receptor.
  • the disease of the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders , Type 1A glycogen storage disease, hypothyroidism or thyroid cancer, wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, cryptogenic cirrhosis or primary Liver cancer, wherein the metabolic disorder comprises a lipid metabolism disorder or a glucose metabolism disorder.
  • the compounds of the present invention can also be applied to veterinary treatment of pets, introduced species of animals and farm animals, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the "effective amount”, “effective therapeutic amount” or “effective dose” of the compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention .
  • the compound or pharmaceutically acceptable pharmaceutical composition of the present invention is effective in a relatively wide dosage range.
  • the daily dose is about 0.1mg-1000mg/person, divided into one or several doses.
  • the methods, compounds and pharmaceutical compositions according to the present invention can be of any dosage and any route of administration to be effectively used to treat or reduce the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, general condition of the patient, severity of infection, special factors, method of administration, etc.
  • the compound or pharmaceutical composition of the present invention can be administered in combination with one or more other therapeutic agents, as discussed in the present invention.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the definition of the substituents is as described in the present invention.
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or/and 19 F-NMR).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts ( ⁇ ) are given in units of parts per million (ppm).
  • 1 H-NMR, 13 C-NMR, 19 F-NMR are measured with Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, and the measuring solvent is deuterated chloroform (CDCl 3 ), deuterated Methanol (CD 3 OD or MeOH-d 4 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • Novasep pump 250 high performance liquid chromatograph is used for preparative purification or preparative resolution.
  • the Agilent-6120Quadrupole LC/MS mass spectrometer is used for the determination of LC-MS.
  • the starting materials of the present invention are known and can be purchased on the market, purchased from Shanghai Accela Company, Energy Company, J&K, Tianjin Alfa Companies such as Alfa Company can alternatively adopt or synthesize according to methods known in the art.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon or steel kettle with a volume of about 1L;
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L or a stainless steel autoclave with a volume of about 1L;
  • the solution refers to an aqueous solution
  • reaction temperature is room temperature
  • the room temperature is 20°C to 40°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent systems used in the reaction are: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system , The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the eluent system of column chromatography includes: A: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and ethyl acetate system
  • C dichloromethane and methanol system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of ammonia and acetic acid.
  • HPLC refers to high performance liquid chromatography
  • HPLC determination uses Agilent 1260 high pressure liquid chromatograph (chromatographic column: Agilent ZORBAX Eclipse Plus C18 4.6mm ⁇ 150mm, 3.5 ⁇ m);
  • HPLC test conditions Running time: 25min Column temperature: 35°C Detection wavelength: 210nm; 245nm;
  • Phase A Phase A: 0.05% phosphoric acid solution
  • Phase B Acetonitrile
  • Flow rate 1.0ml/min
  • the mobile phase gradient is shown in Table A:
  • the analytical LC/MS/MS system used in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column incubator, Agilent G6430 triple quadruple with electrospray ionization source (ESI) Grade rod mass spectrometer. Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table B:
  • the Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ m column was used for analysis, and 5 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min.
  • the mobile phase gradient is shown in Table C:
  • the test conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ m, 6min, flow rate 0.6mL/min, mobile phase: 5%- The ratio of 95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)) was detected by UV at 210 nm/254 nm, and electrospray ionization (ESI) mode was used.
  • Agilent 6120 Quadrupole HPLC-MS column model: Zorbax SB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ m, 6min, flow rate 0.6mL/min, mobile phase: 5%- The ratio of 95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)) was detected by UV at 210 nm/254 nm, and electrospray i
  • DMSO-d 6 deuterated dimethyl sulfoxide; Boc: tert-butoxycarbonyl;
  • DCC Dicyclohexylcarbodiimide
  • DMSO Dimethyl sulfoxide
  • CD 3 OD Deuterated methanol; mL,ml: mL;
  • ⁇ mol/L, ⁇ mol/l, ⁇ M micromol/l
  • nmol/L, nmol/l, nM nanomol/l
  • TFA trifluoroacetic acid
  • H 2 O water
  • the compound having the structure represented by the general formula (IA) can be prepared by the general synthesis method described in Synthetic Scheme 1, wherein R 4a is -CN or -CF 3 .
  • compound (Ia) and (Ib) are reacted under the action of a base (such as potassium carbonate) to obtain compound (Ic); compound (Ic) is reduced to obtain compound (Id); the amino group of compound (Id) is diazotized, And react with (Ie) to obtain compound (If); compound (If) is ring closed under the action of a base (such as potassium acetate) to obtain the target compound represented by general formula (IA).
  • a base such as potassium carbonate
  • the intermediate having the structure represented by the general formula (Id) can also be prepared by the general synthesis method described in Synthesis Scheme 2, wherein PG 1 and PG 2 are each independently an amino protecting group, or PG 1 and PG 2 are connected to The nitrogen atoms together form a heterocyclic group consisting of 5-10 atoms or a heteroaryl group consisting of 5-10 atoms, and the heterocyclic group consisting of 5-10 atoms or a heteroaryl group consisting of 5-10 atoms has a protected amino group.
  • the role of; LG is a leaving group.
  • compound (Ig) and (Ib) are reacted under the action of a base (such as potassium carbonate) to obtain compound (Ih); compound (Ih) is reduced to obtain compound (Ii); compound (Ii) is protected to obtain compound (Ij); Compound (Ij) is reacted with compound (Ik) to obtain (Il); Compound (Il) is deprotected from the amino group to obtain an intermediate represented by general formula (Id). .
  • a base such as potassium carbonate
  • the intermediate having the structure represented by the general formula (I-d) can also be prepared by the general synthesis method described in Synthetic Scheme 3, where LG is a leaving group.
  • the compound (I-m) is reacted with the compound (I-k) to obtain (I-n); the compound (I-n) is deprotected from the amino group to obtain an intermediate of the structure represented by the general formula (I-d).
  • An intermediate having the general formula (I-m) can be prepared by the general synthesis method described in Synthesis Scheme 4, where X is a halogen.
  • compound (Io) and (Ib) are reacted under the action of a base (such as potassium carbonate) to obtain compound (Iq); compound (Iq) is demethylated to obtain compound (Ih); compound (Ih) is reduced to obtain Compound (Ii); Compound (Ii) protects the amino group to obtain Compound (Im).
  • a base such as potassium carbonate
  • the intermediate having the structure represented by the general formula (I-d) can also be prepared by the general synthesis method described in Synthesis Scheme 5, where LG is a leaving group.
  • the compound (I-h) reacts with the compound (I-k) to obtain (I-r); the compound (I-r) is deprotected from the amino group to obtain an intermediate having the structure represented by the general formula (I-d).
  • the intermediates having the general formula (I-h) can also be prepared by the general synthesis method described in Synthetic Scheme 6.
  • compound (I-s) and (I-b) are reacted under the action of a base (such as potassium carbonate) to obtain compound (I-t); compound (I-t) is hydrolyzed to obtain compound (I-h).
  • a base such as potassium carbonate
  • the compound having the structure represented by the general formula (IB) can be prepared by the general synthesis method described in Synthesis Scheme 4, wherein R 0 is an alkoxy group, -OH or -NH 2 .
  • Compound (Iu) is reacted under acidic (such as concentrated hydrochloric acid) conditions to obtain compound (IB).
  • N-[2-[[4-[(1-benzyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy-3,5-dichlorophenyl]hydrazinide] -2-cyano-acetyl]carbamate f (0.15g, 0.26mmol) was dissolved in N,N-dimethylacetamide (2mL), potassium acetate (0.11g, 1.06mmol) was added, and reacted at 120°C 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated.
  • reaction solution was cooled to room temperature, saturated sodium carbonate solution (50mL) was added, stirred for 10 minutes, extracted with ethyl acetate (10mL ⁇ 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated with suction to obtain the title compound 3d( 0.85g, yield 99%), as a dark solid.
  • reaction solution was cooled to room temperature, poured into water (20 mL), stirred for 10 minutes, filtered with suction, and the filter cake was collected and dried under vacuum to obtain the title compound 3e (0.70 g, yield 74%) as a gray solid.
  • Step 7 2-[3,5-Dichloro-4-[(1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5 -Dioxo-1,2,4-triazine-6-carbonitrile 3
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [43% ACN/57% H 2 O (0.1% TFA), Kromasil specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 3 (30 mg, yield 74%, HPLC purity: 98.16%), a white solid.
  • Step 6 2-[3,5-Dichloro-4-[(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]phenyl]-3,5- Dioxo-1,2,4-triazine-6-carbonitrile 4
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [60% ACN/40% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 4 (7 mg, yield 2.8%, HPLC purity: 92.99%) was obtained as a white solid.
  • Step 4 2-[3,5-Dichloro-4-(1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy-phenyl]-3,5-di Oxo-1,2,4-triazine-6-carbonitrile 5
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [40% ACN/60% H 2 O (0.1% TFA), Kromasil specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 5 (50 mg, yield 9%, HPLC purity: 97.78%), is a white solid.
  • the 6-(4-amino-2,6-dichloro-phenoxy)-2-cyclopropyl-pyridazine-3(2H)-one 6b (0.05g, 0.20mmol), N-cyanoacetyluria Alkane (0.03g, 0.20mmol) and concentrated hydrochloric acid (0.04mL) were dissolved in acetic acid (2mL), and sodium nitrite (0.010g, 0.20mmol) in water (0.5mL) was added dropwise at 3°C, followed by reaction for 10 minutes . Water (20 mL) was added to the reaction solution, stirred for 10 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain the title compound 6c (80 mg, yield 99%) as a black solid.
  • Step 4 2-[3,5-Dichloro-4-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy-phenyl]-3,5- Dioxo-1,2,4-triazine-6-carbonitrile 6
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [45% ACN/55% H 2 O (0.1% TFA), Kromasil specification: C1810um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 6. (8mg, yield 10%, HPLC purity: 95.4%), it is a light-colored solid.
  • Step 1 6-[2,6-Dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy]-2-phenyl-pyridazine-3(2H)-one 21a
  • Step 4 2-[3,5-Dichloro-4-(6-oxo-1-phenyl-1,6-dihydropyridazin-3-yl)oxy-phenyl]-3,5-di Oxo-1,2,4-triazine-6-carbonitrile 21
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [48% ACN/52% H 2 O (0.1% TFA), Kromasil specifications: C1810um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 21 (4mg, yield 1.2%, HPLC purity: 81.9%), it is a dark solid.
  • Step 4 2-[3,5-Dichloro-4-[1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl]oxy-phenyl]- 3,5-dioxo-1,2,4-triazine-6-carbonitrile 27
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [45% ACN/55% H 2 O (0.1% TFA), Kromasil specification: C1810um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 27 (48 mg, yield 74%, HPLC purity: 86.92%), as a yellow solid.
  • Step 1 6-[2,6-Dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy]-2-(1-phenethyl)pyridazine-3( 2H)-keto 37a
  • Step 4 2-[3,5-Dichloro-4-[6-oxo-1-(1-phenethyl)-1,6-dihydropyridazin-3-yl]oxy-phenyl]- 3,5-dioxo-1,2,4-triazine-6-carbonitrile 37
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [40% ACN/60% H 2 O (0.1% TFA), Kromasil specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 36 (100 mg, yield 15%, HPLC purity: 97.91%), as a red solid.
  • the resulting crude product was prepared Separation and purification [37%ACN/63%H2O(0.1%TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], to obtain the target compound 38 (0.18g, yield 45.0%, HPLC Purity: 98.37%), as a yellow solid.
  • reaction solution was cooled to room temperature, quenched by adding saturated sodium carbonate solution (50mL), extracted with ethyl acetate (10mL ⁇ 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated with suction to obtain the title compound 39b (1.90g , The yield is 92%), it is a gray solid.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [48% ACN/52% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 39 (25 mg, yield 8.6%, HPLC purity: 88.95%) was obtained as a red solid.
  • N-cyanoacetylurethane (0.11g, 0.59mmol) was dissolved in acetic acid (3mL) and concentrated hydrochloric acid (0.18mL), and an aqueous solution of sodium nitrite (0.05g, 0.59mmol) (2mL) was added dropwise at 3°C , And then react for 30 minutes. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (5 mL ⁇ 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered off with suction and spin-dried to obtain the title compound 40c (0.33 g, yield 100%). It is a deep red solid.
  • Step 4 2-[3,5-Dichloro-4[[6-oxo-1-[[4-(trifluoromethoxy)phenyl]methyl]pyridin-3-yl]oxy]phenyl ]-3,5-dioxo-1,2,4-triazine-6-methyl Nitrile 40
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [52% ACN/48% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 40 (7.0 mg, yield 2.0%, purity 82.25%) was obtained as a yellow solid.
  • Step 6 2-[3,5-Dichloro-4-[[1-[(4-fluorophenyl)methyl]-6-oxo-1,6-dihydropyridin-3-yl]oxy] Phenyl]-3,5-dioxo-1,2,4-triazine-6-methan Nitrile 41
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [48% ACN/52% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 41 (94 mg, yield 24%, HPLC purity: 98.27%) was obtained as a red solid.
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [50% ACN/50% H 2 O (0.1% TFA), Philomon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 42 (38 mg, yield 8.7%, HPLC purity: 98.74%) was obtained as a red solid.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [60% ACN/40% H 2 O (0.1% TFA), Ferromon ACE specifications: C1810um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], title Compound 43 (15 mg, yield 6.3%, HPLC purity: 99.15%) was a yellow solid.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [58% ACN/42% H 2 O (0.1% TFA), Ferromon ACE specifications: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 48 (55 mg, yield 12%, HPLC purity: 93.99%) was obtained as a yellow solid.
  • Step 4 2-[3,5-Dichloro-4-[[1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl]oxy]phenyl ]-3,5-dioxo-1,2,4-triazine-6-carbonitrile 49
  • Step 1 2-[3-[2,6-Dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)phenoxy]-6-oxo-pyridazine-1(6H )-Yl]ethyl acetate 52a
  • Step 2 2-[3-(4-Amino-2,6-dichloro-phenoxy)-6-oxo-pyridazine-1(6H)-yl]ethyl acetate 52b
  • Step 4 2-[3-[2,6-Dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-6 -Oxo-pyridazine-1(6H)-yl) ethyl acetate 52
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared and separated and purified [40% ACN/60% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10um ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 52 (70.0 mg, yield 48%, HPLC purity: 98.24%) was obtained as a white solid.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue obtained was separated and purified by preparation [37% ACN/63% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/ min], the title compound 50 (70 mg, yield 25%, HPLC purity: 96.63%) was obtained as a white solid.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [45% ACN/55% H 2 O (0.1% TFA), Ferromon ACE specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 55 (15 mg, yield 3.6%, HPLC purity: 93.79%) was obtained as a white solid.
  • Step 2) 2-[5-(4-Amino-2,6-dichloro-phenoxy)-2-oxo-pyridine-1(2H)-yl]propionic acid ethyl ester 57b
  • reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 2-[4-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]-3,5-dichlorophenyl]-3,5-diox Substitution-1,2,4-triazine-6-carboxylic acid 62a
  • Step 2 2-[4-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]-3,5-dichlorophenyl]-1,2,4- Triazine-3,5-dione 62
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was prepared, separated and purified [45% CAN/55% H 2 O (0.1% formic acid), Ferromon ACE specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], The title compound 64 (15 mg, yield 10%, HPLC purity: 90.73%) was obtained as a yellow solid.
  • Step 1) 1-[2-[tert-butyl(dimethyl)siloxy]ethyl]-5-[2,6-dichloro-4-(2,5-dimethyl-1H-pyrrole- 1-yl)phenoxy)pyridine-2(1H)-one 65a
  • Step 2) 5-(4-Amino-2,6-dichlorophenoxy)-1-[2-[tert-butyl(dimethyl)siloxy]ethyl]pyridine-2(1H)-one 65b
  • reaction solution was cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the reaction solution was concentrated, the residue was dissolved in ethanol (20mL), decolorized with activated carbon (0.20g) at 85°C, filtered, and the filtrate was concentrated.
  • the resulting residue was slurried with ethanol/petroleum ether (1/2, 15mL) and filtered. The filter cake was collected to obtain the title compound 65 (76 mg, yield 31%, HPLC purity 87.26%) as a yellow solid.
  • reaction solution was concentrated, and the resulting residue was prepared, separated and purified [38% ACN/62% H 2 O (0.1% TFA), Kromasil specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min] to obtain the title compound 66( 21mg, yield 11%, HPLC purity: 97.67%), as a pale yellow solid.
  • Step 1) 2-[3,5-Dichloro-4-[[1-[(4-fluorophenyl)methyl]-6-oxopyridin-3-yl]oxy]phenyl]-3, 5-dioxo-1,2,4-triazine-6-carboxylic acid 69a
  • reaction solution was cooled to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered with suction, and concentrated.
  • reaction solution was cooled to room temperature, water (5mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain the crude product after preparation, separation and purification [47% ACN/53% H 2 O (0.1% TFA), Kromasil specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], the title compound 70 (0.19g, yield 42%, HPLC purity: 99.40%) was obtained as a white solid.
  • reaction solution was cooled to room temperature, water (5mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected and dried under vacuum to obtain the crude product after preparation, separation and purification [47% ACN/53% H 2 O (0.1% TFA), Kromasil specification: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100mL/min], the title compound 71 (0.13g, yield 34%, HPLC purity: 99.16%) was obtained as a white solid.
  • Step 1) 2-[3,5-Dichloro-4-[[6-oxo-1-(tetrahydropyran-4-ylmethyl)pyridin-3-yl]oxy]phenyl]-3 ,5-Dioxo-1,2,4-triazine-6-carboxylic acid 72a
  • Step 1) 2-[3,5-Dichloro-4-[(1-isopropyl-6-oxopyridin-3-yl)oxy]phenyl]-3,5-dioxo-1, 2,4-Triazine-6-carboxylic acid 73a
  • Step 2 2-[3,5-Dichloro-4-[(1-isopropyl-6-oxopyridin-3-yl)oxy]phenyl]-1,2,4-triazine-3 ,5-Diketone 73
  • HEK293 cells purchased from ATCC, Cat No. CRL-1573;
  • Fugene HD transfection reaagent purchased from Promega, Cat No. E231A;
  • DMEM fetal calf serum
  • FBS purchased from Biosera, Cat No. FB-1280/500;
  • Trypsin-EDTA purchased from Gibco, Cat No. 25200-072;
  • Dual-Luciferase Reporter Assay System purchased from Promega, Cat No. E1960;
  • 96-well plate (round bottom), purchased from Corning, Cat No. 3365.
  • HEK293 cells were cultured in 10% FBS+DMEM complete medium. Mix pBind-TR ⁇ or pBind-TR ⁇ (100ng/ ⁇ l), pG5Luc (100ng/ ⁇ l), FuGENE HD, and Opti-MEM thoroughly, and incubate at room temperature for 15 minutes. At the same time, HEK293 cells were digested with 0.25% Trypsin-EDTA and then whole Resuspend the medium, calculate the cell density, adjust the cell density to 500,000 cells/ml, then add the transcription mixture and the cell suspension to mix, spread the plate in a 96-well plate (100 ⁇ L/well), and incubate at 37°C for 24 hours.
  • test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations. Then, the compound was diluted with DMEM into a compound solution containing 10% DMSO, and 5 ⁇ L of the compound was placed in a 96-well plate. The DMSO content of the compound The final concentration was 0.5%, and the compound was co-cultured with the cells for 18 hours. After 18h, use Dual-Luciferase Reporter Assay System to detect the fluorescence signal of firefly and Renilla. Divide the firefly fluorescence signal (F) by the Renilla fluorescence signal (R) to calculate the F/R ratio, use Graph Pad Prism software to draw the curve and calculate the EC 50 value. The test results show that the compound of the present invention has a good activity to agonize TR ⁇ . At the same time, the compounds of the present invention have good selectivity to TR ⁇ .
  • test results show that the compound of the present invention has obvious agonistic activity and selectivity for TR ⁇ .
  • LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit purchased from Invitrogen, Cat.No.PV4686;
  • This method uses LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit for experiment.
  • the test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations, and then diluted with TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO.
  • TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO.
  • test results show that the compound of the present invention has strong binding affinity and selectivity to TR ⁇ .
  • Test purpose The following method is used to determine the pharmacokinetics of the compounds of this invention.
  • SD rat male, 180-220g, 7-8 weeks old, purchased from Hunan Slack Experimental Animal Co., Ltd.
  • test solution According to 5% DMSO + 5% Kolliphor HS15 + 90% normal saline solution, the test solution is configured, and the specific adjustment is made according to the dissolution of each compound, so that the compound can be completely dissolved.
  • Dosage Dosing concentration Dosing volume Intravenous I.V. male 3 1mg/kg 1mg/mL 1mL/kg Oral gavage I.G. male 3 5mg/kg 1mg/mL 5mL/kg
  • test substance stock solution accurately weigh an appropriate amount of the test substance, dissolve it with DMSO, dilute it to 1 mg/mL with acetonitrile, and shake it well. Store at -20°C for later use.
  • the samples are processed by liquid-liquid extraction and chromatographic separation is performed. Quantitative analysis is performed on a triple quadrupole tandem mass spectrometer with multiple reactive ion monitoring (MRM) mode, and the results are calculated by the quantitative software of the instrument.
  • MRM reactive ion monitoring
  • the LC/MS/MS method was used to determine the content of the test compound in rat plasma after the administration of different compounds.
  • test results show that when administered by intravenous injection or oral gavage, the example compounds of the present invention (Examples 16 and 29) exhibit excellent pharmacokinetic properties.
  • the present invention is implemented
  • the example compounds have higher blood concentration and exposure, that is, have better pharmacokinetic properties.
  • MCD diet purchased from Nantong Trofe Feed Technology Co., Ltd., item number: TP3006R;
  • ALT, AST, ALP, TG, CHO, HDL, LDL and GLU purchased from Roche, the product numbers are: 20764957322, 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 04404483190;
  • OB/OB mice are leptin gene-deficient mice.
  • the NASH model of OB/OB mice induced by Western diet is a commonly used model for evaluating the efficacy of NASH in vivo.
  • the experiment began after the animals were adapted for 1 week. OB/OB mice are fed with Western diet feed. The feed is changed three times a week (Monday, Wednesday, Friday). The mice start to be administered on the fifth week after feeding, and they are administered orally once a day for 6 weeks. The entire experimental period is 10 weeks. During the experiment, the basic condition of the animals was monitored every day, and the weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight.
  • mice After the mice were anesthetized, blood was collected from the orbit and the whole blood was collected by centrifugation at 4°C, 4,000 rpm, and 10 min to obtain serum, which was stored at -80°C. Serum is used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, and their livers were taken and weighed. The middle lobe of the liver is stored in an EP tube at -80°C for the determination of TG and CHO content in the liver. After the left liver lobe was fixed in 10% formalin, HE staining and NAS score were performed.
  • NASH non-alcoholic steatohepatitis
  • db/db mice are mice lacking the leptin receptor gene, and the NASH model of db/db mice induced by MCD diet is a commonly used model for evaluating the efficacy of NASH in vivo.
  • the experiment began after the animals were adapted for 1 week. The db/db mice were fed with MCD feed, and the feed was changed three times a week (Monday, Wednesday, Friday). The mice were modeled and administrated for the experiment. Oral administration was administered once a day for 8 weeks. The entire experiment The cycle is 8 weeks. During the experiment, the basic condition of the animals was monitored every day, and the weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight.
  • mice After the mice were anesthetized, blood was collected from the orbit and the whole blood was collected by centrifugation at 4°C, 4,000 rpm, and 10 min to obtain serum, which was stored at -80°C. Serum is used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, and the liver was taken and weighed. The middle lobe of the liver is stored in an EP tube at -80°C for the determination of the content of TG and CHO in the liver. After the left liver lobe was fixed in 10% formalin, HE staining and NAS score were performed.
  • test results show that the compound of the present invention can effectively reduce fat accumulation in the liver, reduce inflammation, and improve liver fibrosis.

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Abstract

一种作为甲状腺激素Beta受体激动剂化合物及其用途，进一步包含所述化合物的药物组合物。所述的化合物或药物组合物可以用于制备预防、治疗或减轻由激动甲状腺激素β受体介导的疾病的药物，尤其用于制备治疗非酒精性脂肪性肝病的药物。

Description

一种作为甲状腺激素Beta受体激动剂的化合物及其用途
相关申请的交叉引用：
本申请要求引用申请号为201910901997.0，202010164947.1和202010231242.7的中国专利的优先权，在先申请在中国国家知识产权局的申请日分别为2019.09.24,2020.03.11和2020.03.27，其全部内容通过引用并入本文。
技术领域
本发明属于药物领域，具体涉及一种作为甲状腺激素Beta受体激动剂的化合物及其用途，进一步涉及包含所述化合物的药物组合物。本发明进一步涉及所述的化合物及药物组合物在制备用于预防、治疗或减轻由激活甲状腺激素β受体介导的疾病的药物中的用途，尤其是制备用于治疗非酒精性脂肪性肝病的药物中的用途。
背景技术
甲状腺激素(thyroid hormone,TH)对于生长、分化、发育和维持代谢平衡具有极其重要的作用。甲状腺激素由甲状腺合成并且以三碘甲腺原氨酸(T3)和四碘甲腺原氨酸(T4)两种主要形式分泌到循环系统中。尽管T4是由甲状腺分泌的主要形式，但T3是生理上更活跃的形式。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，但是主要存在于肝和肾中。
TH的生理作用主要是通过甲状腺激素受体(thyroid hormone receptor,TR)进行的。TR属于核受体超家族的一员，是配体T3诱导的转录因子，在介导配体T3的作用过程中处于核心地位。TR主要位于细胞核中，与维甲酸X受体(retinoid X receptor,RXR)及其它核受体形成异二聚体结合到靶基因启动子区域的甲状腺激素反应元件(thyroid hormone response element,TRE)上，从而调节基因转录。TR有两种亚型：TRα和TRβ。TRα又可分为TRα1和TRα2，TRβ又可分为TRβ1和TRβ2。其中只有TRα1、TRβ1和TRβ2能够结合配体T3。TRα主要调节心率，TRβ在控制肝脏胆固醇代谢和抑制促甲状腺激素(TSH)释放方面起关键作用，这可能与TRβ在肝脏和脑下垂体的高度表达有关。
如果副作用可最小化或者消除，那么甲状腺激素具有一定的治疗益处(Paul M.Yen et.al.Physiological Reviews,Vol.81(3):pp.1097-1126(2001)；Paul Webb et.al.Expert Opin.Investig.Drugs,Vol.13(5):pp.489-500(2004))。例如，甲状腺激素可增加代谢率、氧消耗和热量产生，从而降低体重。降低体重将改善与肥胖有关的共发病而对肥胖患者具有有益效果，并且还可以对患有2型糖尿病的肥胖患者的血糖控制具有有益效果。
甲状腺激素也可降低血清低密度脂蛋白(LDL)(Eugene Morkin et.al.Journal of Molecular and Cellular Cardiology,Vol.37:pp.1137-1146(2004))。已经发现，甲状腺机能亢进与低的总血清胆固醇有关，这归因于甲状腺激素增加肝LDL受体表达并且刺激胆固醇向胆汁酸的代谢(JJ.Abrams et.al.J.Lipid Res.,Vol.22:pp.323-38(1981))。甲状腺功能减退又与高胆固醇血症有关，并且已经有甲状腺激素替代疗法降低了总胆固醇的报道(M.Aviram et.al.Clin.Biochem.,Vol.15:pp.62-66(1982)；JJ.Abrams et.al.J.Lipid Res.,Vol.22:pp.323-38(1981))。在动物模型中，甲状腺激素已经显示出具有增加HDL胆固醇和通过增加apo A-1(HDL的主要脱辅基脂蛋白之一)的表达提高LDL向HDL的转化率的有益效果(Gene C.Ness et.al.Biochemical Pharmacology,Vol.56:pp.121-129(1998)；GJ.Grover et.al.Endocrinology,Vol.145:pp.1656-1661(2004)；GJ.Grover et.al.Proc.Natl.Acad.Sci.USA,Vol.100:pp.10067-10072(2003))。动脉粥样硬化血管病的发病率与LDL胆固醇水平直接相关，通过对LDL和HDL的调控作用，甲状腺激素可能还可以降低动脉粥样硬化和其它心血管疾病的危险。另外，有证据表明，甲状腺激素能够降低脂蛋白(a)，脂蛋白(a)是动脉粥样硬化的一种危险因子，其在动脉粥样硬化患者中升高(Paul Webb et.al.Expert Opin.Investig.Drugs,Vol.13(5):pp.489-500(2004)；de Bruin et.al.J.Clin.Endo.Metab.,Vol.76:pp.121-126(1993))。
另外，非酒精性脂肪性肝病(NAFLD)与甲状腺激素也有密切的关系。一方面，NAFLD患者对甲状腺激素的转化、灭活等功能有影响，可导致血清甲状腺激素水平的下降；另一方面甲状腺激素水平的下降进一步造成脂质代谢紊乱、糖代谢紊乱，参与NAFLD的发生。有研究表明，用胆碱-蛋氨酸缺乏饮食诱导 大鼠脂肪肝形成，再喂饲T3后可以观察到脂肪肝的逆转(Perra A,et al.Faseb,2008,22(8):2981)。
然而，内源性的甲状腺激素是非选择性的，存在副作用，例如甲状腺机能亢进，特别是心血管毒性有关的副作用。因此，避免甲状腺机能亢进的不良效果，同时保持甲状腺激素的有益效果的甲状腺激素类似物(例如甲状腺激素β受体激动剂)的开发将打开治疗以下疾病患者的新途径：如肥胖，高脂血症，高胆固醇血症，糖尿病，肝脂肪变性，非酒精性脂肪性肝病，动脉粥样硬化，心血管疾病，甲状腺功能减退，甲状腺癌，甲状腺疾病，以及相关病症和疾病。
发明内容
本发明提供了一类对甲状腺激素β受体具有较好的激动活性的化合物，此类化合物及其组合物可以制备用于预防、治疗或减轻患者非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌的药物。
一方面，本发明涉及一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2020117131-appb-000001
其中，
Y为-O-、-S-、-NR c-、-CR aR b-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-；
L为不存在、-O-、-S-、-NR c-、-CR dR e-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-；
各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基；
R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1- 6烷基或氰基C 1-6烷基；
M为-C(＝O)-、-C(＝S)-、-S(＝O) 2-或-S(＝O)-；E 1为N、CH或CR z，其中R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1- 6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基；
E 2为CR 2；
E 3为N或CR 3；
R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基；
R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1- 6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-C(＝O)-C 1- 6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-C(＝O)-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、 -SH、-OH、-NH 2、＝O、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1- 6卤代烷氧基的取代基所取代；W为-OCH 2COOH、-NHC(＝O)COOH、-NHCH 2COOH、
Figure PCTCN2020117131-appb-000002
Figure PCTCN2020117131-appb-000003
R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1- 6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或氰基C 1-6烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基和氰基C 1-6烷基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代；
R 5为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。
在一些实施方案中，R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、甲氨基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基或氰基甲基。
在一些实施方案中，各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3或三氟甲氧基。
在一些实施方案中，R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基；
R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1- 4烷氨基、-C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、C 1-4烷基、C 1-4 烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基的取代基所取代。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基或噁唑基，其中所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CHF 2、-CH 2F、-CH 2CF 3、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基和噁唑基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF 3、-CHF 2、-CH 2CF 3、三氟甲氧基或二氟甲氧基的取代基所取代。
在一些实施方案中，R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)NH 2、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基或氰基甲基，其中所述甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)NH 2、S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基和氰基甲基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代。
在一些实施方案中，R 5为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基、萘基或5-6个原子组成的杂芳基。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物，任选地，进一步包含药学上可 接受的载体、赋形剂、辅剂、媒介物中的任意一种或它们的任意组合。
另一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于激动甲状腺激素受体；或用于预防、治疗或减轻由激活甲状腺激素受体介导的疾病。
在一些实施方案中，本发明所述甲状腺激素受体为甲状腺激素β受体。
在一些实施方案中，本发明所述由激活甲状腺激素受体介导的疾病为非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌。
在一些实施方案中，本发明所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、隐源性肝硬化或原发性肝癌。
在一些实施方案中，本发明所述代谢紊乱为脂质代谢紊乱或糖代谢紊乱。
前面所述内容只概述了本发明的某些方面，但不限于这些方面。这些方面及其他的方面的内容将在下面更加具体完整的描述。
具体实施方式
本发明提供了一类对甲状腺激素β受体具有较好的激动活性的化合物及其制备方法，包含所述化合物的药物组合物及其用途。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的范围中。
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料，在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用的方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999和"March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley & Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
除非另有说明，本发明所用在说明书和权利要求书中的术语具有下述定义。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“未被取代或被……取代”这个术语可以交换使用。术语“任选地”，“任选的”或“任选”是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。一般而言，除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的 结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、＝O、-NH 2、-SH、-OCH 2COOH、-NHC(＝O)COOH、-NHCH 2COOH、
Figure PCTCN2020117131-appb-000004
Figure PCTCN2020117131-appb-000005
-C(＝O)-烷氧基、-C(＝O)-烷基、-C(＝O)-烷氨基、-S(＝O) 2-烷基、-S(＝O) 2-C 1-6烷氨基、烷基、烷氧基、烷硫基、烷氨基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、氰基烷基、羧基烷基、烯基、炔基、环烷基、碳环基、杂环基、芳基、杂芳基，等等，其中所述R 4和R 5具有本发明所述的定义。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各……独立地为”与“……各自独立地为”和“……独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的C 1烷基(甲基)、C 2烷基(乙基)、C 3烷基、C 4烷基、C 5烷基和C 6烷基；“C 3-8环烷基”特别指独立公开的C 3环烷基、C 4环烷基、C 5环烷基、C 6环烷基、C 7环烷基和C 8环烷基；“5-8个原子组成的杂芳基”指5个原子组成的杂芳基、6个原子组成的杂芳基、7个原子组成的杂芳基和8个环原子组成的杂芳基。
在本说明书的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应当理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“烷基”或“烷基基团”是指含1-20个碳原子的，饱和的直链或支链的一价的烃基基团，其中所述烷基基团可以任选地被一个或多个本发明所述的取代基所取代。在一些实施方案中，烷基基团含有1-10个碳原子，即C 1-10烷基；在一些实施方案中，烷基基团含有1-8个碳原子，即C 1-8烷基；在一些实施方案中，烷基基团含有1-6个碳原子，即C 1-6烷基；在一些实施方案中，烷基基团含有1-4个碳原子，即C 1-4烷基；在一些实施方案中，烷基基团含有1-3个碳原子，即C 1-3烷基；在一些实施方案中，烷基含有1-2个碳原子，即C 1-2烷基。
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点为碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。在一些实施方案中，烯基基团包含2-8个碳原子，即C 2-8烯基；在一些实施方案中，烯基基团包含2-6个碳原子，即C 2-6烯基；在一些实施方案中，烯基基团包含2-4个碳原子，即 C 2-4烯基。
烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、丙烯基(-CH＝CHCH 3)、丁烯基(-CH＝CHCH 2CH 3、-CH 2CH＝CHCH 3、-CH 2CH 2CH＝CH 2、-CH＝C(CH 3) 2、-CH＝C(CH 3) 2、-CH 2C(CH 3)＝CH 2)、戊烯基(-CH 2CH 2CH 2CH＝CH 2、-CH 2CH 2CH＝CHCH 3、-CH 2CH 2CH＝CHCH 3、-CH 2CH＝CHCH 2CH 3、-CH＝CHCH 2CH 2CH 3、-CH 2CH 2C(CH 3)＝CH 2、-CH 2CH＝C(CH 3) 2、-CH＝CHCH(CH 3) 2、-C(CH 2CH 3)＝CHCH 3、-CH(CH 2CH 3)CH＝CH 2)，等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点为碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子，即C 2-8炔基；在一些实施方案中，炔基基团包含2-6个碳原子，即C 2-6炔基；在一些实施方案中，炔基基团包含2-4个碳原子，即C 2-4炔基。炔基的实例包括，但并不限于，乙炔基(-C≡CH)、1-丙炔基(-C≡CH-CH 3)、炔丙基(-CH 2C≡CH)、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、1-己炔基、1-庚炔基、1-辛炔基，等等。
术语“烷氧基”是指烷基基团通过氧原子与分子其余部分相连，即-O-烷基，其中烷基基团具有如本发明所述的含义，其中，所述烷氧基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，烷氧基基团含有1-8个碳原子，即C 1-8烷氧基；在一些实施方案中，烷氧基基团含有1-6个碳原子，即C 1-6烷氧基；在一些实施方案中，烷氧基基团含有1-4个碳原子，即C 1-4烷氧基；在一些实施方案中，烷氧基基团含有1-3个碳原子，即C 1-3烷氧基；在一些实施方案中，烷氧基含有1-2个碳原子，即C 1-2烷氧基。
烷氧基基团的实例包含，但并不限于，甲氧基(MeO,-OCH 3)，乙氧基(EtO,-OCH 2CH 3)，正丙基氧基(n-PrO,n-丙氧基,-OCH 2CH 2CH 3)，异丙基氧基(i-PrO,i-丙氧基,-OCH(CH 3) 2)，1-丁氧基(n-BuO,n-丁氧基,-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO,i-丁氧基,-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO,s-丁氧基,-OCH(CH 3)CH 2CH 3)，2-甲基-异丙基氧基(t-BuO,t-丁氧基,-OC(CH 3) 3)，1-戊氧基(n-戊氧基,-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。
术语“烷氨基”包括“N-烷氨基”和“N,N-二烷氨基”，表示氨基基团分别独立地被一个或两个烷基基团所取代，所述烷基基团具有本发明所述的定义。其中，所述烷氨基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，烷氨基是一个或两个C 1-6烷基连接到氮原子上的烷氨基基团，即C 1-6烷氨基；在一些实施方案中，烷氨基是一个或两个C 1-4烷基连接到氮原子上的烷氨基基团，即C 1-4烷氨基；在一些实施方案中，烷氨基是一个或两个C 1-2烷基连接到氮原子上的烷氨基基团，即C 1-2烷氨基。烷氨基基团的实例包括，但并不限于，甲氨基(N-甲氨基)，乙氨基(N-乙氨基)，二甲氨基(N,N-二甲氨基)，二乙氨基(N,N-二乙氨基),正丙基氨基(N-正丙基氨基)，异丙基氨基(N-异丙基氨基)，叔丁基氨基(N-叔丁基氨基)等等。
术语“烷硫基”是指烷基基团通过硫原子与分子其余部分相连，即-S-烷基，其中烷基基团具有如本发明所述的含义，其中，所述烷硫基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，烷硫基基团含有1-8个碳原子，即C 1-8烷硫基；在一些实施方案中，烷硫基基团含有1-6个碳原子，即C 1-6烷硫基；在一些实施方案中，烷硫基基团含有1-4个碳原子，即C 1-4烷硫基；在一些实施方案中，烷硫基基团含有1-3个碳原子，即C 1-3烷硫基；在一些实施方案中，烷硫基基团含有1-2个碳原子，即C 1-2烷硫基。烷硫基基团的实例包括，但并不限于，甲硫基(-SCH 3)，乙硫基(-SCH 2CH 3)等等。
术语“卤代烷基”是指具有一个或者多个卤素取代基的烷基，其中，所述卤代烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，卤代烷基基团含有1-10个碳原子，即C 1-10卤代烷基；在一些实施方案中，卤代烷基基团含有1-8个碳原子，即C 1-8卤代烷基；在一些实施方案 中，卤代烷基基团含有1-6个碳原子，即C 1-6卤代烷基；在一些实施方案中，卤代烷基基团含有1-4个碳原子，即C 1-4卤代烷基；在一些实施方案中，卤代烷基基团含有1-3个碳原子，即C 1-3卤代烷基；在一些实施方案中，卤代烷基基团含有1-2个碳原子，即C 1-2卤代烷基。卤代烷基的实例包括，但并不限于，氟甲基(-CH 2F)、二氟甲基(-CHF 2)、三氟甲基(-CF 3)、氟乙基(-CHFCH 3,-CH 2CH 2F)、二氟乙基(-CF 2CH 3,-CFHCFH 2,-CH 2CHF 2)、全氟乙基、氟丙基(-CHFCH 2CH 3,-CH 2CHFCH 3,-CH 2CH 2CH 2F)、二氟丙基(-CF 2CH 2CH 3,-CFHCFHCH 3,-CH 2CH 2CHF 2,-CH 2CF 2CH 3,-CH 2CHFCH 2F)、三氟丙基、1,1-二氯乙基、1,2-二氯丙基，等等。
术语“卤代烷氧基”是指烷氧基基团被一个或多个卤素取代基所取代，其中，所述卤代烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中，卤代烷氧基基团含有1-10个碳原子，即C 1-10卤代烷氧基；在一些实施方案中，卤代烷氧基基团含有1-8个碳原子，即C 1-8卤代烷氧基；在一些实施方案中，卤代烷氧基基团含有1-6个碳原子，即C 1-6卤代烷氧基；在一些实施方案中，卤代烷氧基基团含有1-4个碳原子，即C 1-4卤代烷氧基；在一些实施方案中，卤代烷氧基基团含有1-3个碳原子，即C 1-3卤代烷氧基；在一些实施方案中，卤代烷基基团含有1-2个碳原子，即C 1-2卤代烷氧基。卤代烷氧基的实例包括，但并不限于，三氟甲氧基(-OCF 3)、二氟甲氧基(-OCHF 2)等。
术语“羟基烷基”是指被一个或多个羟基(-OH)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述羟基烷基可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，本发明所述的羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-6烷基，即，羟基C 1-6烷基；在一些实施方案中，羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-4烷基，即，羟基C 1-4烷基；在一些实施方案中，羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-2烷基，即，羟基C 1-2烷基。羟基烷基基团的实例包括，但不限于，羟基甲基(例如，-CH 2OH)、羟基乙基(例如，2-羟基乙基)、羟基正丙基(例如，-CH 2CH 2CH 2OH)，等等。
术语“氨基烷基”是指被一个或多个氨基(-NH 2)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述氨基烷基可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，本发明所述的氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-6烷基，即，氨基C 1-6烷基；在一些实施方案中，氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-4烷基，即，氨基C 1-4烷基；在一些实施方案中，氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-2烷基，即，氨基C 1-2烷基。氨基烷基基团的实例包括，但不限于，氨基甲基(-CH 2NH 2)、二氨基甲基(-CH(NH 2) 2)、氨基乙基(例如，2-氨基乙基)、氨基正丙基(例如，-CH 2CH 2CH 2NH 2)，等等。
术语“氰基烷基”是指被一个或多个氰基(-CN)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述氰基烷基可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，本发明所述的氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-6烷基，即，氰基C 1-6烷基；在一些实施方案中，氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-4烷基，即，氰基C 1-4烷基；在一些实施方案中，氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-2烷基，即，氰基C 1-2烷基。氰基烷基基团的实例包括，但不限于，氰基甲基(例如，-CH 2CN)、氰基乙基(例如，2-氰基乙基)等等。
术语“羧基烷基”是指被一个或多个羧基(-COOH)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述羧基烷基可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，本发明所述的羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-6烷基，即，羧基C 1-6烷基；在一些实施方案中，羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-4烷基，即，羧基C 1-4烷基；在一些实施方案中，羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-2烷基，即，羧基C 1-2烷基。羧基烷基基团的实例包括，但不限于，羧基甲基、羧基乙基(例如，2-羧基乙基)等等。
术语“环烷基”表示含有3-12个环碳原子的，单价或多价的非芳香性的饱和单环、双环或三环体系，其中，所述环烷基基团任选被本发明所描述的取代基所取代。在一些实施方案中，环烷基是含3-10个环碳原 子的环体系，即C 3-10环烷基；在一些实施方案中，环烷基是含3-8个环碳原子的环体系，即C 3-8环烷基；在一些实施方案中，环烷基是含3-6个环碳原子的环体系，即C 3-6环烷基。环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基，环庚基，环辛基等等。
术语“碳环基”是指含有3-14个环碳原子的，单价或多价的非芳香性的饱和或部分不饱和的单环、双环或三环碳环体系。术语“碳环”、“碳环基”或“碳环的”在此处可交换使用。在一些实施方案中，碳环的环碳原子的数量为3-12个，即C 3-12碳环基；在一些实施方案中，碳环的环碳原子的数量为3-10个，即C 3-10碳环基；在一些实施方案中，碳环的环碳原子的数量为3-8个，即C 3-8碳环基；在一些实施方案中，碳环的环碳原子的数量为3-6个，即C 3-6碳环基；在一些实施方案中，碳环的环碳原子的数量为5-6个，即C 5-6碳环基；在一些实施方案中，碳环的环碳原子的数量为5-8个，即C 5-8碳环基。在一些实施方案中，碳环的环碳原子的数量为6-8个，即C 6-8碳环基。碳环基基团的实例包括，但并不限于，环烷基，环烯基和环炔基。碳环基基团的实例进一步包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基，二环[2.2.2]辛基，二环[2.2.1]庚基，二环[3.3.1]壬基，二环[3.2.3]壬基，等等。
术语“杂环基”是指包含3-12个原子的饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少有一个环原子选自氮、硫、氧和磷原子等杂原子，其中，所述杂环基是非芳香性的，且不含任何的芳香环，所述杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。术语“杂环基”包括单环、双环或多环稠合、螺式或桥连杂环环系。双环杂环基包括桥连双环杂环基、稠合双环杂环基和螺双环杂环基。术语“杂环基”和“杂环”在此处可交换使用。除非另有说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选被-C(＝O)-替代。环的硫原子可以任选被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。环的磷原子可以任选地被氧化成P-氧化合物。在一些实施方案中，杂环基为3-10个原子组成的环体系，即3-10个原子组成的杂环基；在一些实施方案中，杂环基为5-10个原子组成的环体系，即5-10个原子组成的杂环基；在一些实施方案中，杂环基为5-8个原子组成的环体系，即5-8个原子组成的杂环基；在一些实施方案中，杂环基为6-8个原子组成的环体系，即6-8个原子组成的杂环基；在一些实施方案中，杂环基为5-6个原子组成的环体系，即5-6个原子组成的杂环基；在一些实施方案中，杂环基为3-6个原子组成的环体系，即3-6个原子组成的杂环基；在一些实施方案中，杂环基为3个环原子组成的体系；在一些实施方案中，杂环基为4个原子组成的环体系；在其他一些实施方案中，杂环基为5个原子组成的环体系；在其他一些实施方案中，杂环基为6个原子组成的环体系。
杂环基的实例包括，但不限于：环氧乙烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢吡咯基，二氢吡咯基，四氢呋喃基，二氢呋喃基，四氢吡喃基，二氢吡喃基，四氢噻吩基，二氢噻吩基，四氢吡啶基，二氢吡啶基(例如，1,2-二氢吡啶基、1,4-二氢吡啶基)，四氢嘧啶基，二氢嘧啶基，四氢吡嗪基，二氢吡嗪基，四氢哒嗪基，二氢哒嗪基，1,3-二氧环戊基，二硫环戊基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，等等。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-哌啶酮基，3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基和1,1-二氧代硫代吗啉基。桥连杂环基基团包括，但不限于，2-氧杂二环[2.2.2]辛基、1-氮杂二环[2.2.2]辛基、3-氮杂二环[3.2.1]辛基，等等。
术语“m个原子组成的”，其中m是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是m。例如，哌啶基是6个原子组成的杂环基，而呋喃基是5个原子组成的杂芳基基团。又如，“5-8个原子组成的杂芳基”是指5、6、7或8个原子组成的杂芳基基团。
术语“芳基”表示含有6-14个环原子的单环，双环或三环的芳香性碳环体系，其中，每一个环包含3-7 个环原子。在一些实施方案中，芳基基团含有6-12个环原子的碳环体系，即C 6-12芳基。在一些实施方案中，芳基基团含有6-10个环原子的碳环体系，即C 6-10芳基。其中，所述芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。术语“芳基”可以和术语“芳环”或“芳香环”交换使用，芳基基团的实例包括，但不限于，苯基，茚基，萘基和蒽基，等等。
术语“杂芳基”表示含有5-14个环原子的，单价或多价的单环、双环或三环的芳香性体系，其中，至少有一个环包含一个或多个杂原子，其中每一个环包含5-7个环原子，其中至少有一个环体系是芳香族的，。其中，所述杂芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。除非另外说明，所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C，或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。当杂芳基基团存在-CH 2-基团时，所述-CH 2-基团可以任选地被-C(＝O)-替代。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S，P和N的杂原子的5-8个原子组成的杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S，P和N的杂原子的5-7个原子组成的杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S，P和N的杂原子的5-6个原子组成的杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S，P和N的杂原子的5个原子组成的杂芳基；在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S，P和N的杂原子的6个原子组成的杂芳基。
杂芳基的实例，包括以下的单环基团，但并不限于这些单环基团：呋喃基(2-呋喃基，3-呋喃基)，咪唑基(N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基)，异噁唑基(3-异噁唑基，4-异噁唑基，5-异噁唑基)，噁唑基(2-噁唑基，4-噁唑基，5-噁唑基)，吡咯基(N-吡咯基，2-吡咯基，3-吡咯基)，吡啶基(2-吡啶基，3-吡啶基，4-吡啶基)，嘧啶基(2-嘧啶基，4-嘧啶基，5-嘧啶基)，哒嗪基(如3-哒嗪基)，噻唑基(2-噻唑基，4-噻唑基，5-噻唑基)，四唑基(如5H-四唑基，2H-四唑基)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，噻吩基(2-噻吩基，3-噻吩基)，吡唑基(如2-吡唑基和3-吡唑基)，异噻唑基，噁二唑基(如1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基)，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，吡嗪基，1,3,5-三嗪基，吡啶-2(1H)-酮基，吡啶-4(1H)-酮基；也包括以下的双环或者三环基团，但绝不限于这些基团：吲哚啉基、1,2,3,4-四氢异喹啉基、苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，吩噁噻基，二苯并咪唑基，二苯并呋喃基，二苯并噻吩基。
术语“环烷基烷基”、“杂环基烷基”、“芳基烷基”和“杂芳基烷基”分别是环烷基、杂环基、芳基和杂芳基各自独立地通过烷基基团与分子其余部分相连接，所述环烷基、杂环基、芳基、杂芳基和烷基分别具有本发明所描述的含义；这样的实例包括但不限于，环丙基甲基、吗啉基甲基、哌啶基甲基、四氢呋喃基甲基、苯基甲基(即，苄基)、苯基乙基、吡啶基甲基、吡啶基乙基或嘧啶基甲基等。
术语“杂原子”是指O、S、N、P和Si，包括S，N和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR T(像N-取代的吡咯烷基中的NR T，R T为N上的取代基)。
术语“卤素”是指F、Cl、Br或I。
术语“硝基”是指-NO 2。
术语“巯基”是指-SH。
术语“羟基”是指-OH。
术语“氨基”是指-NH 2。
术语“氰基”是指-CN。
术语“羧酸”或“羧基”是指-C(＝O)OH或-COOH。
术语“羰基”，表示-(C＝O)-。
术语“氘”是指氘代，即 2H。
术语“氧代”是指＝O。
术语“保护基团”或“PG”是指当化合物中其他官能团发生反应的时候，用来阻断或保护特定的功能性的取代基团。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括，但不限于，乙酰基、苯甲酰基、苄基、对甲氧基苄基和硅烷基等。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
术语“离去基团”或“LG”是指在化学反应中从一较大分子中脱离的原子或官能基，是亲核取代反应与消除反应中应用的术语。在亲核取代反应中，被亲核试剂进攻的反应物称为底物，而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。常见的离去基团例如但不限于，卤素原子、酯基、磺酸酯基、硝基、叠氮基或羟基等。
术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。优选地，本发明所述的“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可药典上列举的在动物中、特别是人体中使用的。
术语“载体”包括任何溶剂，分散介质，包衣衣料，表面活性剂，抗氧化剂，防腐剂(例如抗细菌剂、抗真菌剂)，等渗剂，盐，药物稳定剂，粘合剂，赋形剂，分散剂，润滑剂，甜味剂，调味剂，着色剂，或其组合物，这些载体都是所属技术领域技术人员已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。除了任意常规载体与活性成分不相容的情况外，涵盖其在治疗或药物组合物中的用途。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体、赋形剂、稀释剂、粘合剂、填充剂等辅料，以及抗糖尿病试剂、抗高血糖试剂、抗肥胖症试剂、抗高血压试剂、抗血小板试剂、抗动脉粥样硬化试剂或者降脂试剂等附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci, 1997,66,1-19所记载的。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。
本发明化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。如果可能的话，具有不饱和双键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。
因此，如本发明所描述的那样，本发明的化合物可以以可能的异构体、旋转异构体、阻转异构体、互变异构体中的一种形式或其混合物的形式存在，例如为基本纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物形式。
可以根据组分的物理化学差异将所得的任何异构体混合物分离成纯或基本纯的几何或光学异构体、非对映异构体、外消旋体，例如通过色谱法和/或分步结晶来进行分离。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高压液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备(如Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972))。
本发明还包括同位素标记的本发明化合物，其除以下事实外与本发明所述的那些化合物相同：一个或多个原子被原子质量或质量数不同于天然常见原子质量或质量数的原子代替。还可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 13C， 14C， 15N， 16O， 17O， 31P， 32P， 36S， 18F和 37Cl。
包含前述同位素和/或其他原子的其他同位素的本发明化合物以及所述化合物的药学上可接受的盐都包括在本发明范围内。同位素标记的本发明化合物，例如放射性同位素，如 3H和 14C掺入到本发明化合物中可用于药物和/或底物组织分布分析。由于易于制备以及检测，氚代的，即， 3H，以及碳-14，即 14C，同位素特别优选。此外，用质量数较大的同位素，如氘，即 2H取代，可提供一些更大的代谢稳定性的治疗上的优势，例如增加的体内半衰期或减少的剂量需求。因此，在一些情形下可能是优选的。
本发明使用的立体化学定义和惯例大体上按照S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley & Sons，Inc.，New York，1994所记载的定义和惯例。本发明化合物可含有不对称中心或手性中心，因此以不同的立体异构形式存在。所预期的是，本发明化合物的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)及它们的混合物如外消旋混合物，也包含在本发明范围之内。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀d和l或(+)和(–)是用于指定化合物所致平面偏振光旋转 的符号，其中(–)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对应异构体混合物，这取决于不对称碳原子的数量。旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。如果此化合物含有一个双键，取代基可能为E或Z构型；如果此化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。
除非另外指出，本发明描述的结构还表示包括此结构的所有异构体(如，对映体、非对映体、阻转异构体(atropisomer)和几何(或构象))形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此，本发明化合物的单个立体化学异构体以及对映体混合物、非对映体混合物和几何异构体(或构象异构体)混合物均在本发明的范围之内。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
术语“几何异构体”也称“顺反异构体”，因双键(包括烯烃的双键、C＝N双键和N＝N双键)或环碳原子的单健不能自由旋转而引起的异构体。
本发明所使用的术语“受治疗者”和“患者”可交换地使用。术语“受治疗者”和“患者”指动物(例如，鸡、鹌鹑或火鸡等鸟类或哺乳动物)，特别是包括非灵长类动物在内的“哺乳动物”(例如，牛、猪、马、羊、兔、豚鼠、大鼠、猫、狗和小鼠)和灵长类动物(例如，猴子、黑猩猩和人类)，更特别的是人类。在一个实施方案中，受治疗者为非人类动物，例如家畜(例如，马、牛、猪或羊)或宠物(例如，狗、猫、豚鼠或兔)。在另一些实施方案中，“患者”是指人类。
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明化合物的描述
本发明提供了一类对甲状腺激素β受体具有较好的激动活性的化合物，用于制备治疗非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌的药物。本发明也提供了制备这些化合物的方法、包含这些化合物的药物组合物，以及使用这些化合物和药物组合物制备治疗哺乳动物，尤其是人类的上述疾病的药物的方法。与已有的同类化合物相比，本发明的化合物不仅具有良好的药理活性和选择性，还具有优良的体内代谢动力学性质和体内药效学性质。本发明所述化合物的制备方法简单易行，工艺方法稳定，适合工业化生产。因此，本发明提供的化合物相对于目前已有的同类化合物而言，具有更优良的成药性。
具体地说：
一方面，本发明涉及一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2020117131-appb-000006
其中，L、W、Y、M、E 1、E 2、E 3、R 1、R 3a、R 3b、R 3c和R 3d具有如本发明所述的定义。
在一些实施方案中，Y为-O-、-S-、-NR c-、-CR aR b-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-，其中所述R a、R b和R c具有本发明所述的定义。
在一些实施方案中，L为不存在、-O-、-S-、-NR c-、-CR dR e-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-，其中所述R c、R d和R e具有本发明所述的定义。
在一些实施方案中，各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基。
在一些实施方案中，R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基或氰基C 1-6烷基。
在一些实施方案中，M为-C(＝O)-、-C(＝S)-、-S(＝O) 2-或-S(＝O)-。在一些实施方案中，E 1为N、CH或CR z，其中R z具有本发明所述的定义。
在一些实施方案中，E 2为N或CR 2，其中所述R 2具有本发明所述的定义。优选地，E 2为CR 2，其中所述R 2具有本发明所述的定义。
在一些实施方案中，E 3为N或CR 3，其中所述R 3具有本发明所述的定义。
在一些实施方案中，R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基。
在一些实施方案中，R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1- 6烷氨基、-C(＝O)-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-C(＝O)-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基的取代基所取代。
在一些实施方案中，W为-OCH 2COOH、-NHC(＝O)COOH、-NHCH 2COOH、
Figure PCTCN2020117131-appb-000007
Figure PCTCN2020117131-appb-000008
其中所述R 4和R 5具有本发明所述的定义。
在一些实施方案中，R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1- 6烷基、-S(＝O) 2-C 1-6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或氰基C 1-6烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基和氰基C 1- 6烷基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代。
在一些实施方案中，R 5为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。
在一些实施方案中，R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、氨基C 1-4烷基或氰基C 1-4烷基。
在一些实施方案中，R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、甲氨基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基或氰基甲基。
在一些实施方案中，各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基。
在一些实施方案中，各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3或三氟甲氧基。
在一些实施方案中，R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)C 1-3烷基、C 6-10芳基、C 6-10芳基C 1-3烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)C 1-3烷基。
在一些实施方案中，R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基。
在一些实施方案中，R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、C 6-10芳基、C 6-10芳基C 1-3烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)C 1-3烷基。
在一些实施方案中，R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、 甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1- 4烷氨基、-C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基的取代基所取代。
在一些实施方案中，R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基或噁唑基，其中所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CHF 2、-CH 2F、-CH 2CF 3、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基和噁唑基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF 3、-CHF 2、-CH 2CF 3、三氟甲氧基或二氟甲氧基的取代基所取代。
在一些实施方案中，R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-4烷基、C 2-4烯基、C 2-4炔基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1- 4烷基、-S(＝O) 2-C 1-4烷氨基、C 1-4烷氨基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基或氰基C 1-4烷基，其中所述C 1-4烷基、C 2-4烯基、C 2-4炔基、-C(＝O)-C 1-4烷氧 基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 1-4烷氨基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、氨基C 1-4烷基、羧基C 1-4烷基和氰基C 1- 4烷基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代。
在一些实施方案中，R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)NH 2、-C(＝O)-N(CH 3) 2、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基或氰基甲基，其中所述甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)NH 2、S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基和氰基甲基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代。
在一些实施方案中，R 5为H、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。
在一些实施方案中，R 5为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基、萘基或5-6个原子组成的杂芳基。
另一方面，本发明涉及以下其中之一的结构，或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2020117131-appb-000009
Figure PCTCN2020117131-appb-000010
Figure PCTCN2020117131-appb-000011
Figure PCTCN2020117131-appb-000012
另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物。
在一些实施方案中，本发明所述的药物组合物，任选地，进一步包含药学上可接受的载体、赋形剂、辅剂、媒介物中的任一种或它们的任意组合。
另一方面，本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备药物中的用途，其中，所述药物用于激动甲状腺激素受体；或用于预防、治疗或减轻由激动甲状腺激素调节的疾病。
另一方面，本发明涉及一种使用本发明所述的化合物或药物组合物来激动甲状腺激素受体的方法，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病的方法，所述方法是给予有需要的个体所述化合物或所述药物组合物的有效治疗量。并且，本发明提供的上述化合物或其药物组合物可以与其它疗法或治疗剂共同施用。施用方式可以为同时、顺序或以一定时间间隔进行。
另一方面，本发明涉及将本发明所述的化合物或药物组合物用于激动甲状腺激素受体，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病。
在一些实施方案中，本发明所述由甲状腺受体调节的疾病为由激动甲状腺受体介导的疾病。
在一些实施方案中，本发明所述甲状腺激素受体为甲状腺激素β受体。
在一些实施方案中，本发明所述的由甲状腺激素受体激动剂调节的疾病为非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌。
在一些实施方案中，本发明所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、隐源性肝硬化或原发性肝癌。
在一些实施方案中，本发明所述的代谢紊乱包含脂质代谢紊乱或糖代谢紊乱。
实施治疗、预防或延缓等作用所需的化合物或药物组合物的剂量通常取决于施用的具体化合物、患者、 具体疾病或病症及其严重程度、给药途径和频率等，并且需要由主治医师根据具体情况判定。例如，在通过经静脉途径施用本发明提供的化合物或药物组合物时，可以每周一次甚至以更长时间间隔进行施用。
在一些实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。
本发明的化合物还包括这样的化合物的其他盐，该其他盐不一定是药学上可接受的盐，并且可以用作用于制备和/或提纯本发明的化合物和/或用于分离本发明的化合物的对映体的中间体。
而且，本发明化合物、包括其盐也可以以其水合物形式获得，或者包括其他用于其结晶的溶剂。本发明化合物可以固有地或通过设计形成具有可药用溶剂(包括水)的溶剂化物；因此，本发明意在包括溶剂化的和未溶剂化的形式。
本发明的化合物的药物组合物、制剂和给药
本发明涉及一种药物组合物，其包括本发明所述化合物或实施例中所示结构的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物及药学上可接受的盐或它们的前药。所述药物组合物进一步包含至少一种药学上可接受的载体、赋形剂、辅剂、媒介物或它们的组合，以及任选地、其它的治疗和/或预防成分。在一些实施方案，所述药物组合物包含治疗有效量的本发明所述化合物和至少一种药学上可接受的载体、赋形剂、辅剂或媒介物。本发明的药物组合物中化合物的量能有效地可探测地激动生物标本或患者体内的甲状腺激素β受体。
药学上可接受的载体可能含有不会过度抑制化合物的生物活性的惰性成分。药学上可接受的载体应生物相容，例如无毒、非炎性、非免疫原性或一旦施用给患者无其它不良反应或副作用。可采用标准制药技术。
像本发明所描述的，本发明所述的药物组合物或药学上可接受的组合物进一步包含药学上可接受的载体、赋形剂、辅剂或媒介物，像本发明所应用的，包括适合于特有的目标剂型的，任何溶剂、稀释剂、液体赋形剂、分散剂、悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂或润滑剂，等等。Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams & Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York公开了配制药学上可接受的组合物中使用的各种载体及其公知制备方法。除了与本发明的化合物不相容的常规载体媒介，例如会产生不良生物效应或与药学上可接受的组合物中的任何其他组分发生有害的相互作用，其他任何常规的载体媒介及它们的用途也是本发明所考虑的范围。
可用作药学上可接受的载体的物质的一些实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质(例如吐温80、磷酸盐、甘氨酸、山梨酸或山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠或锌盐)、硅胶、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧化丙烯-嵌段共聚物、甲基纤维素、羟丙基甲基纤维素、羊毛脂、糖类(例如乳糖、葡萄糖和蔗糖)、淀粉(例如玉米淀粉和马铃薯淀粉)、纤维素及其衍生物(例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素)、粉状黄蓍胶、麦芽、凝胶、滑石、赋形剂(例如可可油和栓剂蜡)、油(例如花生油、棉花子油、红花油、芝麻油、橄榄油、玉米油和大豆油)、乙二醇(例如丙二醇或聚乙二醇)、酯(例如油酸乙酯和十二酸乙酯)、琼脂、缓冲剂(例如氢氧化镁和氢氧化铝)、褐藻酸、无热原水、等渗盐水、林格氏溶液(Ringer'ssolution)、乙醇和磷酸盐缓冲液以及其它无毒相容性滑润剂(例如硫酸月桂酯钠和硬脂酸镁)以及根据配制人的判断着色剂、防粘剂、涂层剂、甜味剂和增香剂、防腐剂和抗氧化剂也可存在于组合物中。
本发明的药物组合物可直接给药或随同合适的载体或赋形剂以医药组合物或药物形式给药，这是本领域所熟知的。本发明的治疗方法可包含向有需要的个体施以有效的本发明化合物。在一些实施方案中，所述个体为哺乳动物个体，在另一些实施方案中，所述个体为人类个体。
本发明所述化合物、药物组合物或药物的有效量可以通过常规方法试验容易地测定，最有效和方便的给药途径及最合适的制剂也可以通过常规试验测定。
本发明的化合物或组合物可以通过任何合适方式给药，可根据疾病的严重程度经口、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如同通过粉剂、药膏或滴剂)或喷鼻剂等向人或其它动物施用以上所述化合物和药学上可接受的组合物。
供口服的液体剂型包括但不限于药学上可接受的乳剂、微型乳剂、溶液、悬浮剂、糖浆和酏剂。除活性化合物外，液体剂型可能含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉花子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨聚糖的脂肪酸酯及其混合物。除惰性稀释剂外，口服组合物也可包括佐剂，例如湿润剂、乳化和悬浮剂、甜味剂、调味剂和增香剂。
可根据已知技术使用适合的分散或湿润剂和悬浮剂配制可注射制剂，例如无菌可注射水或油悬浮剂。无菌可注射制剂也可能是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮剂或乳剂，例如1,3-丁二醇中的溶液。在可接受的媒介物和溶剂中，可采用的是水、林格氏溶液.和等渗氯化钠溶液。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，脂肪酸，例如十八烯酸，用于制备注射剂。
例如，可通过细菌保留过滤器过滤或通过加入呈无菌固体组合物形式，使用之前可溶于或分散于无菌水或其它无菌可注射介质中的杀菌剂为可注射制剂灭菌。
为延长本发明所述化合物或组合物的作用，常常希望减缓化合物由皮下或肌肉注射的吸收。这可通过使用水溶性差的晶体或无定形物质的液体悬浮液实现。然后，化合物的吸收速率取决于其溶解速率，而溶解速率又取决于晶体大小和晶形。或者，通过将化合物溶解或悬浮于油媒介物中实现延迟吸收经肠胃外施用的化合物。通过在生物可降解的聚合物例如聚交酯-聚羟基乙酸中形成化合物的微胶囊矩阵制成可注射的储存形式。根据化合物与聚合物之比和采用的特殊聚合物的性质，可控制化合物释放速率。其它生物可降解的聚合物的实例包括聚原酸酯和聚酸酐。也可通过将化合物截留在与身体组织相容的脂质体或微型乳剂中制备可注射的储存制剂。
经直肠或阴道施用的组合物特别是可通过混合本发明所述化合物和适合的非刺激性赋形剂或载体，例如可可油、聚乙二醇或栓剂蜡制备的栓剂，所述赋形剂或载体在环境温度下为固体但在体温下为液体，并因此在直肠或阴道腔内融化并释放活性化合物。
口服固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒。在这种固体剂型中，活性化合物混有至少一种惰性的药学上可接受的赋形剂或载体例如柠檬酸钠或磷酸二钙和/或a)填料或膨胀剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；b)粘合剂，例如羧基甲基纤维素、藻酸盐、凝胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；c)保湿剂，例如甘油；d)崩解剂，例如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠；e)溶液阻滞剂，例如石蜡；f)吸收加速剂，例如季铵化合物；g)湿润剂，例如鲸蜡醇和单硬脂酸甘油酯；h)吸收剂，例如高岭土和膨润土；和i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、硫酸月桂酯钠及其混合物。在剂型为胶囊、片剂和丸剂的情况下，剂型也可包含缓冲剂。
也可使用如乳糖或奶糖以及高分子聚乙二醇等赋形剂将相似类型的固体组合物用作软和硬凝胶胶囊中的填料。可用包衣和壳，例如肠溶衣和制药领域众所周知的其它包衣制备片剂、糖锭、胶囊、丸剂和颗粒的固体剂型。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。
活性化合物也可呈现具有一种或多种上述赋形剂的微密封形式。在这种固体剂型中，活性化合物可能混有至少一种惰性稀释剂，例如蔗糖、乳糖或淀粉。一般地，这种剂型也可能包含除惰性稀释剂外的另外的物质，例如压片润滑剂和其它压片辅助剂，例如硬脂酸镁和微晶纤维素。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。
本发明所述化合物的局部或经皮施用剂型包括药膏、软膏、乳膏、洗剂、凝胶、粉剂、溶液、喷剂、吸入剂或贴片。在无菌条件下，活性化合物与药学上可接受的载体和任何需要的防腐剂或可能需要的缓冲剂。眼科制剂、耳滴剂和眼药水也被考虑到本发明的范围之内。另外，本发明考虑到具有提供控制化合物向身体递送的附加优点的皮肤贴片的用途。可通过将化合物溶解或分散于恰当介质中制成这种剂型。吸收促进剂也可用于提高化合物通过皮肤的流量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中控制速率。
也可经口、肠胃外，通过吸入喷剂经局部、直肠、鼻、口腔、阴道或通过植入药盒施用本发明所述的组合物。如本发明使用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉、关节内、滑膜腔内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。特别地，经口、腹膜内或静脉内施用组合物。
本发明所述组合物的无菌可注射形式可为水或油悬浮液。这些悬浮液可跟进本领域已知的技术使用适合的分散或湿润剂和悬浮剂制备。无菌可注射制剂也可能是于无毒的可经肠胃外接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液，例如，于1,3-丁二醇中的溶液。在可接受的媒介物和溶剂中，可采用的是水、林格氏溶液和等渗氯化钠溶液。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，正如尤其呈聚氧乙烯化形式的天然药学上可接受的油，例如橄榄油或蓖麻油，脂肪酸例如十八烯酸及其甘油酯衍生物用于制备注射剂。这些油溶液或悬浮液也可能含有长链醇稀释剂或分散剂，例如羧甲基纤维素或在配制药学上可接受的剂型(包括乳剂和悬浮液)中常用的类似分散剂。其它常用表面活性剂，例如Tweens、Spans和在生产药学上可接受的固体、液体或其它剂型中常用的其它乳化剂或生物利用率增强剂也可用于配制的目的。
可以任何口服可接受的剂型，包括但不限于胶囊、片剂、水悬浮液或溶液，口服本发明所述药物组合物。在为供口服片剂的情况下，常用载体包括但不限于乳糖和淀粉。通常还加入润滑剂，例如硬脂酸镁。为了以胶囊形式口服，有用的稀释剂包括乳糖和干玉米淀粉。当口服需要水悬浮液时，活性成分与乳化剂和悬浮剂结合。若需要，还可加入某些甜味剂、增味剂或着色剂。
或者，可以供直肠使用的栓剂形式施用本发明所述的药物组合物。可通过混合试剂和非刺激性赋形剂制备这些药物组合物，这种物质包括但不限于可可油、蜂蜡和聚乙二醇。
尤其是当治疗目标包括局部滴施易于接近的区域或器官，包括眼部、皮肤或低位肠道疾病时，还可局部施用本发明所述的药物组合物。易于为这些区域或器官的每一个制备适合的局部制剂。
以直肠栓剂制剂(见上文)或适合的灌肠剂制剂可实现对低位肠道的局部滴施。也可使用局部皮肤贴片。
对于局部滴施而言，可将药物组合物配制为含有悬浮或溶于一种或多种载体中的活性组分的适合药膏。适于局部滴施本发明的化合物的载体包括但不限于矿物油、凡士林油、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者，可将药物组合物配制为含有悬浮或溶于一种或多种药学上可接受的载体中的活性组分的适合洗剂或乳膏。适合的载体包括但不限于矿物油、山梨醇酐单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二醇、苯甲醇和水。
为了眼科使用，可用或不用防腐剂例如苯扎氯铵，将药物组合物配制为在等渗pH调节无菌盐水中的微粉化悬浮液，或特别是等渗pH调节无菌盐水中的溶液。或者，为了眼科使用，可将药物组合物配制为药膏，例如凡士林。
也可通过鼻用气化喷雾剂或吸入施用药物组合物。根据制药领域中众所周知的技术制备这种组合物并且采用苯甲醇和其它适合的防腐剂、提高生物利用率的吸收促进剂、碳氟化合物和/或其它常规增溶剂或分散剂制备成盐水中的溶液。
本发明化合物及药物组合物的用途
本发明提供的化合物或药物组合物可用于制备激动甲状腺激素受体的药物，或用于制备预防、治疗或减轻由甲状腺激素受体调节的疾病的药物。
本发明提供的化合物或药物组合物可用于激动甲状腺激素受体，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病。
本发明提供一种用于激动甲状腺激素受体的方法，或用于预防、治疗或减轻由甲状腺激素受体调节的疾病的方法，所述方法包括给予有治疗需要的患者治疗有效量的上述化合物或其药物组合物。并且，本发明提供的上述化合物或其药物组合物可以与其它疗法或治疗剂共同施用。施用方式可以为同时、顺序或以一定时间间隔进行。
本发明所述由甲状腺激素受体调节的疾病为激动甲状腺激素受体介导的疾病。
本发明所述甲状腺激素受体为甲状腺激素β受体。
本发明所述疾病是非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌，其中所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、隐源性肝硬化或原发性肝癌，其中所述代谢紊乱包含脂质代谢紊乱或糖代谢紊乱。
本发明的化合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
本发明的化合物或药学上可接受的药物组合物的“有效量”、“有效治疗量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。本发明的化合物或药学上可接受的药物组合物在相当宽的剂量范围内是有效的。例如，每天服用的剂量约在0.1mg-1000mg/人范围内，分为一次或数次给药。根据本发明的方法、化合物和药物组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度，特殊的因素，给药方式等。本发明的化合物或药物组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。
一般合成和检测方法
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如本发明所述。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的药物除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
化合物的结构是通过核磁共振( 1H-NMR、 13C-NMR或/和 19F-NMR)来确定的。 1H-NMR、 13C-NMR、 19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。 1H-NMR、 13C-NMR、 19F-NMR的测定是用Bruker Ultrashield-400核磁共振谱仪和Bruker Avance III HD 600核磁共振谱仪，测定溶剂为氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD或MeOH-d 4)或者氘代二甲基亚砜(DMSO-d 6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet,单峰)，d(doublet,双峰)，t(triplet,三重峰)，m(multiplet,多重峰)，br(broadened,宽峰)，dd(doublet of doublets,双二重峰)，dt(doublet of triplets,双三重峰)，td(triplet of doublets,三双重峰)，brs(broadened singlet,宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
制备纯化或制备拆分一般使用Novasep pump 250高效液相色谱仪。
LC-MS的测定用Agilen-6120Quadrupole LC/MS质谱仪。
柱层析一般使用青岛海洋化工300目～400目硅胶为载体。
本发明的起始原料是已知的，并且可以在市场上购买到得，购买自上海韶远公司(Shanghai Accela Company)、安耐吉公司(Energy Company)、百灵威公司(J&K)、天津阿法埃莎公司(Alfa Company)等公司，或者可以采用或者按照本领域已知的方法来合成。
氮气氛围是指反应瓶连接一个约1L容积的氮气气球或钢釜；
氢气氛围是指反应瓶连接一个约1L容积的氢气气球或者是一个约1L容积的不锈钢高压反应釜；
实施例中若无特殊说明，溶液是指水溶液；
实施例中若无特殊说明，反应温度为室温；
实施例中若无特殊说明，室温为20℃～40℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：二氯甲烷和甲醇体系，二氯甲烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节。
柱层析的洗脱剂的体系包括：A：石油醚和乙酸乙酯体系，B：二氯甲烷和乙酸乙酯体系，C：二氯甲烷和甲醇体系。溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。
HPLC是指高效液相色谱；
HPLC的测定使用安捷伦1260高压液相色谱仪(色谱柱:Agilent ZORBAX Eclipse Plus C18 4.6mm×150mm,3.5μm)；
HPLC测试条件：运行时间：25min 柱温：35℃ 检测波长：210nm；245nm；
流动相：A相：0.05％磷酸溶液 B相：乙腈；流速：1.0ml/min；
流动相梯度如表A所示：
表A
时间 流动相A的梯度 流动相B的梯度
0min 90％ 10％
15min 10％ 90％
20min 10％ 90％
25min 90％ 10％
生物测试试验中的分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离源(ESI)的Agilent G6430三重四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表B所示：
表B
全扫描 50～1400
碎裂电压 230V
毛细管电压 55V
干燥器温度 350℃
雾化器 0.28MPa
干燥器流速 10L/min
分析使用Agilent XDB-C18，2.1×30mm，3.5μm柱，注入5μL样品。分析条件：流动相为0.1％的甲酸水溶液(A)和0.1％的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表C所示：
表C
时间 流动相B的梯度
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min 终止
低分辨率质谱(MS)数据的测试条件是：Agilent 6120 Quadrupole HPLC-MS(柱子型号：Zorbax SB-C18,2.1×30mm,3.5μm,6min,流速为0.6mL/min，流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例)，在210nm/254nm用UV检测，用电喷雾电离(ESI)模式。
下面简写词的使用贯穿本发明：
DMSO-d 6：              氘代二甲基亚砜；         Boc：                  叔丁氧羰基；
DCC：                  二环己基碳二亚胺；       DMSO：                 二甲基亚砜；
CDCl 3：                氘代氯仿；               ％wt,mass％：          重量百分比；
CD 3OD：                氘代甲醇；               mL,ml：                毫升；
μL,μl：              微升；                   mol/L,mol/l：          摩尔/每升；
mol：                  摩尔；                   mmol/L,mmol/l,mM：     毫摩尔/升；
μmol/L,μmol/l,μM：  微摩尔/升；              nmol/L,nmol/l,nM：     纳摩尔/升；
g：                    克；                     h：                    小时；
mg：                   毫克；                   μg：                  微克；
ng：                   纳克；                   nm：                   纳米；
μm：                  微米；                   mm：                   毫米；
H 2：                   氢气；                   N 2：                   氮气；
min：                  分钟；                   MPa：                  兆帕；
TBSO：                 叔丁基二甲基硅氧基；     Et：                   乙基；
Me：                   甲基；                   ACN：                  乙腈；
TFA：                  三氟乙酸；               H 2O：                  水。
一般合成方法
制备本发明公开化合物的典型合成步骤如下面的合成方案所示。除非另外说明，X为氟、氯、溴或碘；各L、E 1、E 2、E 3、R 3a、R 3d和R 1具有如本发明所述的定义。
合成方案1：
Figure PCTCN2020117131-appb-000013
具有如通式(I-A)所示结构的化合物可以通过合成方案1描述的一般合成方法制备得到，其中R 4a为-CN或-CF 3。首先，化合物(I-a)与(I-b)在碱(如碳酸钾)作用下反应，得到化合物(I-c)；化合物(I-c)硝基还原，得到化合物(I-d)；化合物(I-d)氨基重氮化，并与(I-e)反应，得到化合物(I-f)；化合物(I-f)在碱(如乙酸钾)作用下关环，得到通式(I-A)所示的目标化合物。
合成方案2：
Figure PCTCN2020117131-appb-000014
具有如通式(I-d)所示结构的中间体也可以通过合成方案2描述的一般合成方法制备得到，其中，PG 1和PG 2各自独立地为氨基保护基，或者PG 1、PG 2与相连的氮原子一起形成5-10个原子组成杂环基或5-10个原子组成的杂芳基，该5-10个原子组成杂环基或5-10个原子组成的杂芳基具有保护氨基的作用；LG为离去基团。首先，化合物(I-g)与(I-b)在碱(如碳酸钾)作用下反应，得到化合物(I-h)；化合物(I-h)硝基还原，得到化合物(I-i)；化合物(I-i)氨基保护，得到化合物(I-j)；化合物(I-j)与化合物(I-k)进行反应得到(I-l)；化合物(I-l)脱去氨基保护，得到通式(I-d)所示的中间体。。
合成方案3：
Figure PCTCN2020117131-appb-000015
具有如通式(I-d)所示结构的中间体也可以通过合成方案3描述的一般合成方法制备得到，其中，LG为离去基团。首先，化合物(I-m)与化合物(I-k)进行反应得到(I-n)；化合物(I-n)脱去氨基保护，得到通式(I-d)所示结构的中间体。
合成方案4：
Figure PCTCN2020117131-appb-000016
具有如通式(I-m)所示中间体可以通过合成方案4描述的一般合成方法制备得到，其中X为卤素。首先，化合物(I-o)与(I-b)在碱(如碳酸钾)作用下反应，得到化合物(I-q)；化合物(I-q)脱甲基，得到化合物(I-h)；化合物(I-h)硝基还原，得到化合物(I-i)；化合物(I-i)氨基保护，得到化合物(I-m)。
合成方案5：
Figure PCTCN2020117131-appb-000017
具有如通式(I-d)所示结构的中间体也可以通过合成方案5描述的一般合成方法制备得到，其中，LG为离去基团。首先，化合物(I-h)与化合物(I-k)进行反应得到(I-r)；化合物(I-r)脱去氨基保护，得到 通式(I-d)所示结构的中间体。
合成方案6：
Figure PCTCN2020117131-appb-000018
具有如通式(I-h)所示中间体也可以通过合成方案6描述的一般合成方法制备得到。首先，化合物(I-s)与(I-b)在碱(如碳酸钾)作用下反应，得到化合物(I-t)；化合物(I-t)水解，得到化合物(I-h)。
合成方案7：
Figure PCTCN2020117131-appb-000019
具有如通式(I-B)所示结构的化合物可以通过合成方案4描述的一般合成方法制备得到，其中R 0为烷氧基、-OH或-NH 2。化合物(I-u)在酸性(如浓盐酸)条件下反应，得到化合物(I-B)。
制备实施例
实施例1 2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物1)
Figure PCTCN2020117131-appb-000020
步骤1)2-氟-5-(甲氧基甲氧基)吡啶1b
0℃下，将氢化钠(1.1g,28mmol,60mass％)加入到无水四氢呋喃(10mL)中，加入6-氟吡啶-3-醇1a(2.0g,18mmol)，随后滴加氯甲基甲醚(1.6mL,21mmol)，保持0℃反应8小时。加入水(50mL)淬灭反应，用乙酸乙酯(100mL)萃取，有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物1b(2.3g,产率83％)，为无色油状物。
步骤2)2-苄氧基-5-(甲氧基甲氧基)吡啶1c
将氢化钠(0.19g,4.8mmol,60mass％)溶于N,N-二甲基甲酰胺(8mL)，加入苯甲醇(0.40mL)和2-氟-5-(甲氧基甲氧基)吡啶1b(0.50g,3.2mmol)，室温反应2小时。加入水(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物 经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝9/1]纯化，得到标题化合物1c(0.55g,产率70％)，为无色液体。
1H NMR(400MHz,CDCl 3)δ(ppm)8.01(d,J＝2.9Hz,1H),7.49(d,J＝7.3Hz,2H),7.38(ddt,J＝18.8,14.5,7.2Hz,4H),6.79(d,J＝8.9Hz,1H),5.37(s,2H),5.13(s,2H),3.52(s,3H)。
步骤3)5-(甲氧基甲氧基)吡啶-2(1H)-酮1d
将2-苄氧基-5-(甲氧基甲氧基)吡啶1c(0.50g,2.0mmol)溶于甲醇(10mL)，加入10％钯碳(50mg)，置换氢气，氢化反应40分钟。将反应液过滤，滤液浓缩，得到标题化合物1d(0.31g,产率98％)，为类白色固体。
1H NMR(400MHz,CDCl 3)δ(ppm)7.36(dd,J＝9.7,3.1Hz,1H),7.27(t,J＝5.2Hz,1H),6.55(d,J＝9.7Hz,1H),4.99(s,2H),3.47(s,3H)。
步骤4)1-苄基-5-(甲氧基甲氧基)吡啶-2(1H)-酮1e
将氢化钠(52mg,1.3mmol,60mass％)溶于N,N-二甲基甲酰胺(5mL)，加入5-(甲氧基甲氧基)吡啶-2(1H)-酮1d(0.10g,0.64mmol)，随后滴加溴化苄(0.10mL,0.84mmol)，室温反应3小时。加入水(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/2]纯化，得到标题化合物1e(0.11g,产率70％)，为无色油状物。
1H NMR(400MHz,CDCl 3)δ(ppm)7.29(dt,J＝12.3,6.9Hz,5H),7.20(dd,J＝9.8,1.4Hz,1H),7.08(d,J＝2.5Hz,1H),6.54(d,J＝9.8Hz,1H),5.07(s,2H),4.89(d,J＝1.1Hz,2H),3.39(dd,J＝2.6,1.3Hz,3H)。
步骤5)1-苄基-5-羟基-吡啶-2(1H)-酮1f
将1-苄基-5-(甲氧基甲氧基)吡啶-2(1H)-酮1e(0.10g,0.41mmol)溶于二氯甲烷(5mL)，加入三甲基溴硅烷(0.82mL,6.1mmol)，室温反应30分钟。将反应液浓缩，得到标题化合物1f(82mg,产率100％)，为黄色固体。
1H NMR(400MHz,CDCl 3)δ(ppm)7.93-7.67(m,2H),7.33(d,J＝14.4Hz,5H),7.28(t,J＝5.0Hz,1H),5.39(d,J＝2.8Hz,2H)。
步骤6)1-苄基-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮1g
将1-苄基-5-羟基-吡啶-2(1H)-酮1f(1.2g,6.0mmol)、碳酸钾(2.5g,18mmol)和1,3-二氯-2-碘-5-硝基苯(1.9g,6.0mmol)溶于N,N-二甲基甲酰胺(15mL)，120℃下反应2小时。反应液冷却至室温，加入水(20ml)淬灭，用乙酸乙酯(30mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝4/1]纯化，得到标题化合物1g(1.2g,产率51％)，为黄色固体。
步骤7)5-(4-硝基-2,6-二氯-苯氧基)-1-苄基-吡啶-2(1H)-酮1h
将1-苄基-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮1g(64mg,0.16mmol)溶于乙酸(3mL)，加入铁粉(6mg)，70℃反应5小时。反应液冷却至室温，浓缩，残留物加入水(10mL)和乙酸乙酯(10mL)，用碳酸钠固体调节pH＝8，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物1h(30mg,产率51％)，为黄色固体。
MS(ESI,pos.ion)m/z:361.1[M+H] +。
步骤8)N-[2-[[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯 1i
将5-(4-硝基-2,6-二氯-苯氧基)-1-苄基-吡啶-2(1H)-酮1h(0.20g，0.6mmol)、N-氰基乙酰尿烷(0.097g,0.6mmol)和浓盐酸(0.14mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(0.043g,0.6mmol)的水溶液(2mL)，随后反应6小时。向反应液中加入水(20mL)，用乙酸乙酯(50mL×2)萃取，合并的有机层用无水硫酸钠干燥，抽滤浓缩，得到深红色固体，直接进行下一步反应。
MS(ESI,pos.ion)m/z:529.2[M+H] +。
步骤9)2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1
将上一步深红色固体溶于N,N-二甲基乙酰胺(2mL)，加入乙酸钾(0.22g,2.2mmol)，120℃反应24小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[49％ACN/51％H 2O(0.1％TFA),菲罗门ACE规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物1(11mg,产率4％,HPLC纯度:92.89％)，为白色固体。
MS(ESI,neg.ion)m/z:481.8[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.77(s,2H),7.58(d,J＝3.3Hz,1H),7.46(dd,J＝9.9,3.3Hz,1H),7.31(d,J＝7.5Hz,2H),7.27(d,J＝7.2Hz,1H),7.22-7.19(m,2H),6.48(d,J＝9.9Hz,1H),5.32(s,1H),5.04(s,2H)。
实施例2 2-[4-(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物2)
Figure PCTCN2020117131-appb-000021
步骤1)3,5-二氯-4-(6-氯哒嗪-3-基)氧基-苯胺2b
将4-氨基-2,6-二氯-苯酚2a(1.82g,10.2mmol)溶于N,N-二甲基乙酰胺(10mL)，加入碳酸铯(3.75g,11.5mmol)和3,6-二氯哒嗪(1.49g,10.0mmol)，110℃反应6小时。将反应液冷却至室温，加入乙酸乙酯(20mL)，用硅藻土过滤，乙酸乙酯(20mL)淋洗，滤液用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[乙酸乙酯/石油醚(v/v)＝1/2]纯化，得到标题化合物2b(1.47g,产率51％)，为棕色固体。
MS(ESI,pos.ion)m/z:291.9[M+H] +。
步骤2)5-溴-2-[3,5-二氯-4-[(6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]异吲哚啉-1,3-二酮2c
将3,5-二氯-4-(6-氯哒嗪-3-基)氧基-苯胺2b(0.2g,0.69mmol)和4-溴苯酐(0.20g,0.69mmol)溶于乙酸(2mL)，120℃反应3小时，加入乙酸钠(0.23g，2.8mmol)，继续120℃反应16小时。反应液冷却至室温，加入饱和碳酸钠溶液(50mL)，搅拌15分钟，过滤，收集滤饼烘干，得到标题化合物2c(0.20g,产率60％)，为白色固体。
MS(ESI,pos.ion)m/z:481.8[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.35(s,1H),8.21(d,J＝1.3Hz,1H),8.13(dd,J＝7.9,1.5Hz,1H),7.94(d,J＝8.0Hz,1H),7.77(s,2H),7.67(d,J＝9.9Hz,1H),7.11(d,J＝9.9Hz,1H)。
步骤3)2-[4-[(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基]-3,5-二氯苯基]-5-溴异吲哚啉-1,3-二酮2d
将5-溴-2-[3,5-二氯-4-[(6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]异吲哚啉-1,3-二酮2c(0.10g,0.21mmol)，碳酸钾(0.058g,0.42mmol)，碘化钾(0.003g,0.02mmol)和苄基溴(0.036g,0.21mmol)溶于N,N-二甲基乙酰胺(1mL)，室温反应13小时。加入水(10mL)淬灭反应，用乙酸乙酯(5mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物2d(50mg,产率42％)，为黄色固体。
1H NMR(600MHz,CDCl 3)δ(ppm)8.15(s,1H),7.99(dd,J＝7.9,1.5Hz,1H),7.87(d,J＝7.9Hz,1H),7.61(s,2H),7.31-7.27(m,3H),7.24(d,J＝6.4Hz,3H),7.06(d,J＝9.7Hz,1H),5.04(s,2H)。
步骤4)6-(4-氨基-2,6-二氯苯氧基)-2-苄基哒嗪-3(2H)-酮2e
将2-[4-[(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基]-3,5-二氯苯基]-5-溴异吲哚啉-1,3-二酮2d(50mg，0.09mmol)溶于乙醇(2mL)，加入35％的水合肼水溶液(0.08mL)，室温反应2小时。将反应液浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝3/1]纯化，得到标题化合物2e(10mg,产率32％)，为白色固体。
MS(ESI,pos.ion)m/z:362.1[M+H] +。
步骤5)N-[2-[[4-[(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基-3,5-二氯苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯 2f
将6-(4-氨基-2,6-二氯苯氧基)-2-苄基哒嗪-3(2H)-酮2e(0.10g，0.28mmol)、N-氰基乙酰尿烷(0.048g,0.30mmol)和浓盐酸(0.07mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(0.021g,0.30mmol)的水溶液(2mL)，随后反应4小时。向反应液中加入水(20mL)，用乙酸乙酯(20mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物2f(0.15g,产率100％)，直接进行下一步反应。
MS(ESI,neg.ion)m/z:529.1[M-H] -。
步骤6)2-[4-(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈2
将N-[2-[[4-[(1-苄基-6-氧代-1,6-二氢哒嗪-3-基)氧基-3,5-二氯苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯f(0.15g,0.26mmol)溶于N,N-二甲基乙酰胺(2mL)，加入乙酸钾(0.11g,1.06mmol)，120℃反应3小时。将反应液冷却至室温，过滤，滤液浓缩，所得残留物经制备分离纯化[50％ACN/50％H 2O(0.1％TFA),菲罗门ACE规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物2(10mg,产率7.8％,HPLC纯度:98.92％)，为白色固体。
MS(ESI,neg.ion)m/z:482.9[M-H] -。
1H NMR(400MHz,DMSO-d 6),δ(ppm)7.79(s,2H),7.68(d,J＝9.8Hz,1H),7.27-7.23(m,3H),7.19(d,J＝9.8Hz,1H),7.06(dd,J＝7.0,1.9Hz,2H),4.92(s,2H)。
实施例3 2-[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物3)
Figure PCTCN2020117131-appb-000022
步骤1 N-[3,5-二氯-4-[(6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]苯甲酰胺3b
将3,5-二氯-4-[(6-氯哒嗪-3-基)氧基]苯胺3a(2.29g,7.88mmol)和苯甲酸酐(2.06g,7.88mmol)溶于乙酸(3mL)中，110℃下反应3小时，随后加入乙酸钠(2.63g,31.5mmol)，反应24小时。将反应液倒入饱和碳酸钠溶液(50mL)中，搅拌15分钟，过滤，收集滤饼，真空干燥，得到标题化合物3b(2.50g,产率84％)，为浅白色固体。
步骤2 6-(4-氨基-2,6-二氯苯氧基)哒嗪-3(2H)-酮3c
将N-[3,5-二氯-4-[(6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]苯甲酰胺3b(2.50g,6.65mmol)和氢氧化钾(4.39g,66.5mmol)溶于50％的乙醇水溶液(18mL)，95℃反应7小时。反应液降至室温，用二氯甲烷(10mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物3c(1.17g,产率65％)，为灰色固体。
MS(ESI,pos.ion)m/z:272.0[M+H] +。
步骤3 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d
将6-(4-氨基-2,6-二氯苯氧基)哒嗪-3(2H)-酮3c(0.67g，2.5mmol)、对甲苯磺酸(0.045g，0.25mmol)和2,5-己二酮(0.29g,2.5mmol)溶于甲苯(3mL)中，110℃反应1.5小时。反应液冷却至室温，加入饱和碳酸钠溶液(50mL)，搅拌10分钟，用乙酸乙酯(10mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物3d(0.85g,产率99％)，为深色固体。
MS(ESI,pos.ion)m/z:409.6[M+H] +。
步骤4 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-异丙基哒嗪-3(2H)-酮3e
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(0.85g,2.4mmol)、碘化亚铜(49mg,0.24mmol)、碳酸钾(0.68g,4.9mmol)和异丙基碘(0.41g,2.4mmol)溶于N,N-二甲基甲酰胺(10mL)中，85℃反应18小时。反应液冷却至室温，倒入水(20mL)，搅拌10分钟，抽滤，收集滤饼真空干燥，得到标题化合物3e(0.70g,产率74％)，为灰色固体。
MS(ESI,pos.ion)m/z:392.0[M+H] +。
步骤5 6-(4-氨基-2,6-二氯苯氧基)-2-异丙基哒嗪-3(2H)-酮3f
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-异丙基哒嗪-3(2H)-酮3e(0.20g，0.51mmol)、盐酸羟胺(0.37g,5.1mmol)和三乙胺(0.14mL)溶于乙醇(10mL)，80℃下反应7小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，抽滤，收集滤饼，经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物3f(30mg,产率19％)，为浅色固体。
MS(ESI,pos.ion)m/z:314.0[M+H] +；
1H NMR(400MHz,CDCl 3)，δ(ppm)7.15(d,J＝9.7Hz,1H),6.98(d,J＝9.7Hz,1H),6.67(s,2H),5.10(dt,J＝13.2,6.6Hz,1H),3.76(s,2H),1.10(d,J＝6.6Hz,6H)。
步骤6 N-[2-氰基-2-[[3,5-二氯-4-(1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯 3g
将6-(4-氨基-2,6-二氯苯氧基)-2-异丙基哒嗪-3(2H)-酮3f(30mg，0.095mmol)、N-氰基乙酰尿烷(16mg,0.105mmol)和浓盐酸(0.4mL)溶于乙酸(1mL)中，3℃下滴加亚硝酸钠(7mg,0.286mmol)的水溶液(1mL)，随后反应10分钟。向反应液中加入水(20mL)，搅拌10分钟，抽滤，收集滤饼真空干燥，得到标题化合物3g(45mg,产率98％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:481.0[M+H] +。
步骤7 2-[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈3
将N-[2-氰基-2-[[3,5-二氯-4-(1-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯3g(45mg,0.093mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(27mg,0.28mmol)，120℃反应1小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[43％ACN/57％H 2O(0.1％TFA),Kromasil规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物3(30mg,产率74％,HPLC纯度:98.16％)，为白色固体。
MS(ESI,neg.ion)m/z:432.9[M-H] -；
1H NMR(400MHz,CDCl 3)δ(ppm)7.69(s,2H),7.34(d,J＝9.7Hz,1H),7.28(d,J＝9.7Hz,1H),5.13(dt,J＝13.1,6.6Hz,1H),1.10(d,J＝6.6Hz,6H)。
实施例4 2-[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化 合物4)
Figure PCTCN2020117131-appb-000023
步骤1 5-(2,6-二氯-4-硝基-苯氧基)-2-甲氧基-吡啶4b
将6-甲氧基吡啶-3-醇4a(0.20g,1.6mmol)和1,3-二氯-2-碘-5-硝基苯(0.51g,1.6mmol)溶于N,N-二甲基乙酰胺(2mL)，加入碳酸钾(0.56g,4.0mmol)，120℃反应1小时。反应液冷却至室温，加入水(20mL)，搅拌5分钟，过滤，收集滤饼真空干燥，得到标题化合物4b(0.30g,产率60％)，为黄色固体。
MS(ESI,pos.ion)m/z:315.0[M+H] +。
步骤2 5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮4c
将5-(2,6-二氯-4-硝基-苯氧基)-2-甲氧基-吡啶4b(0.35g,1.1mmol)溶于N,N-二甲基甲酰胺(2mL)，加入对甲苯磺酸(0.86g,4.7mmol)和氯化锂(0.20g,4.7mmol)，120℃反应30分钟。反应液冷却至室温，加入饱和碳酸钠溶液(50mL)，用乙酸乙酯(20mL×2)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物4c(0.30g,产率90％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:301.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)11.25(s,1H),8.50(s,2H),7.40(dd,J＝9.6,3.3Hz,1H),7.24(d,J＝2.6Hz,1H),6.46(d,J＝9.6Hz,1H)。
步骤3 5-(2,6-二氯-4-硝基-苯氧基)-1-异丙基-吡啶-2(1H)-酮4d
将5-(2,6-二氯-4-硝基-苯氧基)-1H-吡啶-2(1H)-酮4c(0.30g,1.0mmol)溶于N,N-二甲基甲酰胺(2mL)，加入碳酸钾(0.28g,2.0mmol)和异丙基碘(0.19g,1.1mmol)，85℃反应16小时。反应液冷却至室温，加入水(30mL),搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物4d(0.34g,产率99％)，为灰色固体。
MS(ESI,pos.ion)m/z:343.0[M+H] +。
步骤4 5-(4-氨基-2,6-二氯-苯氧基)-1-异丙基-吡啶-2(1H)-酮4e
将5-(2,6-二氯-4-硝基-苯氧基)-1-异丙基-吡啶-2(1H)-酮4d(0.34g,0.99mmol)和硫化钠(0.39g,5.00mmol)溶于乙醇(3mL)，80℃反应40分钟。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物4e(0.17g,产率55％)，为棕色固体。
MS(ESI,pos.ion)m/z:313.3[M+H] +。
步骤5 N-[2-氰基-2-[[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙 酯4f
将5-(4-氨基-2,6-二氯-苯氧基)-1-异丙基-吡啶-2(1H)-酮4e(0.17g，0.54mmol)、N-氰基乙酰尿烷(0.095g,0.59mmol)和浓盐酸(0.18mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(0.041g,0.59mmol)的水(2mL)溶液，随后反应4小时。向反应液中加入水(20mL)，用乙酸乙酯(5mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物4f(0.26g,产率100％)，为深红色固体。
MS(ESI,pos.ion)m/z:480.0[M+H] +。
步骤6 2-[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈4
将N-[2-氰基-2-[[3,5-二氯-4-[(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯4f(0.26g,0.54mmol)溶于N,N-二甲基乙酰胺(2mL)，加入乙酸钾(0.21g,2.2mmol)，120℃反应2小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[60％ACN/40％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物4(7mg,产率2.8％,HPLC纯度:92.99％)，为白色固体。
MS(ESI,pos.ion)m/z:434.5[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.30(s,1H),7.90(s,1H),7.76(s,2H),7.54(d,J＝8.8Hz,1H),7.27(d,J＝8.6Hz,1H),5.35-5.29(m,1H),1.46(d,J＝10.2Hz,6H)。
实施例5 2-[3,5-二氯-4-(1-乙基-6-氧代- 1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物5)
Figure PCTCN2020117131-appb-000024
步骤1 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-乙基哒嗪-3(2H)-酮5d
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(1.20g,3.43mmol)、碘化亚铜(68mg,0.34mmol)、碳酸钾(0.95g,6.85mmol)和乙基碘(0.53g,3.43mmol)溶于N,N-二甲基甲酰胺(2mL)，70℃反应1小时。反应液冷却至室温，倒入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物5d(1.20g,产率92.6％)，为灰色固体。
MS(ESI,pos.ion)m/z:378.0[M+H] +。
步骤2 6-(4-氨基-2,6-二氯-苯氧基)-2-乙基哒嗪-3(2H)-酮5e
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-乙基哒嗪-3(2H)-酮5d(1.20g，3.17mmol)、盐酸羟胺(2.32g,31.7mmol)和三乙胺(0.89mL)溶于乙醇(10mL)，80℃下反应24小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物5e(0.40g,产率42％)，为黑色固体。
MS(ESI,pos.ion)m/z:300.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-(1-乙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯5f
将6-(4-氨基-2,6-二氯-苯氧基)-2-乙基哒嗪-3(2H)-酮5e(0.40g，1.00mmol)、N-氰基乙酰尿烷(0.20g,1.00mmol)和浓盐酸(0.30mL)溶于乙酸(2mL)中，3℃下滴加亚硝酸钠(0.10g,1.00mmol)的水溶液(0.5mL)，随后反应10分钟。向反应液中加入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物5f(0.60g,产率100％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:467.6[M+H] +。
步骤4 2-[3,5-二氯-4-(1-乙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈5
将N-[2-氰基-2-[[3,5-二氯-4-(1-乙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯5f(0.60g,1.30mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.38g,3.90mmol)，120℃反应4.5小 时。将反应液冷却至室温，过滤，滤液经制备分离纯化[40％ACN/60％H 2O(0.1％TFA),Kromasil规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物5(50mg,产率9％,HPLC纯度:97.78％)，为白色固体。
MS(ESI,neg.ion)m/z:419.5[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.31(s,1H),7.82(s,2H),7.67(d,J＝9.8Hz,1H),7.18(d,J＝9.8Hz,1H),2.04-1.95(m,2H),1.05(t,J＝7.1Hz,3H)。
实施例6 2-[3,5-二氯-4-(1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物6)
Figure PCTCN2020117131-appb-000025
步骤1 2-环丙基-6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮6a
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(0.85g,2.4mmol)、碘化亚铜(29mg,0.24mmol)和碳酸钾(0.68g,4.9mmol)溶于N,N-二甲基甲酰胺(4mL)，130℃反应40小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，粗品经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/1]纯化，得到标题化合物6a(0.10g,产率11％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:390.1[M+H] +。
步骤2 6-(4-氨基-2,6-二氯-苯氧基)-2-环丙基-哒嗪-3(2H) -酮6b
将2-环丙基-6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮6a(0.10g，0.26mmol)、盐酸羟胺(0.19g,2.60mmol)和三乙胺(0.07mL)溶于乙醇(3mL)，80℃下反应15小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物6b(50mg,产率60％)，为黑色固体。
MS(ESI,pos.ion)m/z:314.1[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-(1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯 6c
将6-(4-氨基-2,6-二氯-苯氧基)-2-环丙基-哒嗪-3(2H)-酮6b(0.05g，0.20mmol)、N-氰基乙酰尿烷(0.03g,0.20mmol)和浓盐酸(0.04mL)溶于乙酸(2mL)中，3℃下滴加亚硝酸钠(0.010g,0.20mmol)的水(0.5mL)溶液，随后反应10分钟。向反应液中加水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物6c(80mg,产率99％)，为黑色固体。
MS(ESI,pos.ion)m/z:479.0[M+H] +。
步骤4 2-[3,5-二氯-4-(1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈6
将N-[2-氰基-2-[[3,5-二氯-4-(1-环丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯6c(0.08g,0.17mmol)溶于N,N-二甲基乙酰胺(2mL)，加入乙酸钾(0.046g,0.50mmol)，120℃反应4小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[45％ACN/55％H 2O(0.1％TFA),Kromasil规格:C1810um×50mm×250mm,流速:100mL/min]，得到标题化合物6(8mg,产率10％,HPLC纯度:95.4％)，为浅 色固体。
MS(ESI,pos.ion)m/z:433.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.65(s,2H),7.30(d,J＝9.8Hz,1H),7.16(d,J＝9.8Hz,1H),5.88-5.74(m,1H),5.13(dd,J＝21.6,13.3Hz,2H),4.50(d,J＝5.8Hz,2H)。
实施例7 2-[3,5-二氯-4-(6-氧代-1-苯基-1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物21)
Figure PCTCN2020117131-appb-000026
步骤1 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-苯基-哒嗪-3(2H)-酮21a
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(0.50g,1.4mmol)、碘化亚铜(29mg,0.14mmol)和碳酸钾(0.40g,2.9mmol)溶于碘苯(3mL)，160℃反应2小时。反应液冷却至室温，倒入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物21a(0.50g,产率82％)，为灰色固体。
MS(ESI,pos.ion)m/z:426.1[M+H] +。
步骤2 6-(4-氨基-2,6-二氯-苯氧基)-2-苯基-哒嗪-3(2H)-酮21b
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-苯基-哒嗪-3(2H)-酮21a(0.50g，1.2mmol)、盐酸羟胺(0.86g,12mmol)和三乙胺(0.33mL)溶于乙醇(10mL)，80℃下反应22小时。降至室温，倒入水(30mL)，有固体析出，抽滤，滤饼真空干燥，滤饼经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物21b(212mg,产率52％)，为黑色固体。
MS(ESI,pos.ion)m/z:348.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-(6-氧代-1-苯基-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯 21c
将6-(4-氨基-2,6-二氯-苯氧基)-2-苯基-哒嗪-3(2H)-酮21b(0.21g，0.61mmol)、N-氰基乙酰尿烷(0.11g,0.67mmol)和浓盐酸(0.15mL)溶于乙酸(2mL)中，3℃下滴加亚硝酸钠(0.05g,0.67mmol)的水(2mL)溶液，随后反应10分钟。向反应液中加水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物21c(0.30g,产率96％)，为黑色固体。
MS(ESI,neg.ion)m/z:515.0[M-H] -。
步骤4 2-[3,5-二氯-4-(6-氧代-1-苯基-1,6-二氢哒嗪-3-基)氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈21
将N-[2-氰基-2-[[3,5-二氯-4-(6-氧代-1-苯基-1,6-二氢哒嗪-3-基)氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯21c(0.30g,0.58mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.17g,0.17mmol)，120℃反应1小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[48％ACN/52％H 2O(0.1％TFA),Kromasil规格:C1810um×50mm×250mm,流速:100mL/min]，得到标题化合物21(4mg,产率1.2％,HPLC纯度:81.9％)，为深色固体。
MS(ESI,pos.ion)m/z:468.9[M+H] +；
1H NMR(600MHz,CDCl 3)δ(ppm)7.65(d,J＝5.3Hz,2H),7.46(d,J＝8.0Hz,2H),7.37(t,J＝8.6Hz,3H),7.31-7.28(m,1H),7.20(d,J＝9.8Hz,1H)。
实施例8 2-[3,5-二氯-4-[1-(4-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基]氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈27
Figure PCTCN2020117131-appb-000027
步骤1 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-(4-氟苯基)哒嗪-3(2H)-酮27a
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(0.50g,1.4mmol)、碘化亚铜(29mg,0.14mmol)、碳酸钾(0.40g,2.9mmol)和对氟碘苯(0.33g,1.4mmol)溶于N,N-二甲基甲酰胺(2mL)，160℃反应22小时。反应液冷却至室温，倒入水(10mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物27a(0.60g,产率95％)，为灰色固体。
MS(ESI,pos.ion)m/z:444.6[M+H] +。
步骤2 6-(4-氨基-2,6-二氯苯氧基)-2-(4-氟苯基)哒嗪-3(2H)-酮27b
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-(4-氟苯基)哒嗪-3(2H)-酮27a(0.60g，1.4mmol)、盐酸羟胺(0.99g,14mmol)和三乙胺(0.38mL)溶于乙醇(10mL)，80℃下反应18小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，过滤，收集滤饼经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物27b(380mg,产率77％)，为黑色固体。
MS(ESI,pos.ion)m/z:365.9.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-[1-(4-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基]氧基-苯基]肼叉]乙酰基]氨基甲酸 乙酯27c
将6-(4-氨基-2,6-二氯苯氧基)-2-(4-氟苯基)哒嗪-3(2H)-酮27b(0.38g，1.0mmol)、N-氰基乙酰尿烷(0.18g,1.1mmol)和浓盐酸(0.3mL)溶于乙酸(2mL)中，3℃下滴加亚硝酸钠(0.26g,3.1mmol)的水(1mL)溶液，随后反应10分钟。向反应液中加水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物27c(0.55g,产率99％)，为黑色固体。
MS(ESI,neg.ion)m/z:531.0[M-H] -。
步骤4 2-[3,5-二氯-4-[1-(4-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基]氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈27
将N-[2-氰基-2-[[3,5-二氯-4-[1-(4-氟苯基)-6-氧代-1,6-二氢哒嗪-3-基]氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯27c(0.55g,1.0mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.31g,3.1mmol)，120℃反应16小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[45％ACN/55％H 2O(0.1％TFA),Kromasil规格:C1810um×50mm×250mm,流速:100mL/min]，得到标题化合物27(48mg,产率74％,HPLC纯度:86.92％)，为黄色固体。
MS(ESI,pos.ion)m/z:487.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.81(s,1H),7.79(s,2H),7.41(dd,J＝9.1,5.0Hz,2H),7.32(d,J＝9.8Hz,1H),7.26(t,J＝8.7Hz,2H)。
实施例9 2-[3,5-二氯-4-[[6-氧代-1-(1-苯乙基)-1,6-二氢哒嗪-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物37)
Figure PCTCN2020117131-appb-000028
步骤1 6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-(1-苯乙基)哒嗪-3(2H)-酮37a
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(1.20g,3.43mmol)、碘化亚铜(68mg,0.34mmol)、碳酸钾(0.95g,6.85mmol)和1-溴乙基苯(0.53g,3.43mmol)溶于N,N-二甲基甲酰胺(2mL)，70℃反应1小时。反应液冷却至室温，倒入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物37a(1.40g,产率89.9％)，为灰色固体。
MS(ESI,pos.ion)m/z:454.0[M+H] +。
步骤2 6-(4-氨基-2,6-二氯-苯氧基)-2-(1-苯乙基)哒嗪-3(2H)-酮37b
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-(1-苯乙基)哒嗪-3(2H)-酮37a(1.40g，3.08mmol)、盐酸羟胺(2.25g,30.8mmol)和三乙胺(0.86mL)溶于乙醇(10mL)，80℃下反应24小时。反应液冷却至室温，倒入水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物37b(0.50g,产率43％)，为黑色固体。
MS(ESI,pos.ion)m/z:376.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-[6-氧代-1-(1-苯乙基)-1,6-二氢哒嗪-3-基]氧基-苯基]肼叉]乙酰基]氨基甲酸 乙酯37c
将6-(4-氨基-2,6-二氯-苯氧基)-2-(1-苯乙基)哒嗪-3(2H)-酮37b(0.50g，1.30mmol)、N-氰基乙酰尿烷(0.23g,1.50mmol)和浓盐酸(0.34mL)溶于乙酸(3mL)中，3℃下滴加亚硝酸钠(0.10g,1.50mmol)的水溶液(0.5mL)，随后反应30分钟。加水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物37c(0.70g,产率100％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:543.6[M+H] +。
步骤4 2-[3,5-二氯-4-[6-氧代-1-(1-苯乙基)-1,6-二氢哒嗪-3-基]氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈37
将N-[2-氰基-2-[[3,5-二氯-4-[6-氧代-1-(1-苯乙基)-1,6-二氢哒嗪-3-基]氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯37c(0.72g,1.30mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.39g,4.00mmol)，120℃反应5小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[40％ACN/60％H 2O(0.1％TFA),Kromasil规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物36(100mg,产率15％,HPLC纯度:97.91％)，为红色固体。
MS(ESI,neg.ion)m/z:495.0[M-H] -；
1H NMR(400MHz,CDCl 3)δ(ppm)7.61(s,2H),7.20(s,5H),7.11(s,2H),4.13(dd,J＝14.2,7.1Hz,1H),1.47(d,J＝6.1Hz,3H)。
实施例10 2-[4-(1-苄基-2-氧代-1,2-二氢嘧啶-5-基)氧基-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物38)
Figure PCTCN2020117131-appb-000029
步骤1 2-氯-5-(2,6-二氯-4-硝基-苯氧基)嘧啶38b
将2-氯嘧啶-5-醇38a(3.00g,23.0mmol)溶于N,N-二甲基甲酰胺(25mL)，加入1,2,3-三氯-5-硝基苯(5.72g,25.3mmol)和碳酸钾(6.42g,46.0mmol)，120℃反应7小时。反应液冷却至室温，然后滴加入水(75mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物38b(6.50g,产率88.2％)，为橙黄色固体。
1H NMR(400MHz,CDCl 3)δ(ppm)8.38(s,2H),8.28(s,2H)。
步骤2 5-(2,6-二氯-4-硝基-苯氧基)-嘧啶-2(1H)-酮38c
将2-氯-5-(2,6-二氯-4-硝基-苯氧基)嘧啶38b(1.43g,4.46mmol)、碳酸钾(1.25g,8.95mmol)和三乙烯二胺(0.255g,2.23mmol)溶于1,4-二氧六环(20mL)和水(20mL)，70℃反应6小时。反应液冷却至室温，减压浓缩，所得残留物过滤，用水(10mL×3)洗涤滤饼，收集滤饼重结晶(石油醚/乙酸乙酯(v/v)＝5/1,50mL)，得到标题目标物38c(1.12g,产率83.1％)，为黄色固体。
MS(ESI,pos.ion)m/z:302.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)11.75(s,1H),8.71(s,1H),8.60(s,1H),8.52(s,1H),8.26(s,1H)。
步骤3 1-苄基-5-(2,6-二氯-4-硝基-苯氧基)嘧啶-2(1H)-酮38d
将5-(2,6-二氯-4-硝基-苯氧基)-嘧啶-2(1H)-酮38c(0.60g,1.99mmol)和溴化苄(0.37mL,2.98mmol)溶于二氯甲烷(10mL)，加入三乙胺(0.57mL,4.0mmol)，室温反应7小时。加入水(10mL)淬灭反应，然后用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化钠溶液(15mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/2]纯化，得到标题化合物38d(0.68g,产率87％)，为黄色固体。
MS(ESI,pos.ion)m/z:392.5[M+H] +。
步骤4 5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-嘧啶-2(1H)-酮38e
将1-苄基-5-(2,6-二氯-4-硝基-苯氧基)嘧啶-2(1H)-酮38d(0.68g,1.7mmol)溶于的乙酸(15mL)，加入铁粉(0.40g,7.0mmol)，90℃反应2.5小时。反应液冷却至室温后，抽滤除去铁粉，将滤液浓缩，得到标题化合物38e(0.55g,88％)，为黄色固体。
MS(ESI,pos.ion)m/z:362.0[M+H] +。
步骤5 N-[2-[[4-(1-苄基-2-氧代-1,2-二氢嘧啶-5-基)氧基-3,5-二氯苯基]肼叉]-2-氰基-乙酰]氨基甲酸乙酯38f
将5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-嘧啶-2(1H)-酮38e(0.30g,0.83mmol)和N-(2-氰基乙酰基)氨基甲酸乙酯(0.155g,0.99mmol)溶于乙酸(4mL)，0℃下滴加亚硝酸钠(0.087g,1.2mmol)水溶液(1mL)，继续反应2小时。反应液直接加入下一步反应。
步骤6 2-[4-(1-苄基-2-氧代-1,2-二氢嘧啶-5-基)氧基-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈38
向上一步反应液中加入乙酸钠(0.343g，4.14mmol)，120℃反应4小时。反应液冷却至室温，减压浓缩除去乙酸，然后加入水(15mL)，用乙酸乙酯(15mL×3)萃取，合并的有机相用无水硫酸钠干燥，抽 滤浓缩，所得粗产物经制备分离纯化[37％ACN/63％H2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到目标化合物38(0.18g,产率45.0％,HPLC纯度:98.37％)，为黄色固体。
MS(ESI,neg.ion)m/z:481.1[M-H] -,
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.27(s,1H),8.80(d,J＝3.8Hz,1H),8.29(d,J＝3.8Hz,1H),7.80(s,2H),7.36(t,J＝7.1Hz,2H),7.30(d,J＝7.0Hz,1H),7.26(d,J＝7.9Hz,2H),5.02(s,2H)。
实施例11 2-[3,5-二氯-4-[[1-(3,4-二氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物39)
Figure PCTCN2020117131-appb-000030
步骤1 5-(4-氨基-2,6-二氯-苯氧基)吡啶-2(1H)-酮39a
将5-(2,6-二氯-4-硝基-苯氧基)吡啶-2(1H)-酮4c(5.00g,1.6mmol)溶于乙酸(10mL)，加入铁粉(2.79g,49.8mmol)，75℃反应3小时。反应液冷却至室温，加入水(100mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物39a(2.00g,产率44.4％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:271.0[M+H] +。
步骤2 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b
将5-(4-氨基-2,6-二氯-苯氧基)吡啶-2(1H)-酮39a(1.60g,5.9mmol)、对甲苯磺酸(0.11g,0.59mmol)和2,5-己二酮(0.69g,5.9mmol)溶于甲苯(5mL)，110℃反应2小时。反应液冷却至室温，加入饱和碳酸钠溶液(50mL)淬灭，用乙酸乙酯(10mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物39b(1.90g,产率92％)，为灰色固体。
MS(ESI,pos.ion)m/z:349.0[M+H] +。
步骤3 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(3,4-二氟苄基)吡啶-2(1H)-酮39c
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(0.30g,0.85mmol)和3,4-二氟苄溴(0.18g,0.86mmol)溶于N,N-二甲基乙酰胺(8mL)，加入碳酸钾(0.30g,2.1mmol)，室温反应24小时。向反应液中加入水(30mL),搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物39c(0.30g,产率73％)，为红色固体。
MS(ESI,pos.ion)m/z:475.1[M+H] +。
步骤4 5-(4-氨基-2,6-二氯-苯氧基)-1-(3,4-二氟苄基)吡啶-2(1H)-酮39d
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(3,4-二氟苄基)吡啶-2(1H)-酮39c(0.30g,0.63mmol)、盐酸羟胺(0.58g,6.3mmol)和三乙胺(0.89mL)溶于乙醇(10mL)，80℃反应16小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物39d(0.20g,产率80％)，为黑色固体。
MS(ESI,pos.ion)m/z:399.0[M+H] +。
步骤5 N-[2-氰基-2-[[3,5-二氯-4-[[1-(3,4-二氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯39e
将5-(4-氨基-2,6-二氯-苯氧基)-1-(3,4-二氟苄基)吡啶-2(1H)-酮39d(0.20g，0.50mmol)、N-氰基乙酰尿烷(0.088g,0.55mmol)和浓盐酸(0.13mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(38mg,0.55mmol)的水(2mL)溶液，随后反应15分钟。向反应液中加入水(20mL)，用乙酸乙酯(10mL×2)萃取，合并的有机层用无水硫酸钠干燥，抽滤浓缩，得到标题化合物39e(0.28g,产率99％)，为深红色固体。
MS(ESI,pos.ion)m/z:564.0[M+H] +。
步 骤6 2-[3,5-二氯-4-[[1-(3,4-二氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈 39
将N-[2-氰基-2-[[3,5-二氯-4-[[1-(3,4-二氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯39e(0.28g,0.50mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.20g,2.00mmol)，120℃反应18小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[48％ACN/52％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物39(25mg,产率8.6％,HPLC纯度:88.95％)，为红色固体。
MS(ESI,neg.ion)m/z:516.5[M-H] -；
1H NMR(400MHz,CDCl 3)δ(ppm)7.64(s,2H),7.39(dd,J＝9.8,3.1Hz,1H),7.35(s,1H),7.18-7.13(m,1H),7.12-7.08(m,1H),6.99(d,J＝3.1Hz,1H),6.94(d,J＝9.8Hz,1H),5.12(s,2H)。
实施例12 2-[3,5-二氯-4[[6-氧代-1-[4-(三氟甲氧基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物40)
Figure PCTCN2020117131-appb-000031
步骤1 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-[4-(三氟甲氧基)苄基]吡啶-2(1H)-酮40a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(0.23g,0.66mmol)，碳酸钾(0.23g,1.65mmol)和4-三氟甲氧基苄溴(0.17g,0.86mmol)溶于N,N-二甲基乙酰胺(4mL)，室温反应24小时。向反应液中加入水(30mL)，搅拌10分钟，抽滤，得到标题化合物40a(0.30g,产率87％)，为红色固体。
MS(ESI,pos.ion)m/z:523.0[M+H] +。
步骤2 5-(4-氨基-2,6-二氯-苯氧基)-1-[4-(三氟甲氧基)苄基]吡啶-2(1H)-酮40b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-[4-(三氟甲氧基)苄基]吡啶-2(1H)-酮40a(0.30g,0.63mmol)，盐酸羟胺(0.58g,6.3mmol)溶于乙醇(10mL)，加入三乙胺(0.89mL)，80℃反应16小时。将反应液降至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物40b(0.24g,产率94％)，为黑色固体。
MS(ESI,pos.ion)m/z:445.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-[4-(三氟甲氧基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基] 氨基甲酸乙酯40c
取5-(4-氨基-2,6-二氯-苯氧基)-1-[4-(三氟甲氧基)苄基]吡啶-2(1H)-酮40b(0.24g,0.54mmol)，N-氰基乙 酰尿烷(0.11g,0.59mmol)溶于乙酸(3mL)和浓盐酸(0.18mL)，3℃下滴加亚硝酸钠(0.05g,0.59mmol)的水溶液(2mL)，随后反应30分钟。加入水(20mL)淬灭反应，用乙酸乙酯(5mL×2)萃取，合并的有机层用无水硫酸钠干燥，抽滤旋干，得到标题化合物40c(0.33g,产率100％)，为深红色固体。
MS(ESI,neg.ion)m/z:610.0[M-H] -。
步骤4 2-[3,5-二氯-4[[6-氧代-1-[[4-(三氟甲氧基)苯基]甲基]吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲 腈40
将N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-[4-(三氟甲氧基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯40c(0.33g,0.54mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钾(0.21g,2.20mmol)，120℃反应2小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[52％ACN/48％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物40(7.0mg,产率2.0％,纯度82.25％)，为黄色固体。
MS(ESI,neg.ion)m/z:564.0[M-H] -；
1H NMR(600MHz,CDCl 3)δ(ppm)10.02(s,1H),7.64(s,2H),7.39(d,J＝8.5Hz,1H),7.31(d,J＝8.0Hz,2H),7.24(d,J＝8.3Hz,1H),7.21(d,J＝7.6Hz,2H),6.61(s,1H),4.33(s,2H)。
实施例13 2-[3,5-二氯-4-[[1-(4-氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物41)
Figure PCTCN2020117131-appb-000032
步骤1 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-氟苄基)吡啶-2(1H)-酮41a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(0.30g,1.0mmol)和对氟苄溴(0.17g,0.86mmol)溶于N,N-二甲基甲酰胺(8mL)，加入碳酸钾(0.30g,2.7mmol)，室温反应16小时。向反应液中加入水(30mL),搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物41a(0.37g,产率94％)，为粉红色固体。
MS(ESI,pos.ion)m/z:457.5[M+H] +。
步骤2 5-(4-氨基-2,6-二氯-苯氧基)-1-(4-氟苄基)吡啶-2(1H) -酮41b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-氟苄基)吡啶-2(1H)-酮41a(0.37g,0.81mmol)、盐酸羟胺(0.59g,8.1mmol)和三乙胺(0.24mL)溶于乙醇(10mL)，80℃反应24小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物41b(0.28g,产率91％)，为黑色固体。
MS(ESI,pos.ion)m/z:381.4[M+H] +。
步骤5 N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸 乙酯41c
将5-(4-氨基-2,6-二氯-苯氧基)-1-(4-氟苄基)吡啶-2(1H)-酮41b(0.28g,0.73mmol)、N-氰基乙酰尿烷(0.13g,0.81mmol)和浓盐酸(0.13mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(0.056g,0.81mmol) 的水(2mL)溶液，随后反应1小时。向反应液中加入水(20mL)，用乙酸乙酯(5mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物41c(0.40g,产率99％)，为深红色固体。
MS(ESI,pos.ion)m/z:546.0[M+H] +。
步骤6 2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲 腈41
将N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-氟苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯41c(0.40g,0.73mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.29g,2.9mmol)，120℃反应4小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[48％ACN/52％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物41(94mg,产率24％,HPLC纯度:98.27％)，为红色固体。
MS(ESI,pos.ion)m/z:500.0[M+H] +；
1H NMR(600MHz,DMSO-d 6)δ(ppm)13.28(s,1H),7.77(s,2H),7.62(d,J＝3.3Hz,1H),7.45(dd,J＝9.9,3.3Hz,1H),7.30(dd,J＝8.4,5.6Hz,2H),7.16(t,J＝8.8Hz,2H),6.47(d,J＝9.9Hz,1H),5.02(s,2H)。
实施例14 2-[3,5-二氯-4-[[6-氧代-1-[3-(三氟甲基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物42)
Figure PCTCN2020117131-appb-000033
步骤1 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-[3-(三氟甲基)苄基]吡啶-2(1H)-酮42a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(0.30g,1.0mmol)和间三氟甲基苄溴(0.21g,0.86mmol)溶于N,N-二甲基甲酰胺(8mL)，加入碳酸钾(0.30g,2.7mmol)，室温反应24小时。向反应液中加入水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物42a(0.40g,产率94％)，为灰色固体。
MS(ESI,pos.ion)m/z:507.0[M+H] +。
步骤2 5-(4-氨基-2,6-二氯-苯氧基)-1-[3-(三氟甲基)苄基]吡啶-2(1H)-酮42b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-[3-(三氟甲基)苄基]吡啶-2(1H)-酮42a(0.40g,0.79mmol)、盐酸羟胺(0.58g,8.1mmol)和三乙胺(0.89mL)溶于乙醇(10mL)，80℃反应16小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物42b(0.34g,产率91％)，为黑色固体。
MS(ESI,pos.ion)m/z:429.0[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-[3-(三氟甲基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基] 氨基甲酸乙酯42c
将5-(4-氨基-2,6-二氯-苯氧基)-1-[3-(三氟甲基)苄基]吡啶-2(1H)-酮42b(0.34g，0.79mmol)、N-氰基乙酰尿烷(0.14g,0.87mmol)和浓盐酸(0.18mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(56mg,0.81mmol)的水(2mL)溶液，随后反应6小时。向反应液中加入水(20mL)，用乙酸乙酯(5mL×2)萃取， 合并的有机层用无水硫酸钠干燥，抽滤浓缩，得到标题化合物42c(0.47g,产率99％)，为深红色固体。
MS(ESI,pos.ion)m/z:596.0[M+H] +。
步骤4 2-[3,5-二氯-4-[[6-氧代-1-[3-(三氟甲基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6- 甲腈42
将N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-[3-(三氟甲基)苄基]-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯42c(0.47g,0.79mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钾(0.31g,3.2mmol)，120℃反应3小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[50％ACN/50％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物42(38mg,产率8.7％,HPLC纯度:98.74％)，为红色固体。
MS(ESI,neg.ion)m/z:548.0[M-H] -；
1H NMR(400MHz,CDCl 3)δ(ppm)7.63(s,2H),7.57(d,J＝7.9Hz,1H),7.46(t,J＝6.9Hz,3H),7.32-7.28(m,1H),6.88(d,J＝3.0Hz,1H),6.71(d,J＝9.8Hz,1H),5.15(s,2H)。
实施例15 2-[3,5-二氯-4-[(6-异丙氧基吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物43)
Figure PCTCN2020117131-appb-000034
步骤1 5-(2,6-二氯-4-硝基-苯氧基)-2-异丙氧基吡啶43a
将5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮4c(0.30g,1.0mmol)溶于N,N-二甲基甲酰胺(2mL)，加入碳酸钾(0.28g,2.0mmol)和异丙基碘(0.19g,1.1mmol)，85℃反应16小时。反应液冷却至室温，加入水(30mL),搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物43a(0.34g,产率99％)，为灰色固体。
MS(ESI,pos.ion)m/z:343.0[M+H] +。
步骤2 3,5-二氯-4-[(6-异丙氧基-吡啶-3-基)氧基]苯胺43b
将5-(2,6-二氯-4-硝基-苯氧基)-2-异丙氧基吡啶43a(0.34g,0.99mmol)和硫化钠(0.39g,5.00mmol)溶于乙醇(3mL)，80℃反应40分钟。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物43b(0.17g,产率55％)，为棕色固体。
MS(ESI,pos.ion)m/z:313.3[M+H] +。
步骤3 N-[2-氰基-2-[[3,5-二氯-4-[(6-异丙氧基-吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯43c
将3,5-二氯-4-[(6-异丙氧基-吡啶-3-基)氧基]苯胺43b(0.17g，0.54mmol)、N-氰基乙酰尿烷(0.095g,0.59mmol)和浓盐酸(0.18mL)加入到乙酸(3mL)中，3℃下滴加亚硝酸钠(0.041g,0.59mmol)的水(2mL)溶液，随后反应4小时。向反应液中加入水(20mL)，用乙酸乙酯(5mL×2)萃取，合并的有机相用无水硫酸钠干燥，抽滤浓缩，得到标题化合物43c(0.26g,产率100％)，为深红色固体。
MS(ESI,pos.ion)m/z:480.0[M+H] +。
步骤4 2-[3,5-二氯-4-[(6-异丙氧基-吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈43
将N-[2-氰基-2-[[3,5-二氯-4-[(6-异丙氧基-吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯43c(0.26g, 0.54mmol)溶于N,N-二甲基乙酰胺(2mL)，加入乙酸钾(0.21g,2.2mmol)，120℃反应2小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[60％ACN/40％H 2O(0.1％TFA),菲罗门ACE规格:C1810um×50mm×250mm,流速:100mL/min]，标题化合物43(15mg,产率6.3％,HPLC纯度:99.15％)，为黄色固体。
MS(ESI,pos.ion)m/z:434.5[M+H] +；
1H NMR(400MHz,DMSO-d 6)，δ(ppm)7.79(d,J＝2.8Hz,1H),7.66(s,2H),7.30(d,J＝2.5Hz,1H),6.73(d,J＝9.0Hz,1H),5.14(dt,J＝11.8,5.9Hz,1H),1.35(d,J＝6.1Hz,6H)。
实施例16 2-[4-(1-苄基-6-氧代-1.6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸甲酯(化合物45)
Figure PCTCN2020117131-appb-000035
将2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1(0.30g,0.60mmol)溶于氯化氢的甲醇溶液(2mL,4.5mol/L)，70℃反应16小时。反应液冷却至室温，浓缩，所得残留物经硅胶柱层析[100％乙酸乙酯]纯化，得到标题化合物45(27mg,产率51％,HPLC纯度:96.10％)，为黄色固体。
MS(ESI,pos.ion)m/z:515.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.10(s,1H),7.67(s,2H),7.44-7.27(m,6H),6.91(d,J＝2.9Hz,1H),6.71(d,J＝9.9Hz,1H),5.14(s,2H),4.01(s,3H)。
实施例17 2-[5-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-2-氧代-吡啶-1(2H)-基]乙酸乙酯(化合物48)
Figure PCTCN2020117131-appb-000036
步骤1 2-[5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-氧代-吡啶-1(2H)-基]乙酸乙酯48a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(1.00g,2.86mmol)，碳酸钾(1.00g,7.16mmol)和溴乙酸乙酯(0.49g,2.86mmol)溶于N,N-二甲基乙酰胺(5mL)，室温反应16小时。向反应液中加入水(50mL),搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物48a(0.75g,产率60％)，为红色固体。
MS(ESI,pos.ion)m/z:435.1[M+H] +。
步骤2 2-[5-(4-氨基-2,6-二氯-苯氧基)-2-氧代-吡啶-1(2H)-基]乙酸乙酯48b
将2-[5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-氧代-吡啶-1(2H)-基]乙酸乙酯48a(0.75g,1.70mmol)，盐酸羟胺(1.40g,17.00mmol)和三乙胺(0.39mL)溶于乙醇(10mL)，80℃反应5小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，得到标题化合物48b(0.46g,产率75％)，为黑色固体。
MS(ESI,pos.ion)m/z:357.0[M+H] +。
步骤3 2-[5-[2,6-二氯-4-[2-[1-氰基-2-(乙氧基甲酰氨基)-2-氧代-乙叉基]肼基]苯氧基]-2-氧代-吡啶-1(2H)-基] 乙酸乙酯48c
将2-[5-(4-氨基-2,6-二氯-苯氧基)-2-氧代-吡啶-1(2H)-基]乙酸乙酯48b(0.46g，1.29mmol)、N-氰基乙酰尿烷(0.23g,1.42mmol)和浓盐酸(0.18mL)溶于乙酸(3mL)中，3℃下滴加亚硝酸钠(0.10g,1.42mmol)的水溶液(2mL)，随后反应1小时。向反应液中加入水(50mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物48c(0.46g,产率68％)，为深红色固体。
MS(ESI,pos.ion)m/z:524.0[M+H] +。
步骤4 2-[5-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-2-氧代-吡啶-1(2H)-基]乙酸乙酯48
将2-[5-[2,6-二氯-4-[2-[1-氰基-2-(乙氧基甲酰氨基)-2-氧代-乙叉基]肼基]苯氧基]-2-氧代-吡啶-1(2H)-基]乙酸乙酯48c(0.46g,0.88mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钾(0.13g,1.30mmol)，120℃反应6小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[58％ACN/42％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物48(55mg,产率12％,HPLC纯度:93.99％)，为黄色固体。
MS(ESI,pos.ion)m/z:478.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.66(s,2H),7.43(d,J＝9.8Hz,1H),6.86(d,J＝9.6Hz,2H),4.65(s,2H),4.27-4.21(m,2H),1.30(s,3H)。
实施例18 2-[3,5-二氯-4-[[1-(2-甲氧基乙基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物49)
Figure PCTCN2020117131-appb-000037
步骤1 5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮49a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(2.0g,5.7mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碳酸钾(1.6g,11mmol)和2-溴乙基甲基醚(0.66mL,6.9mmol)，70℃反应5小时。反应液降至室温，加入水(20mL)，用乙酸乙酯(80mL×2)萃取，合并的有机相用饱和氯化钠溶液(40mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物49a(1.2g,产率51％)，为红棕色油状物。
步骤2 5-(4-氨基-2,6-二氯-苯氧基)-1-(2-甲氧基乙基)吡啶-2(1H)-酮49b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(2-甲氧基乙基)吡啶-2(1H)-酮49a(0.50g,1.2 mmol)和盐酸羟胺(1.3g,19mmol)溶于乙醇(4mL)，加入三乙胺(0.51mL,3.7mmol)，85℃反应16小时。反应液冷却至室温，加入乙酸乙酯(20mL)，搅拌10分钟，过滤，滤液浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝2/3]纯化，得到标题化合物49b(0.20g,产率49％)，为黄色固体。
步骤3 N-[2-氰基2-[[3,5-二氯-4-[[1-(2-甲氧基乙基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯49c
将5-(4-氨基-2,6-二氯-苯氧基)-1-(2-甲氧基乙基)吡啶-2(1H)-酮49b(0.20g,0.61mmol)、N-氰基乙酰尿烷(0.11g,0.69mmol)溶于乙酸(4mL)中，0℃下滴加亚硝酸钠(85mg,1.2mmol)的水溶液(2mL)，随后反应2小时。向反应液中加入水(10mL)，搅拌10分钟，过滤，用水(2mL)洗涤，收集滤饼真空干燥，得到标题化合物49c(0.30g，收率99％)，为红色固体。
步骤4 2-[3,5-二氯-4-[[1-(2-甲氧基乙基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈 49
将N-[2-氰基2-[[3,5-二氯-4-[[1-(2-甲氧基乙基)-6-氧代-1,6-吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯49c(0.30g,0.60mmol)溶于N,N-二甲基乙酰胺(3mL)，加入乙酸钠(53mg,0.65mmol)，120℃反应5小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/3]纯化，得到的黄色固体用乙醇/乙酸乙酯/石油醚(0.3/5/8,13.3mL)85℃重结晶，得到标题化合物49(0.10g，产率37％,HPLC纯度:98.02％)，为白色固体。
MS(ESI,neg.ion)m/z:448.0[M-H] -。
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.27(s,1H),7.78(s,2H),7.44(dd,J＝9.9,3.3Hz,1H),7.32(d,J＝3.2Hz,1H),6.43(d,J＝9.9Hz,1H),4.01(t,J＝5.2Hz,2H),3.51(t,J＝5.2Hz,2H),3.20(s,3H)。
实施例19 2-[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-6-氧代-哒嗪-1(6H)-基]乙酸乙酯(化合物52)
Figure PCTCN2020117131-appb-000038
步骤1 2-[3-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-6-氧代-哒嗪-1(6H)-基]乙酸乙酯52a
将6-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]哒嗪-3(2H)-酮3d(1.00g,2.86mmol)，碳酸钾(0.80g,5.70mmol)和溴乙酸乙酯(0.49g,2.86mmol)溶于N,N-二甲基乙酰胺(2mL)中，70℃反应24小时。向反应液中加入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物52a(1.05g,产率84％)，为灰色固体。
步骤2 2-[3-(4-氨基-2,6-二氯-苯氧基)-6-氧代-哒嗪-1(6H)-基]乙酸乙酯52b
将2-[3-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-6-氧代-哒嗪-1(6H)-基]乙酸乙酯52a(1.05g,2.41mmol)，盐酸羟胺(1.76g,24.10mmol)和三乙胺(0.67mL)溶于乙醇(10mL)，80℃反应15小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，滤液浓缩，所得残留物经硅胶柱层析[石油醚/乙酸乙酯(v/v)＝1/1]纯化，得到标题化合物52b(0.15g,产率17％)，为红色固体。
MS(ESI,pos.ion)m/z:357.9[M+H] +。
步骤3 2-[3-[2,6-二氯-4-[2-[1-氰基-2-(乙氧基甲酰氨基)-2-氧代-乙叉基]肼基]苯氧基]-6-氧代-哒嗪-1(6H)-基] 乙酸乙酯52c
取2-[3-(4-氨基-2,6-二氯-苯氧基)-6-氧代-哒嗪-1(6H)-基]乙酸乙酯52b(0.15g，0.42mmol)、N-氰基乙酰尿烷(0.07g,0.42mmol)和浓盐酸(0.11mL)溶于乙酸(3mL)中，3℃下滴加亚硝酸钠(0.03g,0.46mmol)的水溶液(2mL)，随后反应50分钟。向反应液中加入水(50mL)，搅拌5分钟，过滤，收集滤饼真空干燥，得到标题化合物52c(156mg，产率71％)，为深红色固体。
MS(ESI,pos.ion)m/z:525.0[M+H] +。
步骤4 2-[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-6-氧代-哒嗪-1(6H)-基]乙酸乙酯52
取2-[3-[2,6-二氯-4-[2-[1-氰基-2-(乙氧基甲酰氨基)-2-氧代-乙叉基]肼基]苯氧基]-6-氧代-哒嗪-1(6H)-基]乙酸乙酯c(0.156g,0.30mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钾(0.05g,0.50mmol)，120℃反应6小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[40％ACN/60％H 2O(0.1％TFA),菲罗门ACE规格:C18 10um×50mm×250mm,流速:100mL/min]，得到标题化合物52(70.0mg,产率48％,HPLC纯度:98.24％)，为白色固体。
MS(ESI,pos.ion)m/z:476.8[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.79(s,2H),7.74(d,J＝9.9Hz,1H),7.25(d,J＝9.9Hz,1H),4.56(s,2H),4.07(q,J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H)。
实施例20 2-[3,5-二氯-4-[1-(4-氟苄基)-2-氧代-1,2-二氢嘧啶-5-基]氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物50)
Figure PCTCN2020117131-appb-000039
步骤1)5-(2,6-二氯-4-硝基-苯氧基)-1-(4-氟苄基)嘧啶-2(1H)-酮50a
将5-(2,6-二氯-4-硝基-苯氧基)-嘧啶-2(1H)-酮38c(1.15g,3.81mmol)、1-(溴甲基)-4-氟苯(0.54mL,4.20mmol)溶于二氯甲烷(25mL)，滴加三乙胺(1.10mL,7.68mmol)，室温反应4.5小时。用水(30mL)淬灭反应，然后用乙酸乙酯(30mL×3)萃取，收集的有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化，得到标题化合物50a(1.25g,产率80％)，为黄色固体。
MS(ESI,pos.ion)m/z:410.0[M+H] +。
步骤2)5-(4-氨基-2,6-二氯-苯氧基)-1-[(4-氟苯基)甲基]嘧啶-2(1H)-酮50b
将5-(2,6-二氯-4-硝基-苯氧基)-1-(4-氟苄基)嘧啶-2(1H)-酮50a(0.51g,1.24mmol)溶于乙酸(20mL)，加入铁粉(0.28g,4.97mmol)，90℃反应2小时。反应液冷却至室温，除去铁粉，减压浓缩，得到标题化合物50b(1.16g,产率94％)，为黄色固体。
MS(ESI,pos.ion)m/z:380.0[M+H] +。
步骤3)N-[2-氰基-2-[[3,5-二氯-4-[1-(4-氟苄基)-2-氧代-1,2-二氢嘧啶-5-基]氧基-苯基]肼叉]乙酰基]氨基甲酸 乙酯50c
将5-(4-氨基-2,6-二氯-苯氧基)-1-[(4-氟苯基)甲基]嘧啶-2(1H)-酮50b(6,0.53g,1.39mmol)和N-氰基乙酰尿烷(0.198g,1.34mmol)溶于乙酸(5mL)，0℃下滴加亚硝酸钠(0.119g,1.69mmol)水溶液(1.5mL)，反应2小时。向反应液中加入水(20mL)，搅拌30分钟，过滤，收集滤饼真空干燥，得到标题化合物50c(0.58g,产率76％)，为黄色固体。
步骤4)2-[3,5-二氯-4-[1-(4-氟苄基)-2-氧代-1,2-二氢嘧啶-5-基]氧基-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈50
将N-[2-氰基-2-[[3,5-二氯-4-[1-(4-氟苄基)-2-氧代-1,2-二氢嘧啶-5-基]氧基-苯基]肼叉]乙酰基]氨基甲酸乙酯50c(0.31g,0.56mmol)溶于乙酸(4mL)，加入乙酸钠(0.23g，2.81mmol)，120℃反应4小时。反应液冷却至室温，减压浓缩，所得残留物经制备分离纯化[37％ACN/63％H 2O(0.1％TFA),菲罗门ACE规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物50(70mg,产率25％,HPLC纯度:96.63％)，为白色固体。
MS(ESI,neg.ion)m/z:498.9[M-H] -。
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.31(s,1H),8.79(d,J＝3.6Hz,1H),8.30(d,J＝3.5Hz,1H),7.80(s,2H),7.37-7.33(m,1H),7.19(t,J＝8.4Hz,1H),7.13(s,1H),7.00(s,1H),4.99(s,2H)。
实施例21 2-[3,5-二氯-4-[[6-氧代-1-(4-吡啶基甲基)-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物46)
Figure PCTCN2020117131-appb-000040
步骤1)5-(2,6-二氯-4-硝基-苯氧基)-1-(4-吡啶基甲基)吡啶-2(1H)-酮46a
将5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮4c(1.0g,3.3mmol)和碳酸铯(2.7g,8.2mmol)溶于乙腈(10mL)，加入4-(溴甲基)吡啶氢溴酸盐(1.0g,4.0mmol)，室温反应12小时。反应液冷却至室温，过滤，滤液浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/4)纯化，得到标题化合物46a(0.83g,产率64％)黄色固体。
步骤2)5-(4-氨基-2,6-二氯-苯氧基)-1-(4-吡啶基甲基)吡啶-2(1H)-酮46b
将5-(2,6-二氯-4-硝基-苯氧基)-1-(4-吡啶基甲基)吡啶-2(1H)-酮46a(0.63g,1.6mmol)溶于乙酸(6mL)，加入铁粉(0.22g,3.9mmol)，60℃反应2.5小时。反应液冷却至室温，除去铁粉，加入水(10mL)，搅拌10分钟，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和氯化钠(10mL×2)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物46b(0.58g，产率100％)，为棕色固体。
步骤3)N-[2-氰基2-[[3,5-二氯-4-[[6-氧代-1-(4-吡啶基甲基)-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯46c
将5-(4-氨基-2,6-二氯-苯氧基)-1-(4-吡啶基甲基)吡啶-2(1H)-酮46b(0.58g,1.6mmol)和N-氰基乙酰尿烷(0.31g,1.9mmol)溶于乙酸(12mL)，0℃下加入亚硝酸钠(0.22g,3.2mmol)的水(5.8mL)溶液，继续0℃反应3小时。0℃下，向反应液中加入水(25mL)，搅拌15分钟，过滤，用水(10mL×2)洗涤，收集滤饼真空干燥，得到标题化合物46c(0.85g,产率99％)，为黄色固体。
步骤4)2-[3,5-二氯-4-[[6-氧代-1-(4-吡啶基甲基)吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈46
将N-[2-氰基2-[[3,5-二氯-4-[[6-氧代-1-(4-吡啶基甲基)-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯46c(0.85g,1.6mmol)溶于N,N-二甲基甲酰胺(8.5mL)，加入乙酸钠(0.14g,1.7mmol)，120℃反应6小时。反应液冷却至室温，将反应液浓缩，所得残留物经硅胶柱层析(二氯甲烷/甲醇＝4/1)纯化，得到的固体85℃重结晶(乙醇/乙酸乙酯/石油醚＝1/3/2,30mL)，得到标题化合物46(0.37g,产率48％,HPLC纯度:99.24％)，为黄色固体。
MS(ESI,neg.ion)m/z:480.0[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.51(d,J＝4.7Hz,2H),7.79(s,2H),7.63-7.44(m,2H),7.11(d,J＝5.2Hz,2H),6.53(d,J＝9.8Hz,1H),5.09(s,2H)。
实施例22 2-[3,5-二氯-4-[[1-[(3-甲氧基苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物55)
Figure PCTCN2020117131-appb-000041
步骤1)5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(3-甲氧基苄基)吡啶-2(1H)-酮55a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(1.00g,2.86mmol)、碳酸钾(0.80g,5.73mmol)和3-甲氧基苄氯(0.46g,2.86mmol)溶于N,N-二甲基乙酰胺(4mL)，室温反应24小时。向反应液中加入水(10mL)，搅拌10分钟，过滤，收集固体烘干，得到标题化合物55a(1.00g,产率74％)，为灰色固体。
MS(ESI,pos.ion)m/z:469.0[M+H] +。
步骤2)5-(4-氨基-2,6-二氯苯氧基)-1-(3-甲氧基苄基)吡啶-2(1H)-酮55b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(3-甲氧基苄基)吡啶-2(1H)-酮55a(1.00g,2.13mmol)溶于乙醇(10mL)，加入盐酸(4mol/L,4mL)，100℃反应1.5小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼真空干燥，所得固体经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物55b(0.37g,产率44％)，为黑色固体。
MS(ESI,pos.ion)m/z:391.0[M+H] +。
步骤3)N-[2-氰基-2-[[3,5-二氯-4-[[1-(3-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯55c
将5-(4-氨基-2,6-二氯苯氧基)-1-[(3-甲氧基苯基)甲基]吡啶-2(1H)-酮55b(0.37g，0.95mmol)和N-氰基乙酰尿烷(0.16g,1.04mmol)溶于乙酸(3mL)中，3℃下滴加亚硝酸钠(0.07g,1.04mmol)的水溶液(2mL)，随后反应4小时。加入水(20mL)，搅拌5分钟，过滤，收集滤饼真空干燥，得到标题化合物55c(0.42g，产率80％)，为橙色固体。
MS(ESI,pos.ion)m/z:558.1[M+H] +。
步骤4)2-[3,5-二氯-4-[[1-[(3-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲 腈55
将N-[2-氰基-2-[[3,5-二氯-4-[[1-(3-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯55c(0.42g,0.76mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钠(0.09g,1.13mmol)，120℃反应7小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[45％ACN/55％H 2O(0.1％TFA),菲罗门ACE规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物55(15mg,产率3.6％,HPLC纯度:93.79％)，为白色固体。
MS(ESI,pos.ion)m/z:514.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ(ppm)7.63(s,2H),7.34-7.28(m,2H),6.97(s,1H),6.87-6.77(m,4H),5.13(s,2H),3.78(s,3H)。
实施例23 2-[3,5-二氯-4-[[1-[(4-甲基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物56)
Figure PCTCN2020117131-appb-000042
步骤1)5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-甲基苄基)吡啶-2(1H)-酮56a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(1.00g,2.86mmol)、碳酸钾(0.80g,5.73mmol)和4-甲基苄氯(0.41g,2.86mmol)溶于N,N-二甲基乙酰胺(4mL)中，室温反应26小时。向反应液中加入水(10mL)，搅拌10分钟，过滤，收集固体烘干，所得固体经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物56a(0.70g,产率54％)，为白色固体。
步骤2)5-(4-氨基-2,6-二氯苯氧基)-1-(4-甲基苄基)吡啶-2(1H)-酮56b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-甲基苄基)吡啶-2(1H)-酮56a(0.70g,1.50mmol)、盐酸羟胺(1.70g,23.0mmol)和三乙胺(1.10mL)溶于乙醇(10mL)，90℃反应18小时。将反应液冷却至室温，加入乙酸乙酯(20mL)，搅拌15分钟，过滤，滤液浓缩，得到标题化合物56b(0.53g,产率91％)，为白色固体。
步骤3)N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-甲基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲 酸乙酯56c
将5-(4-氨基-2,6-二氯苯氧基)-1-[(4-甲基苯基)甲基]吡啶-2(1H)-酮56b(0.53g，1.41mmol)和N-氰基乙酰尿烷(0.24g,1.55mmol)溶于乙酸(3mL)，3℃下滴加亚硝酸钠(0.11g,1.55mmol)的水溶液(2mL)，随后反应2小时。向反应液中加入水(20mL)，搅拌5分钟，过滤，滤饼烘干，得到标题化合物56c(0.70g，产率91％)，为橙色固体。
MS(ESI,pos.ion)m/z:542.1[M+H] +。
步骤4)2-[3,5-二氯-4-[[1-[(4-甲基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈 56
将N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-甲基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯56c(0.70g,1.30mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钠(0.16g,1.90mmol)，120℃反应5小时。将反应液冷却至室温，加入水(30mL)，搅拌10分钟，过滤，收集滤饼烘干，所得固体经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物56(77mg,产率11％,HPLC纯度:87.52％)，为白 色固体。
MS(ESI,pos.ion)m/z:496.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.30(s,1H),7.77(s,2H),7.56(d,J＝3.2Hz,1H),7.43(dd,J＝9.9,3.3Hz,1H),7.12(s,4H),6.46(d,J＝9.9Hz,1H),4.99(s,2H),2.25(s,3H)。
实施例24 2-[5-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-2-氧代吡啶-1(2H)-基]丙酸乙酯(化合物57)
Figure PCTCN2020117131-appb-000043
步骤1)2-[5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-氧代吡啶-1(2H)-基]丙酸乙酯57a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(0.83g,2.40mmol)、碳酸钾(0.66g,4.80mmol)和2-溴丙酸乙酯(0.44g,2.40mmol)溶于N,N-二甲基乙酰胺(4mL)，60℃反应21小时。向反应液中加入水(50mL)，搅拌10分钟，过滤，收集的滤饼经硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到标题化合物57a(0.34g,产率32％)，为黄色油状物。
步骤2)2-[5-(4-氨基-2,6-二氯-苯氧基)-2-氧代-吡啶-1(2H)-基]丙酸乙酯57b
将2-[5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-2-氧代吡啶-1(2H)-基]丙酸乙酯57a(0.34g,0.76mmol)、盐酸羟胺(0.86g,11.00mmol)和三乙胺(0.55mL)溶于乙醇(10mL)，90℃反应21小时。反应液冷却至室温，加入乙酸乙酯(20mL)，-10℃下搅拌15分钟，过滤，滤液浓缩，得到标题化合物57b(0.28g,产率100％)，为白色固体。
步骤3)2-[5-[2,6-二氯-4-[2-[1-氰基-2-((乙氧基羰基)氨基)-2-氧代-亚乙基]肼叉]苯氧基]-2-氧代吡啶-1(2H)-基] 丙酸乙酯57c
将2-[5-(4-氨基-2,6-二氯-苯氧基)-2-氧代-吡啶-1(2H)-基]丙酸乙酯57b(0.28g，0.75mmol)和N-氰基乙酰尿烷(0.14g,0.83mmol)溶于乙酸(3mL)，3℃下滴加亚硝酸钠(0.06g,0.83mmol)的水溶液(2mL)，随后反应1小时。向反应液中加入水(20mL)，搅拌5分钟，过滤，滤饼烘干，得到标题化合物57c(0.23g,产率57％)，为橙色固体。
MS(ESI,pos.ion)m/z:538.1[M+H] +。
步骤4)2-[5-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-2-氧代吡啶-1(2H)-基]丙酸乙酯57
将2-[5-[2,6-二氯-4-[2-[1-氰基-2-((乙氧基羰基)氨基)-2-氧代-亚乙基]肼叉]苯氧基]-2-氧代吡啶-1(2H)-基]丙酸乙酯57c(0.23g,0.43mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钠(0.06g,0.64mmol)，120℃反应6小时。将反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集的滤饼经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到标题化合物57(44.0mg,产率19％,HPLC纯度:91.31％)，为红色固体。
MS(ESI,pos.ion)m/z:492.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ(ppm)7.65(s,2H),7.23(d,J＝2.6Hz,1H),7.02(d,J＝2.8Hz,1H),6.67(d,J＝9.7Hz,1H),5.56(d,J＝7.4Hz,1H),4.20(dd,J＝7.1,2.4Hz,2H),1.61(d,J＝7.2Hz,3H),1.28-1.25(m,3H)。
实施例25 2-[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物58)
Figure PCTCN2020117131-appb-000044
步骤1)5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-((四氢吡喃-4-基)甲基)吡啶-2(1H)-酮58a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(2.0g,5.7mmol)溶于N,N-二甲基甲酰胺(15mL)，加入碳酸钾(1.6g,11mmol)和4-(溴甲基)四氢吡喃(0.90mL,6.8mmol)，70℃反应6小时。反应液冷却至室温，加入水(50mL)，用乙酸乙酯(80mL×2)萃取，合并的有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物58a(0.79g,产率31％)，为黄色固体。
步骤2)5-(4-氨基-2,6-二氯苯氧基)-1-((四氢吡喃-4-基)甲基)吡啶-2(1H)-酮58b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-((四氢吡喃-4-基)甲基)吡啶-2(1H)-酮58a(89g,2.0mmol)和盐酸羟胺(2.1g,30mmol)溶于乙醇(10mL)，加入三乙胺(1.4mL,10mmol)，85℃反应17小时。反应液冷却至室温，加入乙酸乙酯(20mL)，搅拌10分钟，过滤，滤液浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝2/3)纯化，得到标题化合物58b(0.54g,产率74％)，为黄色固体。
步骤3)N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰 基]氨基甲酸乙酯58c
将5-(4-氨基-2,6-二氯苯氧基)-1-((四氢吡喃-4-基)甲基)吡啶-2(1H)-酮58b(0.54g,1.5mmol)、N-氰基乙酰尿烷(0.26g,1.6mmol)溶于乙酸(8mL)中，0℃下滴加亚硝酸钠(0.20g,2.9mmol)的水溶液(4mL)，随后反应2小时。向反应液中加入水(20mL)，搅拌10分钟，过滤，用水(4mL)洗涤，收集滤饼烘干，得到标题化合物58c(0.78g,收率99％)，为红色固体。
步骤4)2-[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三 嗪-6-甲腈58
将N-[2-氰基-2-[[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯58c(0.78g,1.5mmol)溶于N,N-二甲基乙酰胺(6mL)，加入乙酸钠(0.13g,1.6mmol)，120℃反应5小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到的棕色固体85℃重结晶(石油醚/乙酸乙酯＝1/4,5mL)，得到标题化合物58(0.38g,产率53％,HPLC纯度:97.44％)，为黄色固体。
MS(ESI,pos.ion)m/z:490.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.28(s,1H),7.79(s,2H),7.49-7.39(m,2H),6.44(d,J＝9.4Hz,1H),3.81(d,J＝9.1Hz,2H),3.75(d,J＝7.3Hz,2H),3.21(t,J＝10.9Hz,2H),1.98(dd,J＝7.9,4.1Hz,1H),1.37(d,J＝11.5Hz,2H),1.21(dt,J＝7.2,5.9Hz,2H)。
实施例26 2-[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4- 三嗪-6-甲酸甲酯(化合物59)
Figure PCTCN2020117131-appb-000045
将2-[3,5-二氯-4-[[6-氧代-1-((四氢吡喃-4-基)甲基)-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈58(0.10g,0.20mmol)溶于氯化氢的甲醇溶液(3mol/L,3mL)，65℃反应48小时。将浓缩反应液，用乙酸乙酯(5mL)打浆，过滤，收集滤饼烘干，得到标题化合物59(17.0mg,产率14％,HPLC纯度:85.59％)，为白色固体。
MS(ESI,pos.ion)m/z:525.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.76(s,1H),7.83-7.77(m,2H),7.42(d,J＝8.3Hz,2H),6.43(d,J＝10.4Hz,1H),3.84(s,3H),3.82-3.78(m,2H),3.74(d,J＝7.4Hz,2H),3.22(d,J＝10.9Hz,2H),1.98(dd,J＝13.2,6.8Hz,1H),1.36(d,J＝12.3Hz,2H),1.22(dd,J＝12.7,8.8Hz,2H)。
实施例27 2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸乙酯(化合物60)
Figure PCTCN2020117131-appb-000046
将氯化氢的乙酸乙酯溶液(3mL,4mol/L)加入到2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1(0.15g,0.31mmol)的乙醇(3mL)溶液，70℃反应19小时。反应液冷却至室温，浓缩，85℃重结晶(石油醚/乙酸乙酯＝1/1,20mL)，得到标题化合物60(0.13g,产率81％,HPLC纯度:92.31％)，为黄色固体。
MS(ESI,pos.ion)m/z:531.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ(ppm)12.76(s,1H),7.80(s,2H),7.60(d,J＝3.3Hz,1H),7.44-7.37(m,1H),7.32(d,J＝7.5Hz,2H),7.22(d,J＝7.1Hz,2H),7.17-7.10(m,1H),6.48(d,J＝9.9Hz,1H),5.06(s,2H),4.32(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H)。
实施例28 2-[4-(1-苄基-6-氧代吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸-2-羟乙酯(化合物61)
Figure PCTCN2020117131-appb-000047
Figure PCTCN2020117131-appb-000048
将氯化氢的1,4-二氧六环溶液(4mL,16mmol,4mol/L)加入到2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1(0.20g,0.41mmol)的乙二醇(4mL)溶液，70℃反应16小时。反应液冷却至室温，浓缩，所得残留物经硅胶柱层析(100％乙酸乙酯)纯化，得到的黄色液体经85℃重结晶(乙醇/乙酸乙酯/石油醚＝1/2/4,17.5mL)，得到标题化合物61(40mg,产率18％,HPLC：95.88％)，为白色固体。
MS(ESI,neg.ion)m/z:543.1[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.77(s,1H),7.81(s,2H),7.60(d,J＝3.2Hz,1H),7.46(dd,J＝9.9,3.3Hz,1H),7.33(t,J＝7.2Hz,2H),7.27(d,J＝7.1Hz,1H),7.22(d,J＝7.2Hz,2H),6.48(d,J＝9.9Hz,1H),5.06(s,2H),4.91(t,J＝5.3Hz,1H),4.34-4.25(m,2H),3.65(dd,J＝10.0,5.1Hz,2H)。
实施例29 2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-1,2,4-三嗪-3,5-二酮(化合物62)
Figure PCTCN2020117131-appb-000049
步骤1 2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸62a
将浓盐酸(1mL)加入到2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1(0.10g,0.21mmol)的乙酸(2mL)溶液，120℃反应24小时。反应液冷却至室温，加入水(10mL)，搅拌10分钟，过滤，收集滤饼，真空干燥，得到标题化合物62a(90mg,产物87％)，为黄色固体。
步骤2 2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-1,2,4-三嗪-3,5-二酮62
将2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸62a(90mg,0.18mmol)溶于巯基乙酸(2mL)，160℃反应24小时。反应液冷却至室温，加入水(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯＝1/3)纯化，得到的黄色固体85℃重结晶(石油醚/乙酸乙酯＝1/2,9mL)，得到标题化合物62(82mg,产率100％,HPLC:96.90％)，为类白色固体。
MS(ESI,neg.ion)m/z:457.9[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.49(s,1H),7.80(s,2H),7.70(s,1H),7.56(d,J＝3.2Hz,1H),7.43(dd,J＝9.9,3.3Hz,1H),7.32(t,J＝7.2Hz,2H),7.27(d,J＝7.0Hz,1H),7.22(t,J＝7.7Hz,2H),6.48(d,J＝9.9Hz,1H),5.05(s,2H)。
实施例30 2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酰胺(化合物63)
Figure PCTCN2020117131-appb-000050
Figure PCTCN2020117131-appb-000051
将2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈1(0.30g,0.62mmol)，溶于氯化氢的1,4-二氧六环溶液(10mL,4.0mol/L)，60℃反应7小时。向反应液中加入乙酸乙酯(10mL)打浆2小时，过滤，收集固体烘干，得到标题化合物63(0.29g,产率93％,HPLC纯度:89.87％)，为白色固体。
MS(ESI,pos.ion)m/z:500.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.78(s,1H),8.08(s,1H),7.94(s,1H),7.86(s,2H),7.59(d,J＝3.2Hz,1H),7.45(dd,J＝9.9,3.2Hz,1H),7.33(t,J＝7.2Hz,2H),7.27(d,J＝7.0Hz,1H),7.23(t,J＝6.3Hz,2H),6.48(d,J＝9.9Hz,1H),5.06(s,2H)。
实施例31 2-[3,5-二氯-4-[[1-[(4-甲氧基苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物64)
Figure PCTCN2020117131-appb-000052
步骤1)5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-甲氧基苄基)吡啶-2(1H)-酮64a
取5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(2.00g,5.73mmol)、碳酸钾(1.60g,11.50mmol)和4-甲氧基苄氯(0.92g,5.73mmol)溶于N,N-二甲基乙酰胺(4mL)，室温反应18小时。向反应液中加入水(10mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物64a(2.00g,产率74％)，为灰色固体。
MS(ESI,pos.ion)m/z:469.1[M+H] +。
步骤2)5-(4-氨基-2,6-二氯苯氧基)-1-(4-甲氧基苄基)吡啶-2(1H)-酮64b
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]-1-(4-甲氧基苄基)吡啶-2(1H)-酮64a(2.00g,4.26mmol)、盐酸羟胺(2.88g,42.6mmol)和三乙胺(1.10mL)溶于乙醇(20mL)，80℃反应16小时。反应液冷却至室温，加入水(30mL)，搅拌15分钟，过滤，收集滤饼烘干，所得固体经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物64b(0.19g,产率11％)，为黑色固体。
MS(ESI,pos.ion)m/z:391.0[M+H] +。
步骤3)N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基 甲酸乙酯64c
将5-(4-氨基-2,6-二氯苯氧基)-1-[(4-甲氧基苄基)吡啶-2(1H)-酮64b(0.19g，0.48mmol)和N-氰基乙酰尿烷(0.09g,0.53mmol)溶于乙酸(3mL)，3℃下滴加亚硝酸钠(0.04g,0.53mmol)的水溶液(2mL)，随后反应30分钟。向反应液中加入水(20mL)，搅拌5分钟，过滤，收集滤饼真空干燥，得到标题化合物64c(0.14g,产率52％)，为橙色固体。
MS(ESI,neg.ion)m/z:560.1[M-H] -。
步骤4)2-[3,5-二氯-4-[[1-(4-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲 腈64
将N-[2-氰基-2-[[3,5-二氯-4-[[1-(4-甲氧基苄基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯64c(0.14g,0.25mmol)溶于N,N-二甲基甲酰胺(3mL)，加入乙酸钠(0.03g,0.38mmol)，120℃反应4小时。将反应液冷却至室温，过滤，滤液经制备分离纯化[45％CAN/55％H 2O(0.1％甲酸),菲罗门ACE规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物64(15mg,产率10％,HPLC纯度:90.73％)，为黄色固体。
MS(ESI,neg.ion)m/z:510.0[M-H] -。
1H NMR(400MHz,CDCl 3)δ(ppm)7.61(s,2H),7.21(d,J＝4.6Hz,4H),6.86(d,J＝8.5Hz,3H),5.04(s,2H),3.79(s,3H)。
实施例32 2-[3,5-二氯-4-[[1-(2-羟乙基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物65)
Figure PCTCN2020117131-appb-000053
步骤1)1-[2-[叔丁基(二甲基)硅氧基]乙基]-5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮 65a
将5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮39b(1.50g,4.30mmol)溶于N,N-二甲基甲酰胺(15mL)，加入碳酸钾(1.2g,8.6mmol)和2-溴乙氧基-叔丁-二甲基-硅烷(1.11g,4.64mmol)，40℃下反应23小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(30mL×2)萃取，合并的有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化，得到标题化合物65a(1.1g,产率50％)，为黄色油状物。
步骤2)5-(4-氨基-2,6-二氯苯氧基)-1-[2-[叔丁基(二甲基)硅氧基]乙基]吡啶-2(1H)-酮65b
将1-[2-[叔丁基(二甲基)硅氧基]乙基]-5-[2,6-二氯-4-(2,5-二甲基-1H-吡咯-1-基)苯氧基]吡啶-2(1H)-酮65a(0.80g,1.6mmol)和盐酸羟胺(2.7g,39mmol)溶于乙醇(15mL)，加入三乙胺(1.0mL,7.2mmol)，85℃反应16小时。反应液冷却至室温，加入乙酸乙酯(20mL)，搅拌10分钟，过滤，滤液浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到标题化合物65b(0.62g,产率92％)，为白色固体。
步骤3)N-[2-[[4-[[1-[2-[叔丁基(二甲基)硅氧基]乙基]-6-氧代-1,6-二氢吡啶-3-基]氧基]-3,5-二氯苯基]肼叉]-2- 氰基-乙酰基]氨基甲酸乙酯65c
将5-(4-氨基-2,6-二氯苯氧基)-1-[2-[叔丁基(二甲基)硅氧基]乙基]吡啶-2(1H)-酮65b(0.51g,1.2mmol)溶于乙酸(10mL)，0℃下加入亚硝酸钠(0.17g,2.4mmol)的水(5mL)溶液，反应20分钟后，加入N-氰基乙酰尿烷(0.23g,1.4mmol)，继续0℃反应。0℃下，向反应液中加入水(10mL)，搅拌10分钟，过滤，用水(2mL)洗涤，收集滤饼真空干燥，得到标题化合物65c(0.45g,产率64％)，为红色固体。
步骤4)2-[4-[[1-[2-[叔丁基(二甲基)硅氧基]乙基]-6-氧代-1,6-二氢吡啶-3-基]氧基]-3,5-二氯苯基]-3,5-二氧代 -1,2,4-三嗪-6-甲腈65d
将N-[2-[[4-[[1-[2-[叔丁基(二甲基)硅氧基]乙基]-6-氧代-1,6-二氢吡啶-3-基]氧基]-3,5-二氯苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯65c(0.45g,0.75mmol)溶于N,N-二甲基甲酰胺(8mL)，加入乙酸钠(93mg,1.13mmol)，120℃反应5.5小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化，得到标题化合物65d(0.32g,产率77％)，为红色油状物。
步骤5)2-[3,5-二氯-4-[[1-(2-羟乙基)-6-氧代-1,6-二氢吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈65
将2-[4-[[1-[2-[叔丁基(二甲基)硅氧基]乙基]-6-氧代-1,6-二氢吡啶-3-基]氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈65d(0.31g,0.56mmol)溶于1,4-二氧六环(5mL)，0℃下加入氯化氢的1,4-二氧六环溶液(0.60mL,2.4mmol,4mol/L)，室温反应45分钟。将反应液浓缩，残留物溶于乙醇(20mL)，用活性碳(0.20g)85℃脱色，过滤，滤液浓缩，所到残留物用乙醇/石油醚(1/2,15mL)打浆，过滤，收集滤饼，得到标题化合物65(76mg,产率31％,HPLC纯度87.26％)，为黄色固体。
MS(ESI,neg.ion)m/z:436.0[M-H] -。
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.28(s,1H),7.78(s,2H),7.41(dd,J＝9.8,3.2Hz,1H),7.36(d,J＝3.0Hz,1H),6.43(d,J＝9.8Hz,1H),4.83(s,1H),3.90(t,J＝5.1Hz,2H),3.62-3.55(m,2H)。
实施例33 2-[4-[[1-苄基-6-氧代-1,6-二氢吡啶-3-基]氧基]-3,5-二氯苯基]-6-羟甲基-1,2,4-三嗪-3,5-二酮(化合物66)
Figure PCTCN2020117131-appb-000054
0℃下，将氯甲酸异丙酯(0.12mL,1.0mmol)滴加入2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二氯苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸62a(0.20g,0.40mmol)和三乙胺(0.2mL,1.2mmol)的四氢呋喃(6mL)溶液中，0℃反应2小时后，加入甲醇(4mL)和氯化钙(0.26g,2.4mmol)，搅拌3分钟，加入硼氢化钠(90mg,0.24mmol)，室温反应12小时。将反应液浓缩，所得残留物经制备分离纯化[38％ACN/62％H 2O(0.1％TFA),Kromasil规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物66(21mg产率11％,HPLC纯度:97.67％)，为浅黄色固体。
MS(ESI,pos.ion)m/z:488.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.88(s,2H),7.56(d,J＝3.0Hz,1H),7.43(dd,J＝9.9,3.1Hz,1H),7.33(t,J＝7.1Hz,2H),7.29-7.18(m,3H),6.48(d,J＝9.9Hz,1H),5.28(s,1H),5.06(s,2H),4.39(s,2H)。
实施例34 2-[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二甲基苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物67)
Figure PCTCN2020117131-appb-000055
Figure PCTCN2020117131-appb-000056
步骤1)5-(2,6-二甲基-4-硝基-苯氧基)-2-甲氧基吡啶67a
将6-甲氧基吡啶-3-醇4a(3.0g,24mmol)、2-氟-1,3-二甲基-5-硝基-苯(4.50g,26.6mmol)和碳酸钾(2.60g,26.2mmol)溶于N,N-二甲基甲酰胺(25mL)，80℃反应24小时。反应液冷却至室温，向反应液加入水(50mL)，搅拌10分钟，过滤，滤饼用水(10mL×2)洗涤，收集滤饼烘干，得到标题化合物67a(6.10g,产率93％)，为淡黄色固体。
步骤2)5-(2,6-二甲基-4-硝基-苯氧基)吡啶-2(1H)-酮67b
将5-(2,6-二甲基-4-硝基-苯氧基)-2-甲氧基吡啶67a(2.00g,7.29mmol)、对甲苯磺酸(6.30g,36.6mmol)和氯化锂(1.50g,35.4mmol)溶于N,N-二甲基甲酰胺(8mL)，120℃反应4小时。将反应液趁热倒入冰水(16mL)中，搅拌10分钟，过滤，滤饼用水(10mL×2)洗涤，收集滤饼烘干，得到标题化合物67b(1.70g,产率90％)，为类白色固体。
步骤3)1-苄基-5-(2,6-二甲基-4-硝基-苯氧基)吡啶-2(1H)-酮67c
将5-(2,6-二甲基-4-硝基-苯氧基)吡啶-2(1H)-酮67b(0.80g,3.1mmol)和碳酸钾(0.61g,6.2mmol)溶于乙腈(8mL)，滴加苄溴(0.60mL,5.1mmol)，60℃反应6小时。反应液冷却到室温，过滤，滤液浓缩，所得残留物85℃重结晶(石油醚/乙酸乙酯＝4/1,12mL)，过滤，收集滤饼烘干，得到标题化合物67c(0.70g,产率65％)，为黄色固体。
步骤4)5-(4-氨基-2,6-二甲基-苯氧基)-1-苄基-吡啶-2(1H)-酮67d
将1-苄基-5-(2,6-二甲基-4-硝基-苯氧基)吡啶-2(1H)-酮67c(0.70g,2.0mmol)溶于乙酸(5mL)，加入铁(0.33g,5.9mmol)，60℃反应2小时。向反应液加水淬灭(15mL)，用乙酸乙酯(20mL×2)萃取，合并的有机相用饱和氯化钠溶液洗涤(10mL×2)洗涤，无水硫酸钠干燥，所得残留物经硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化，得到标题化合物67d(0.32g,收率50％)，为黄色固体。
步骤5)N-[2-[[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二甲基苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙 脂67e
将5-(4-氨基-2,6-二甲基-苯氧基)-1-苄基-吡啶-2(1H)-酮67d(0.30g,0.94mmol)和N-氰基乙酰脲烷(0.18g,1.2mmol)溶于乙酸(6mL)，0℃下加入亚硝酸钠(0.13g,1.9mmol)的水(3mL)溶液，继续反应4小时。向反应液中加入水(30mL)，搅拌10分钟，过滤，收集滤饼烘干，得到标题化合物67d(0.20g,收率44％)，为红棕色固体。
步骤6)2-[4-(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二甲基苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈67
将N-[2-[[4-[(1-苄基-6-氧代-1,6-二氢吡啶-3-基)氧基]-3,5-二甲基苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙脂67e(1.5g,3.1mmol)溶于N,N-二甲基甲酰胺(15mL)，加入乙酸钠(0.28g,3.4mmol)，120℃反应6小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化钠溶液(20mL×3)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物用乙醇/乙酸乙酯/石油醚(1/5/10,16mL)85℃重结晶，过滤，收集滤饼烘干，得到标题化合物67(0.50g,收率40％,HPLC纯度:99.16％)，为淡黄色固体。
MS(ESI,neg.ion)m/z:440.4[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.04(s,1H),7.41-7.14(m,9H),6.48(d,J＝9.8Hz,1H),5.05(s,2H),2.15(s,6H)。
实施例35 2-[4-[(1-苄基-6-氧代吡啶-3-基)氧基]-3,5-二溴-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物68)
Figure PCTCN2020117131-appb-000057
步骤1)5-(2,6-二溴-4-硝基-苯氧基)-2-甲氧基-吡啶68a
将3-羟基-6-甲氧基吡啶4a(0.50g,4.0mmol)、1,3-二溴-2-氟-5-硝基苯(1.20g,4.8mmol)溶于N,N-二甲基甲酰胺(16mL)，加入碳酸钾(1.66g,12.0mmol)，60℃反应13小时。反应液冷却至室温，加入水(15mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物68a(1.60g,产率99％)，为浅红色固体。
步骤2)5-(2,6-二溴-4-硝基-苯氧基)-吡啶-2(1H)-酮68b
将5-(2,6-二溴-4-硝基-苯氧基)-2-甲氧基-吡啶68a(1.60g,3.96mmol)、对甲苯磺酸一水合物(3.80g,20.0mmol)和氯化锂(0.85g,20mmol)溶于N,N-二甲基甲酰胺(6mL)，120℃反应2小时。反应液冷却至室温，加入水(12mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物68b(1.54g,产率99％)，为类白色固体。
步骤3)1-苄基-5-(2,6-二溴-4-硝基-苯氧基)吡啶-2(1H)-酮68c
将5-(2,6-二溴-4-硝基-苯氧基)-吡啶-2(1H)-酮68b(1.54g,3.95mmol)溶于乙腈(15mL)，加入碳酸铯(2.57g,7.90mmol)和溴化苄(0.7mL,5.92mmol)，60℃反应5小时。反应液冷却至室温，浓缩，向残留物中加入水(20mL)，用乙酸乙酯(40mL×2)萃取，合并的有相机用无水硫酸钠干燥，抽滤浓缩，所得残留物经硅胶柱层析(100％乙酸乙酯)纯化，得到标题化合物68c(1.45g,产率76％)，为白色固体。
步骤4)5-(4-氨基-2,6-二溴-苯氧基)-1-苄基-吡啶-2(1H)-酮68d
将1-苄基-5-(2,6-二溴-4-硝基-苯氧基)吡啶-2(1H)-酮68c(1.45g,3.02mmol)溶于乙酸(15mL)，加入铁粉(0.50g,9.06mmol)，60℃反应6小时。反应液冷却至室温，加入水(15mL)，搅拌10分钟，过滤，用水(15mL)洗涤，收集滤饼真空干燥，得到标题化合物68d(1.35g,产率99％)，为黄色固体。
步骤5)N-[2-[[4-[(1-苄基-6-氧代吡啶-3-基)氧基]-3,5-二溴-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯68e
将5-(4-氨基-2,6-二溴-苯氧基)-1-苄基-吡啶-2(1H)-酮68d(1.35g,3.0mmol)溶于乙酸(12mL)，0℃下加入N-氰基乙酰尿烷(0.58g,3.6mmol)，搅拌5分钟，加入亚硝酸钠(0.41g,6.0mmol)的水(10mL)溶液，随后0℃下反应1小时。向反应液中加入水(5mL)，搅拌10分钟，过滤出固体，收集滤饼真空干燥，得到标题化合物68e(1.80g,产率95％)，为红棕色固体。
步骤6)2-[4-[(1-苄基-6-氧代吡啶-3-基)氧基]-3,5-二溴-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈68
将N-[2-[[4-[(1-苄基-6-氧代吡啶-3-基)氧基]-3,5-二溴-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯68e(1.80g,2.84mmol)溶于N,N-二甲基甲酰胺(15mL)，加入乙酸钠(0.29g,3.5mmol)，120℃反应18小时。反应液冷却至室温，加水(15mL)，搅拌10min，过滤，收集滤饼真空干燥，得到的粗品经硅胶柱层析(100％乙酸乙酯)纯化，得到标题化合物68(0.31g,产率19％,HPLC纯度:95.24％)，为白色固体。
MS(ESI,pos.ion)m/z:570.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.27(s,1H),7.93(s,2H),7.53-7.41(m,2H),7.37-7.19(m,5H),6.50(d,J＝10.0Hz,1H),5.06(s,2H)。
实施例36 2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-1,2,4-三嗪-3,5-二酮(化合物69)
Figure PCTCN2020117131-appb-000058
步骤1)2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸69a
将2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈41(0.50g,1.0mmol)溶于乙酸(6mL)，加入浓盐酸(3mL)，120℃反应11小时。反应液冷却至室温，加入饱和食盐水(30mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物69a(0.51g,产率99％)，为黄色固体。
步骤2)2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-1,2,4-三嗪-3,5-二酮69
将2-[3,5-二氯-4-[[1-[(4-氟苯基)甲基]-6-氧代吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸69a(0.51g,0.99mmol)溶于巯基乙酸(3mL)，160℃反应24小时。反应液冷却至室温，加入水(20mL)淬灭，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤，浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/2)纯化，得到标题化合物69(0.15g,产率32％,HPLC纯度:99.10％)，为白色固体。
MS(ESI,neg.ion)m/z:473.0[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.49(s,1H),7.81(s,2H),7.61(d,J＝16.6Hz,2H),7.42(s,1H),7.23(d,J＝56.0Hz,4H),6.59-6.34(m,1H),5.03(s,2H)。
实施例37 2-[4-[(1-苄基-5-甲基-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物70)
Figure PCTCN2020117131-appb-000059
步骤1)5-(2,6-二氯-4-硝基-苯氧基)-2-氟-3-甲基-吡啶70b
将6-氟-5-甲基-吡啶-3-醇70a(0.70g,5.5mmol)、1,2,3-三氯-5-硝基苯(1.50g,6.62mmol)溶于N,N-二 甲基甲酰胺(10mL)，加入碳酸钾(1.83g,13.2mmol)，60℃反应5小时。反应液冷却至室温，加入水(10mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物70b(1.74g,产率95％)，为灰色固体。
步骤2)5-(2,6-二氯-4-硝基-苯氧基)-3-甲基-吡啶-2(1H)-酮70c
将5-(2,6-二氯-4-硝基-苯氧基)-2-氟-3-甲基-吡啶70b(1.74g,5.23mmol)溶于乙酸(16mL)和水(8mL)，120℃反应24小时。反应液冷却至室温，加入水(20mL)，用饱和碳酸钠溶液调节pH＝7，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤，浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物70c(0.75g,产率45％)，为白色固体。
步骤3)1-苄基-5-(2,6-二氯-4-硝基-苯氧基)-3-甲基-吡啶-2(1H)-酮70d
将5-(2,6-二氯-4-硝基-苯氧基)-3-甲基-吡啶-2(1H)-酮70c(0.75g,2.4mmol)溶于乙腈(10mL)，加入碳酸铯(1.56g,4.8mmol)和溴化苄(0.43mL,3.6mmol)，60℃反应4.5小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤，浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物70d(0.80g,产率83％)，为黄色液体。
步骤4)5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-3-甲基-吡啶-2(1H)-酮70e
将1-苄基-5-(2,6-二氯-4-硝基-苯氧基)-3-甲基-吡啶-2(1H)-酮70d(0.80g,2.0mmol)溶于乙酸(10mL)，加入铁粉(0.34g,6.0mmol)，60℃反应6小时。反应液冷却至室温，加入水(10mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物70e(0.73g,产率99％)，为黄色固体。
步骤5)N-[2-[[4-[(1-苄基-5-甲基-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯 70f
将5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-3-甲基-吡啶-2(1H)-酮70e(0.45g,1.20mmol)溶于乙酸(12mL)，加入N-氰基乙酰尿烷(0.23g,1.44mmol)，0℃下反应5分钟，加入亚硝酸钠(0.17g,2.40mmol)的水(4mL)溶液，随后继续反应1小时。向反应液中加入水(5mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物70f(0.50g,产率77％)，为红棕色固体。
步骤6)2-[4-[(1-苄基-5-甲基-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈70
将N-[2-[[4-[(1-苄基-5-甲基-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯70f(0.50g,0.92mmol)溶于N,N-二甲基甲酰胺(8mL)，加入乙酸钠(0.15g,1.8mmol)，120℃反应5小时。反应液冷却至室温，加水(5mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到粗品经制备分离纯化[47％ACN/53％H 2O(0.1％TFA),Kromasil规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物70(0.19g,产率42％,HPLC纯度:99.40％)，为白色固体。
MS(ESI,pos.ion)m/z:496.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.29(s,1H),7.77(s,2H),7.43-7.37(m,2H),7.32(t,J＝7.2Hz,1H),7.28-7.23(m,1H),7.21(d,J＝7.2Hz,1H),5.06(s,2H),2.03(s,3H)。
实施例38 2-[4-[(1-苄基-5-氯-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物71)
Figure PCTCN2020117131-appb-000060
Figure PCTCN2020117131-appb-000061
步骤1)3-氯-5-(2,6-二氯-4-硝基-苯氧基)-2-氟-吡啶71b
将5-氯-6-氟-吡啶-3-醇71a(1.48g,10.0mmol)、1,2,3-三氯-5-硝基苯(2.71g,12.0mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸钾(2.77g,20.0mmol)，60℃反应6小时。反应液冷却至室温，加入水(10mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物71b(3.30g,产率97％)，为灰色固体。
步骤2)3-氯-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮71c
将3-氯-5-(2,6-二氯-4-硝基-苯氧基)-2-氟-吡啶71b(1.10g,3.26mmol)溶于乙酸(10mL)和水(5mL)，120℃反应24小时。反应液冷却至室温，加入水(20mL)，用饱和碳酸钠溶液调节pH＝7，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物71c(0.40g,产率37％)，为白色固体。
步骤3)1-苄基-3-氯-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮71d
将3-氯-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮71c(0.40g,1.2mmol)溶于乙腈(8mL)，加入碳酸铯(0.78g,2.4mmol)和溴化苄(0.22mL,1.8mmol)，60℃反应4.5小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤，浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物71d(0.50g,产率99％)，为黄色液体。
步骤4)5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-3-氯-吡啶-2(1H)-酮71e
将1-苄基-3-氯-5-(2,6-二氯-4-硝基-苯氧基)-吡啶-2(1H)-酮71d(0.50g,1.2mmol)溶于乙酸(10mL)，加入铁粉(0.20g,3.6mmol)，60℃反应6小时。反应液冷却至室温，加入水(10mL)，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物71e(0.32g,产率69％)，为白色固体。
步骤5)N-[2-[[4-[(1-苄基-5-氯-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯71f
将5-(4-氨基-2,6-二氯-苯氧基)-1-苄基-3-氯-吡啶-2(1H)-酮71e(0.32g,0.81mmol)溶于乙酸(5mL)，加入N-氰基乙酰尿烷(0.15g,0.97mmol)，0℃下反应5分钟，加入亚硝酸钠(0.11g,1.62mmol)的水(3mL)溶液，随后继续反应1小时。向反应液中加入水(5mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物71f(0.42g,产率99％)，为红棕色固体。
步骤6)2-[4-[(1-苄基-5-氯-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈71
将N-[2-[[4-[(1-苄基-5-氯-6-氧代吡啶-3-基)氧基]-3,5-二氯-苯基]肼叉]-2-氰基-乙酰基]氨基甲酸乙酯71f(0.42g,0.75mmol)溶于N,N-二甲基甲酰胺(8mL)，加入乙酸钠(73g,0.90mmol)，120℃反应5小时。反应液冷却至室温，加水(5mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到粗品经制备分离纯化[47％ACN/53％H 2O(0.1％TFA),Kromasil规格:C18 10μm×50mm×250mm,流速:100mL/min]，得到标题化合物71(0.13g,产率34％,HPLC纯度:99.16％)，为白色固体。
MS(ESI,neg.ion)m/z:516.0[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.36(s,1H),7.98(d,J＝3.2Hz,1H),7.79(s,2H),7.69(d,J＝3.2Hz,1H),7.34(t,J＝7.2Hz,2H),7.30-7.25(m,1H),7.22(d,J＝7.6Hz,2H)，5.12(s,2H)。
实施例39 2-[3,5-二氯-4-[[6-氧代-1-(四氢吡喃-4-基甲基)吡啶-3-基]氧基]苯基]-1,2,4-三嗪-3,5-二酮(化合物 72)
Figure PCTCN2020117131-appb-000062
步骤1)2-[3,5-二氯-4-[[6-氧代-1-(四氢吡喃-4-基甲基)吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸 72a
将2-[3,5-二氯-4-[[6-氧代-1-(四氢吡喃-4-基甲基)吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈58(0.15g,0.31mmol)溶于乙酸(4mL)，加入浓盐酸(1.5mL)，120℃反应24小时。反应液冷却至室温，加入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物72a(0.136g,产率86.2％)，为黄色固体。
步骤2)2-[3,5-二氯-4-[[6-氧代-1-(四氢吡喃-4-基甲基)吡啶-3-基]氧基]苯基]-1,2,4-三嗪-3,5-二酮72
将2-[3,5-二氯-4-[[6-氧代-1-(四氢吡喃-4-基甲基)吡啶-3-基]氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲酸72a(0.11g,0.22mmol)溶于巯基乙酸(3mL)，160℃反应24小时。反应液冷却至室温，加入水(15mL)淬灭，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/2)纯化，得到标题化合物72(75mg,产率75％,HPLC纯度:92.35％)，为淡黄色固体。
MS(ESI,pos.ion)m/z:465.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.54(s,1H),7.71(s,2H),7.60(s,1H),7.33(dd,J＝9.8,3.0Hz,1H),6.79(dd,J＝18.2,6.3Hz,2H),3.79(d,J＝7.2Hz,2H),3.73(d,J＝7.4Hz,2H),3.52(dd,J＝10.3,5.0Hz,2H),3.35(t,J＝11.4Hz,2H),2.21–2.09(m,1H),1.53(d,J＝12.1Hz,2H).
实施例40 2-[3,5-二氯-4-[(1-异丙基-6-氧代吡啶-3-基)氧基]苯基]-1,2,4-三嗪-3,5-二酮(化合物73)
Figure PCTCN2020117131-appb-000063
步骤1)2-[3,5-二氯-4-[(1-异丙基-6-氧代吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-羧酸73a
将2-[3,5-二氯-4-[(1-异丙基-6-氧代吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈4(0.13g,0.29mmol)溶于乙酸(4mL)，加入浓盐酸(1.5mL)，120℃反应24小时。反应液冷却至室温，加入水(20mL)，搅拌10分钟，过滤，收集滤饼真空干燥，得到标题化合物73a(0.12g,产率94％)，为黄色固体。
步骤2)2-[3,5-二氯-4-[(1-异丙基-6-氧代吡啶-3-基)氧基]苯基]-1,2,4-三嗪-3,5-二酮73
将2-[3,5-二氯-4-[(1-异丙基-6-氧代-3-吡啶基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-羧酸73a(85mg,0.19mmol)溶于巯基乙酸(4mL)，160℃反应24小时。反应液冷却至室温，加入水(10mL)淬灭，用乙酸乙 酯(20mL×3)萃取，合并的有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，抽滤浓缩，所得残留物经胶硅柱层析(石油醚/乙酸乙酯(v/v)＝1/2)纯化，得到标题化合物73(58mg,产率76％,HPLC纯度:91.57％)，为黄色固体。
MS(ESI,pos.ion)m/z:409.0[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)12.49(s,1H),7.81(s,2H),7.71(s,1H),7.53(d,J＝3.2Hz,1H),7.19(dd,J＝9.9,3.3Hz,1H),6.38(d,J＝9.9Hz,1H),5.07-4.95(m,1H),1.26(d,J＝6.8Hz,6H).
实施例41 2-[3,5-二氯-4-[(1-异丁基-6-氧代-吡啶-3基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈(化合物74)
Figure PCTCN2020117131-appb-000064
步骤1)5-(2,6-二氯-4-硝基-苯氧基)-1-异丁基-吡啶-2-酮74a
将5-(2,6-二氯-4-硝基-苯氧基)-1H-吡啶-2-酮4c(1.0g,3.3mmol)和碳酸钾(0.70g,4.98mmol)溶于乙腈(60mL)，加入溴代异丁烷(0.54mL,4.98mmol)，室温反应18小时。反应液冷却至室温，过滤，滤液浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化，得到标题化合物74a(0.125g,产率11％)，为黄色固体。
MS(ESI,pos.ion)m/z:358.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.34-8.31(m,3H),6.79(d,J＝3.3Hz,1H),6.60(d,J＝9.9Hz,1H),3.69(d,J＝7.5Hz,2H),2.15(tt,J＝6.9Hz,1H),0.94(d,J＝6.7Hz,6H)。
步骤2)5-(4-氨基-2,6-二氯-苯氧基)-1-异丁基-吡啶-2-酮74b
将5-(2,6-二氯-4-硝基-苯氧基)-1-异丁基-吡啶-2-酮74a(0.23g,0.63mmol)溶于乙酸(6mL)，加入铁粉(0.072g,1.3mmol)，50℃反应2.5小时。反应液冷却至室温，除去铁粉，加入水(30mL)，搅拌10分钟，用乙酸乙酯(50mL×2)萃取，合并的有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，抽滤浓缩，得到标题化合物74b(0.11g,产率53％)，为黄色固体。
MS(ESI,pos.ion)m/z:328.1[M+H] +。
步骤3)N-[2-氰基2-[[3,5-二氯-4-[(1-异丁基-6-氧代吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯74c
将5-(4-氨基-2,6-二氯-苯氧基)-1-异丁基-吡啶-2-酮74b(0.11g,0.34mmol)和N-氰基乙酰尿烷(0.058g,0.37mmol)溶于乙酸(4mL)，0℃下加入亚硝酸钠(0.050g,0.72mmol)的水(2mL)溶液，反应3小时。0℃下，向反应液中加入水(10mL)，搅拌20分钟，过滤，用水(5mL)洗涤，收集滤饼真空干燥，得到标题化合物74c(0.14g,产率85％)，为黄色固体。
步骤4)2-[3,5-二氯-4-[(1-异丁基-6-氧代吡啶-3-基)氧基]苯基]-3,5-二氧代-1,2,4-三嗪-6-甲腈74
将N-[2-氰基2-[[3,5-二氯-4-[(1-异丁基-6-氧代吡啶-3-基)氧基]苯基]肼叉]乙酰基]氨基甲酸乙酯74c(0.14g,0.29mmol)溶于N,N-二甲基甲酰胺(4mL)，加入乙酸钠(0.05g,0.37mmol)，120℃反应16小时。反应液冷却至室温，将反应液浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/8)纯化，得到 标题化合物74(62mg,产率48％,HPLC纯度:91.13％)，为浅黄色固体。
MS(ESI,neg.ion)m/z:447.0[M-H] -；
1H NMR(400MHz,DMSO-d 6)δ(ppm)13.30(s,1H),7.78(s,2H),7.50-7.28(m,2H),6.43(d,J＝8.5Hz,1H),3.66(s,2H),1.99(s,1H),0.81(s,6H)。
活性试验实施例
一、本发明化合物在双荧光素酶报告基因实验中对TRα或TRβ激动活性检测
试验材料：
HEK293细胞，购于ATCC，Cat No.CRL-1573；
Fugene HD transfection reaagent，购于Promega，Cat No.E231A；
DMEM，购于Gibco，Cat No.11995；
FBS，购于Biosera，Cat No.FB-1280/500；
0.25％Trypsin-EDTA，购于Gibco，Cat No.25200-072；
Dual-Luciferase Reporter Assay System，购于Promega，Cat No.E1960；
96-well plate(round bottom)，购于Corning，Cat No.3365。
试验方法：
将HEK293细胞培养于10％FBS+DMEM的全培养基中。将pBind-TRα或pBind-TRβ(100ng/μl)、pG5Luc(100ng/μl)、FuGENE HD和Opti-MEM充分混匀后室温孵育15min，同时将HEK293细胞用0.25％Trypsin-EDTA消化后，用全培养基重悬，计算细胞密度，将细胞密度调至500,000cells/ml，然后加入转录混合液与细胞悬液混匀，铺板于96孔板中(100μL/孔)，37℃培养24h。24h后，将试验化合物溶于DMSO中并进行3倍稀释，共稀释10个浓度，随后用DMEM将化合物稀释成含10％DMSO的化合物溶液，取5μL化合物于96孔板中，化合物的DMSO含量终浓度为0.5％，化合物与细胞共培养18h。18h后，用Dual-Luciferase Reporter Assay System检测萤火虫荧光信号和海肾荧光信号。将萤火虫荧光信号(F)除以海肾荧光信号(R)计算出F/R比值，使用Graph Pad Prism软件绘制曲线并计算出EC 50值。试验结果表明，本发明化合物具有很好的激动TRβ的活性。同时，本发明化合物对TRβ的选择性好。
试验结果显示：本发明化合物对TRβ有明显的激动活性及选择性。
二、本发明化合物对TRα或TRβ体外结合活性检测
试验材料：
LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit购于Invitrogen，Cat.No.PV4686；
LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit购于Invitrogen，Cat.No.PV4687。
试验方法：
该方法使用LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit进行实验。将试验化合物溶于DMSO中并进行3倍稀释，共稀释10个浓度，随后用试剂盒中的TR-FRET Coregulator Buffer C稀释成含2％DMSO的化合物溶液。取10μL含2％DMSO的化合物溶液至384孔板中，然后加入5μL 4×TRα-LBD或TRβ-LBD、5μL含0.4μM fluorescein-SRC2-2和8nM Tb anti-GST antibody的混合液至各个孔中，充分混匀后，室温避光孵育1h。1h后，使用BMG LABTECH的PHERAstar FSX酶标仪在激发520nm和发射495nm下读取荧光值(RFU)。将520nm处的发射信号除以495nm处的发射信号计算出TR-FRET比值。使用Graph Pad Prism 5软件绘制曲线并计算出EC 50值，结果如下表1所示。
表1 本发明实施例化合物体外结合活性数据
Figure PCTCN2020117131-appb-000065
Figure PCTCN2020117131-appb-000066
试验结果显示：本发明化合物对TRβ有较强的结合亲和力及选择性。
三、本发明化合物的药代动力学测定
试验目的:下面的方法是用来测定本发明化合物的药代动力学。
试验材料：
所用实验试剂及供试品：Propranolol(普萘洛尔(内标))、甲醇、乙酸铵、K 2EDTA(乙二胺四乙酸钾)、甲酸、乙腈、MTBE(甲基叔丁基醚)、KolliphorHS15(聚乙二醇12羟基硬脂酸酯)、DMSO(二甲亚砜)均为市售可得；
SD大鼠：雄性，180-220g，7-8周龄，购自湖南斯莱克实验动物有限公司。
试验方法：
1、供试品配制
按5％DMSO+5％KolliphorHS15+90％生理盐水配置供试品溶液，具体根据每个化合物的溶解情况进行调整，使化合物能完全溶解。
2、动物实验设计
Figure PCTCN2020117131-appb-000067
Figure PCTCN2020117131-appb-000068
3、动物给药剂量表
组别 性别 动物数量 给药剂量 给药浓度 给药体积
静脉注射I.V. 雄性 3 1mg/kg 1mg/mL 1mL/kg
口服灌胃I.G. 雄性 3 5mg/kg 1mg/mL 5mL/kg
4、溶液配制
(1)供试品储备液的配置：精密称取适量供试品，用DMSO溶解，用乙腈稀释至1mg/mL，摇匀即得。置于-20℃条件下保存待用。
(2)内标物溶液配制：精密吸取一定量1mg/mL Propranolol储备液，用水稀释至100ng/mL。
5、样品分析
采用液液萃取法处理样品，进行色谱分离，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析，用仪器定量软件对结果进行浓度计算。
6、血浆样品预处理
精密吸取30μL的血浆样品，加入250μL内标，涡旋混合均匀。用1mL的MTBE提取一次，13,000rpm，4℃下离心2min，吸取上清液800μL，于96孔氮吹仪中挥干，残留物用150μL甲醇/水(v/v＝50/50)复溶，涡旋混合，进样，进样量为8μL。
7、标准样品的制备
准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为3、5、10、30、100、300、1,000、3,000、5,000和10,000ng/mL的血浆样品，均按“血浆样品预处理”操作，每一浓度进行双样本分析，建立标准曲线。
8、分析方法
使用LC/MS/MS法测定不同化合物给药后大鼠血浆中的待测化合物含量。
9、数据处理
采用WinNonlin 6.1软件，非房室模型法计算药动学参数。
本发明部分实施例化合物的药代动力学实验结果如下表2所示。
表2 本发明部分实施例化合物的药代动力学数据
Figure PCTCN2020117131-appb-000069
试验结果表明，静脉注射给药或口服灌胃给药时，本发明实施例化合物(实施例16和29)表现出优良的药代动力学性质，特别是，相对于对照化合物MGL3196，本发明实施例化合物具有更高的血药浓度和暴露量，即，具有更优良的药代动力学性质。
四、本发明化合物的药效学评价
试验材料：
Western diet：购于Research diet，货号：D12079B；
MCD diet：购于南通特洛菲饲料科技有限公司，货号：TP3006R；
ALT，AST，ALP，TG，CHO，HDL，LDL和GLU：购于Roche，货号分别为：20764957322，20764949322，03333701190，20767107322，03039773190，04399803190，03038866322和04404483190；
8周龄的雄性OB/OB小鼠：购于江苏集萃药康生物科技有限公司；
8周龄的雄性db/db小鼠：购于江苏集萃药康生物科技有限公司。
A、化合物在Western diet饮食诱导的OB/OB小鼠非酒精性脂肪性肝炎(NASH)模型中的药效学评价
OB/OB小鼠为瘦素基因缺失小鼠，利用Western diet饮食诱导的OB/OB小鼠NASH模型为常用的NASH体内药效评价模型。动物适应1周后开始进行实验。OB/OB小鼠采用Western diet饲料喂养，饲料每周更换三次(周一，三，五)，小鼠于喂养后第五周开始给药，一天一次口服给药，持续6周，整个实验周期为10周。实验过程中每天监管动物的基本情况，每周一次记录小鼠体重。实验结束后，禁食过夜，对小鼠麻醉后进行眼眶采血收集全血，4℃，4,000rpm，离心10min获得血清，保存于-80℃。血清用于ALT，AST，ALP，TG，CHO，HDL，LDL和GLU的检测。对小鼠进行解剖，取肝脏并进行称重。肝中叶置于EP管中保存于-80℃，用于肝内TG和CHO含量的测定。肝左叶置于10％的福尔马林中固定后，进行HE染色，并做NAS评分。
B、化合物在MCD饮食诱导的db/db小鼠非酒精性脂肪性肝炎(NASH)模型中的药效学评价
db/db小鼠为瘦素受体基因缺失小鼠，利用MCD饮食诱导的db/db小鼠NASH模型为常用的NASH体内药效评价模型。动物适应1周后开始进行实验。db/db小鼠采用MCD饲料喂养，饲料每周更换三次(周一，周三，周五)，小鼠采用边造模边给药的方式进行实验，一天一次口服给药，持续8周，整个实验周期为8周。实验过程中每天监管动物的基本情况，每周一次记录小鼠体重。实验结束后，禁食过夜，对小鼠麻醉后进行眼眶采血收集全血，4℃，4,000rpm，离心10min获得血清，存于-80℃。血清用于ALT，AST，ALP，TG，CHO，HDL，LDL和GLU的检测。对小鼠进行解剖，取肝脏并进行称重。肝中叶置于EP管中保存于-80℃，用于肝内TG和CHO含量的测定。肝左叶置于10％的福尔马林中固定后，进行HE染色，并做NAS评分。
试验结果表明，本发明化合物能有效降低肝内脂肪堆积、减轻炎症，对肝纤维化有改善作用。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (13)

  1. 一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
    Figure PCTCN2020117131-appb-100001
    其中，
    Y为-O-、-S-、-NR c-、-CR aR b-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-；
    L为不存在、-O-、-S-、-NR c-、-CR dR e-、-S(＝O) 2-、-S(＝O)-或-C(＝O)-；
    各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1-6卤代烷氧基；
    R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1- 6烷基或氰基C 1-6烷基；
    M为-C(＝O)-、-C(＝S)-、-S(＝O) 2-或-S(＝O)-；E 1为N、CH或CR z，其中R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1- 6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基；
    E 2为CR 2；
    E 3为N或CR 3；
    R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-6烷基；
    R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1- 6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-C(＝O)-C 1- 6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-C(＝O)-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 2- 6烯基、C 2-6炔基、C 3-8环烷基、5-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基或C 1- 6卤代烷氧基的取代基所取代；W为-OCH 2COOH、-NHC(＝O)COOH、-NHCH 2COOH、
    Figure PCTCN2020117131-appb-100002
    Figure PCTCN2020117131-appb-100003
    R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1- 6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基或氰基C 1-6烷基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氨基、-C(＝O)NH 2、-S(＝O) 2-C 1-6烷基、-S(＝O) 2-C 1-6烷氨基、C 1-6烷氨基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、氨基C 1-6烷基、羧基C 1-6烷基和氰基C 1-6烷基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代；
    R 5为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基。
  2. 根据权利要求1所述的化合物，其中所述R 3a、R 3b、R 3c和R 3d各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、甲氨基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基或氰基甲基。
  3. 根据权利要求1或2所述的化合物，其中所述各R a、R b、R c、R d和R e独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3或三氟甲氧基。
  4. 根据权利要求1-3任意一项所述的化合物，其中所述R z为氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3- 6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基；
    R 2和R 3各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、二氟甲基、三氟甲氧基、二氟甲氧基、甲氧基、乙氧基、正丙氧基、异丙氧基、C 2-4烯基、C 2-4炔基、羟基甲基、羟基乙基、羟基丙基、C 3-6环烷基、C 3-6环烷基C 1-3烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)C 1-3烷基、苯基、苯基甲基、苯基乙基、吡啶基、嘧啶基、哒嗪基、吡咯基、吡啶基甲基、吡啶基乙基或嘧啶基甲基。
  5. 根据权利要求1-4任意一项所述的化合物，其中所述R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、- C(＝O)-C 1-4烷基、-S(＝O) 2-C 1-4烷基、-S(＝O) 2-C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基或C 1-4卤代烷氧基的取代基所取代。
  6. 根据权利要求1-5任意一项所述的化合物，其中所述R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、三氟甲氧基、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基或噁唑基，其中所述甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CHF 2、-CH 2F、-CH 2CF 3、二氟甲氧基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-CH 2CH 2CH 3、-S(＝O) 2-NHCH 3、-S(＝O) 2-N(CH 3) 2、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、四氢吡咯基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢吡嗪基、四氢哒嗪基、二氢吡咯基、二氢呋喃基、二氢吡喃基、二氢噻吩基、二氢吡啶基、二氢嘧啶基、二氢吡嗪基、二氢哒嗪基、苯基、萘基、呋喃基、噻吩基、咪唑基、吡唑基、嘧啶基、吡啶基、吡咯基、吡嗪基、哒嗪基、噻唑基、四唑基、三唑基、异噁唑基、异噻唑基、噁二唑基和噁唑基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-C(＝O)NH 2、-S(＝O) 2NH 2、-SH、-OH、-NH 2、＝O、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF 3、-CHF 2、-CH 2CF 3、三氟甲氧基或二氟甲氧基的取代基所取代。
  7. 根据权利要求1-6任意一项所述的化合物，其中所述R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)NH 2、-S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、三氟甲氧基、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基或氰基甲基，其中所述 甲基、乙基、正丙基、异丙基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-C(＝O)-OCH(CH 3) 2、-C(＝O)-OCH 2CH 2CH 3、-C(＝O)-O(CH 2) 3CH 3、-C(＝O)-OCH 2CH(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-CH 2CH 3、-C(＝O)-NHCH 3、-C(＝O)-N(CH 3) 2、-C(＝O)NH 2、S(＝O) 2-CH 3、-S(＝O) 2-CH 2CH 3、-S(＝O) 2-NHCH 3、甲氨基、乙氨基、甲氧基、乙氧基、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2CHF 2、二氟甲氧基、羟基甲基、氨基甲基、羧基甲基和氰基甲基各自独立地未被取代或被1、2或3个独立地选自氘、F、Cl、Br、I、-CN、-NO 2、-COOH、-OH、-NH 2、-SH、C 1-6烷基、C 2-6烯基或C 2-6炔基的取代基所取代。
  8. 根据权利要求1-7任意一项所述的化合物，R 5为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、-CH＝CH 2、-CH 2CH＝CH 2、-CH＝CHCH 3、-C≡CH、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基、萘基或5-6个原子组成的杂芳基。
  9. 一种化合物，其具有以下其中之一的结构：
    Figure PCTCN2020117131-appb-100004
    Figure PCTCN2020117131-appb-100005
    Figure PCTCN2020117131-appb-100006
    Figure PCTCN2020117131-appb-100007
    或其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
  10. 一种药物组合物，其包含权利要求1-9任意一项所述的化合物，任选地，进一步包含药学上可接受的载体、赋形剂、辅剂、媒介物中的任意一种或它们的任意组合。
  11. 权利要求1-9任意一项所述的化合物或权利要求10所述的药物组合物在制备药物中的用途，其中，所述药物用于激动甲状腺激素受体；或用于预防、治疗或减轻由激活甲状腺激素受体介导的疾病。
  12. 根据权利要求11所述的用途，其中所述甲状腺激素受体为甲状腺激素β受体。
  13. 根据权利要求11所述的用途，其中所述由激活甲状腺激素受体介导的疾病为非酒精性脂肪性肝病、动脉粥样硬化、冠心病、高血压、高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、肥胖症、糖尿病、代谢紊乱、1A型糖原贮积病、甲状腺功能减退症或甲状腺癌；
    其中所述非酒精性脂肪性肝病为非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎、隐源性肝硬化或原发性肝癌；
    其中所述代谢紊乱为脂质代谢紊乱或糖代谢紊乱。
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CN113244208A (zh) * 2021-05-20 2021-08-13 云南中医药大学 Hpa在制备治疗非酒精性脂肪性肝病药物中的应用
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WO2024120426A1 (zh) * 2022-12-07 2024-06-13 昆药集团股份有限公司 一种甲状腺激素β受体激动剂、晶型、制备方法和用途

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