WO2021043185A1 - Composé utilisé comme agoniste du récepteur bêta des hormones thyroïdiennes et son utilisation - Google Patents

Composé utilisé comme agoniste du récepteur bêta des hormones thyroïdiennes et son utilisation Download PDF

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WO2021043185A1
WO2021043185A1 PCT/CN2020/113115 CN2020113115W WO2021043185A1 WO 2021043185 A1 WO2021043185 A1 WO 2021043185A1 CN 2020113115 W CN2020113115 W CN 2020113115W WO 2021043185 A1 WO2021043185 A1 WO 2021043185A1
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alkylene
alkyl
compound
membered
cycloalkyl
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PCT/CN2020/113115
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Zheng Gu
Jianhao LI
Zheng Li
Xinshan DENG
Daoqian CHEN
Jianchao DENG
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Sunshine Lake Pharma Co., Ltd.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a compound as a thyroid hormone ⁇ receptor agonist and use thereof, and further relates to a pharmaceutical composition comprising the compound.
  • the invention further relates to the use of the compound and the pharmaceutical composition in the manufacture of a medicament for preventing, treating or alleviating diseases regulated by thyroid hormone ⁇ receptors, especially in the manufacture of a medicament for treating non-alcoholic fatty liver disease.
  • Thyroid hormone plays an extremely important role in growth, differentiation, development and maintenance of metabolic balance. Thyroid hormone is synthesized by the thyroid gland and is 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 a physiologically more active form. T4 is converted to T3 by tissue-specific deiodinase, which is present in all tissues, but mainly in the liver and kidney.
  • TR thyroid hormone receptor
  • TR belongs to the nuclear receptor superfamily and is a transcription factor induced by ligand T3. It is at the core of mediating the role of ligand T3.
  • TR is mainly located in the nucleus and forms a heterodimer with the retinoid X receptor (RXR) and other nuclear receptors and binds to the thyroid hormone response element (TRE) of the target gene promoter region, 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. Among them, only TR ⁇ 1, TR ⁇ 1 and TR ⁇ 2 can bind to ligand T3.
  • TR ⁇ mainly regulates heart rate, 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 body weight. Reducing body weight will improve the co-morbidity associated with obesity and have a beneficial effect on obese patients, and may also have a beneficial effect on glycemic control in obese patients with type 2 diabetes.
  • Thyroid hormone 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 attributed to the fact that thyroid hormone increases liver LDL receptor expression and stimulates 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 hormone has been shown to have the beneficial effect of increasing HDL cholesterol and increasing the conversion rate of LDL to HDL by increasing the expression of apo A-1 (one of HDL’s major apolipoproteins) (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.
  • non-alcoholic fatty liver disease is also closely related to thyroid hormones.
  • NAFLD non-alcoholic fatty liver disease
  • the decrease in thyroid hormone levels further causes disorders of lipid metabolism and glucose metabolism, and participates in the occurrence of NAFLD.
  • Studies have shown that a diet deficient in choline-methionine induces the formation of fatty liver in rats, and 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 ⁇ receptor agonists
  • hyperthyroidism especially cardiovascular toxicity-related side effects
  • cardiovascular disease a malignant steatosis originating from the central nervous system
  • hypothyroidism thyroid cancer
  • thyroid disease and related conditions and diseases.
  • diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular disease, 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 compositions thereof can be used in the manufacture of a medicament for preventing, treating or alleviating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer in a subject.
  • the invention relates to a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • each of R 3a , R 3b , R 3c and R 3d is 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;
  • R 2 is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl;
  • X is N or CH
  • each R a , R b , R c , R d , R e , R f , R h , R i , R j , R k , R m and R n is independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH , -NH 2 , -SH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-6 membered heteroaryl or (5-6 membere
  • R a and R b together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, or R c and R d together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, or R e and R f together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, wherein each C 3-8 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 ;
  • each R 4 and R g is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl) -C 1-4 alkylene, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C
  • each R y is independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino;
  • each R y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino.
  • each of R 3a , R 3b , R 3c , and R 3d is 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 , -CH 2 CHF 2 , trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.
  • each R a , R b , R c , R d , R e , R f , R h , R i , R j , R k , R m and R n is independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH , -NH 2 , -SH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, 5-6 membered heteroaryl or
  • R a and R b together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, or R c and R d together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, or R e and R f together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, wherein each C 3-8 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 .
  • R a and R b together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, or R c and R d together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, or R e and R f together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 5-6 membered heterocycle is independently unsub
  • each R y is independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CF 3 , -CHF 2 , trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or methylamino.
  • each R y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, -CF 3 , -CHF 2 , trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or methylamino.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention, optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof.
  • the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in the manufacture of a medicament for agonizing thyroid hormone receptors; or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject.
  • the present invention relates to a method of agonizing thyroid hormone receptors; or preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject comprising administering to the subject a therapeutically effective amount of the compound or the the pharmaceutical composition disclosed herein.
  • the present invention relates to the compound or the pharmaceutical composition disclosed herein for use in agonizing thyroid hormone receptors; or in preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject.
  • the thyroid hormone receptor of the present invention is a thyroid hormone ⁇ receptor.
  • the disease regulated by thyroid hormone receptors of the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism 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, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone ⁇ receptor, a preparation method, a pharmaceutical composition and use thereof. Skilled in the art can learn from this article to properly improve the process parameters to implement the preparation method. Of particular note is that all similar substitutions and modifications to the skilled person is obvious, and they are deemed to be included in the present invention.
  • grammatical articles “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles used herein refer to one or more than one (i.e. at least one) articles of the grammatical objects.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • the terms “optionally” or “optional” mean that the subsequently described event or condition can but does not necessarily occur, and the description includes the case where the event or condition occurs, and the case where the event or condition does not occur.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • the substituent may be either the same or different at each position.
  • the substituents described therein may be, but not limited to, H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH, -NH 2 , -SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl, aryl-alkylene, heteroaryl, heteroaryl-alkylene, and so on.
  • substitutes of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl particularly 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
  • 3-6 membered heterocyclyl refers to a heterocyclic group consisting of 3 ring atoms, a heterocyclic group consisting of 4 ring atoms, a heterocyclic group consisting of 5 ring atoms and a heterocyclic group
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-8 carbon atoms. In other embodiments, the alkylene group contains 1-6 carbon atoms, i.e., C 1-6 alkylene. In other embodiments, the alkylene group contains 1-4 carbon atoms, i.e., C 1-4 alkylene. In still other embodiments, the alkylene group contains 1-3 carbon atoms, i.e., C 1-3 alkylene.
  • the alkylene group contains 1-2 carbon atoms, i.e., C 1-2 alkylene.
  • Such examples include, but are not limited to, methylene (-CH 2 -) , ethylene (including -CH 2 CH 2 -or -CH (CH 3 ) -) , isopropylidene (including -CH (CH 3 ) CH 2 -or -C (CH 3 ) 2 -) , n-propylene (including -CH 2 CH 2 CH 2 -, -CH (CH 2 CH 3 ) -or -CH 2 CH (CH 3 ) -) , n-butylene (including -CH 2 (CH 2 ) 2 CH 2 -, -CH (CH 2 CH 2 CH 3 ) -, -CH 2 CH (CH 2 CH 3 ) -, -CH 2 CH 2 CH (CH 3 ) -or -CH (CH 3 ) CH (CH 3 ) -) , tert-but
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein.
  • the alkyl group contains 1-10 carbon atoms.
  • the alkyl group contains 1-8 carbon atoms, i.e., C 1-8 alkyl.
  • the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 alkyl.
  • the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 alkyl.
  • the alkyl group contains 1-2 carbon atoms, i.e., C 1-2 alkyl.
  • alkyl group examples include, 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 )
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be optionally substituted with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • the alkenyl contains 2 to 8 carbon atoms.
  • the alkenyl contains 2 to 6 carbon atoms, i.e., C 2-6 alkenyl.
  • the alkenyl contains 2 to 4 carbon atoms, i.e., C 2-4 alkenyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents described herein.
  • the alkynyl contains 2 to 8 carbon atoms.
  • the alkynyl contains 2 to 6 carbon atoms, i.e., C 2-6 alkynyl.
  • the alkynyl contains 2 to 4 carbon atoms, i.e., C 2-4 alkynyl.
  • alkynyl group examples include ethynyl (-C ⁇ CH) , 1-propynyl (-C ⁇ CH-CH 3 ) , propargyl (-CH 2 C ⁇ CH) , 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl and 1-octynyl, etc.
  • alkoxy refers to an alkyl group, as previously defined, attached to parent molecular moiety via an oxygen atom, i.e., -O-alkyl, wherein the alkoxy group may be optionally substituted with one or more substituents described in the present invention.
  • the alkoxy group contains 1-20 carbon atoms. In other embodiments, the alkoxy group contains 1-10 carbon atoms. In other embodiments, the alkoxy group contains 1-8 carbon atoms.
  • the alkoxy group contains 1-6 carbon atoms, i.e., C 1-6 alkoxy. In still other embodiments, the alkoxy group contains 1-4 carbon atoms, i.e., C 1-4 alkoxy. In yet other embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 alkoxy.
  • alkoxy group examples 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-butoxy (s-BuO, s-butoxy, -OCH (CH 3 ) CH 2 CH 3 ) , 2-methyl-isopropyloxy (t-BuO, t-butoxy, -OC (CH 3 ) 3 ) , 1-p
  • alkylamino embraces “N-alkylamino” and “N, N-dialkylamino” , i.e., an amino group is independently substituted with one or two alkyl radicals and wherein the alkyl group is as defined herein. Wherein, the alkyl group may be optionally substituted with one or more substituents disclosed herein.
  • the alkylamino group is one or two C 1-6 alkyl groups attached to a nitrogen atom, i.e., C 1-6 alkylamino.
  • the alkylamino group is one or two C 1-4 alkyl groups attached to a nitrogen atom, i.e., C 1-4 alkylamino.
  • the alkylamino group is one or two C 1-2 alkyl groups attached to a nitrogen atom, i.e., 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, as previously defined, attached to parent molecular moiety via a sulfur atom, i.e., -S-alkyl, wherein the alkylthio group may be optionally substituted with one or more substituents described in the present invention.
  • the alkylthio group contains 1-20 carbon atoms.
  • the alkylthio group contains 1-10 carbon atoms.
  • the alkylthio group contains 1-8 carbon atoms.
  • the alkylthio group contains 1-6 carbon atoms, i.e., C 1-6 alkylthio.
  • the alkylthio group contains 1-4 carbon atoms, i.e., C 1-4 alkylthio. In yet other embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., C 1-3 alkylthio. Examples of such groups include, but are not limited to, methylthio, ethylthio 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 disclosed herein.
  • the haloalkyl group contains 1-10 carbon atoms.
  • the haloalkyl group contains 1-8 carbon atoms.
  • the haloalkyl group contains 1-6 carbon atoms, i.e., C 1-6 haloalkyl.
  • the haloalkyl group contains 1-4 carbon atoms, i.e., C 1-4 haloalkyl.
  • the haloalkyl group contains 1-3 carbon atoms, i.e., C 1-3 haloalkyl. In yet other embodiment, the haloalkyl group contains 1-2 carbon atoms, i.e., C 1-2 haloalkyl.
  • 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 having one or more halogen substituents, wherein the haloalkoxy group may be optionally substituted with one or more substituents disclosed herein.
  • the haloalkoxy group contains 1-10 carbon atoms.
  • the haloalkoxy group contains 1-8 carbon atoms.
  • the haloalkoxy group contains 1-6 carbon atoms, i.e., C 1-6 haloalkoxy.
  • the haloalkoxy group contains 1-4 carbon atoms, i.e., C 1-4 haloalkoxy.
  • the haloalkoxy group contains 1-3 carbon atoms, i.e., C 1-3 haloalkoxy. In yet other embodiment, the haloalkoxy group contains 1-2 carbon atoms, i.e., C 1-2 haloalkoxy. Some non-limiting examples of the haloalkoxy group include trifluoromethoxy, difluoromethoxy, etc.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups (-OH) , wherein the alkyl group are as defined herein, wherein the hydroxyalkyl group may be optionally substituted with one or more substituents disclosed herein.
  • the hydroxyalkyl group in the present invention refers to C 1-6 alkyl substituted with one or more hydroxy groups (-OH) , i.e., hydroxy C 1-6 alkyl; in some embodiments, the hydroxyalkyl group refers to C 1-4 alkyl substituted with one or more hydroxy groups (-OH) , i.e., hydroxy C 1-4 alkyl; in some embodiments, the hydroxyalkyl group refers to C 1-2 alkyl substituted with one or more hydroxy groups (-OH) , i.e., hydroxy C 1-2 alkyl.
  • 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) , and the like.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups (-NH 2 ) , wherein the alkyl group are as defined herein, wherein the aminoalkyl group may be optionally substituted with one or more substituents disclosed herein.
  • the aminoalkyl group in the present invention refers to C 1-6 alkyl substituted with one or more amino groups (-NH 2 ) , i.e., amino C 1-6 alkyl; in some embodiments, the aminoalkyl group refers to C 1-4 alkyl substituted with one or more amino groups (-NH 2 ) , i.e., amino C 1-4 alkyl; in some embodiments, the aminoalkyl group refers to C 1-2 alkyl substituted with one or more amino groups (-NH 2 ) , i.e., amino C 1-2 alkyl.
  • 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 (e.g., -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) , wherein the alkyl group are as defined herein, wherein the cyanoalkyl group may be optionally substituted with one or more substituents disclosed herein.
  • the cyanoalkyl group in the present invention refers to C 1-6 alkyl substituted with one or more cyano groups (-CN) , i.e., cyano C 1-6 alkyl; in some embodiments, the cyanoalkyl group refers to C 1-4 alkyl substituted with one or more cyano groups (-CN) , i.e., cyano C 1-4 alkyl; in some embodiments, the cyanoalkyl group refers to C 1-2 alkyl substituted with one or more cyano groups (-CN) , i.e., cyano C 1-2 alkyl.
  • 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 carboxy groups (-COOH) , wherein the alkyl group are as defined herein, wherein the carboxyalkyl group may be optionally substituted with one or more substituents disclosed herein.
  • the carboxyalkyl group in the present invention refers to C 1-6 alkyl substituted with one or more carboxy groups (-COOH) , i.e., carboxy C 1-6 alkyl; in some embodiments, the carboxyalkyl group refers to C 1-4 alkyl substituted with one or more carboxy groups (-COOH) , i.e., carboxy C 1-4 alkyl; in some embodiments, the carboxyalkyl group refers to C 1-2 alkyl substituted with one or more carboxy groups (-COOH) , i.e., carboxy C 1-2 alkyl.
  • Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl) , and the like.
  • cycloalkyl refers to a saturated ring having 3 to 12 ring carbon atoms as a monocyclic, bicyclic, or tricyclic ring system, which has one or more attachments attaching to the rest of the molecule, wherein the cycloalkyl group is optionally substituted with the substituents described in the present invention.
  • cycloalkyl is a ring system containing 3-10 ring carbon atoms, i.e., C 3-10 cycloalkyl; in still other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms, i.e., C 3-8 cycloalkyl; in yet other embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms, i.e., C 3-6 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturation, nonaromatic ring having 3 to 12 ring atoms as a monocyclic, bicyclic, or tricyclic ring system, in which at least one ring member is selected from heteroatoms such as nitrogen, sulfur, oxygen and phosphorus.
  • the heterocyclic group is non-aromatic and does not contain any aromatic ring, and the ring system has one or more connection points connected to the rest of the molecule.
  • the heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems.
  • Bicyclic heterocyclic groups include bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spiro bicyclic heterocyclyl.
  • heterocyclyl , “heterocyclic group” and “heterocycle” are used interchangeably herein.
  • the sulfur can be optionally oxygenized to S-oxide
  • the nitrogen can be optionally oxygenized to N-oxide
  • the phosphorus can be optionally oxygenized to P-oxide.
  • the heterocyclyl is a ring system composed of 3-10 ring atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-10 ring atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-8 ring atoms; in some embodiments, the heterocyclyl is a ring system composed of 6-8 ring atoms; in some embodiments, the heterocyclyl is a ring system composed of 5-6 ring atoms, i.e., 5-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a ring system composed of 3-6 ring atoms, i.e., 3-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a ring system composed of 3 ring atoms; in other embodiments, the heterocyclyl is a ring system composed of 4 ring atoms; in other embodiments, the heterocyclyl is a ring system composed of ring system
  • heterocyclyl group examples include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl,
  • heterocyclyl group wherein the ring sulfur atom is oxidized is sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • 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] octyl, etc.
  • m-membered where m is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is m.
  • piperidinyl is an example of a 6 membered heterocyclyl group and furanyl is an example of a 5 membered heteroaryl group.
  • 3-6 membered heterocyclyl refers to a heterocyclic group consisting of 3, 4, 5, or 6 atoms.
  • aryl refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems having a total of six to fourteen ring members, or six to twelve ring members, or six to ten ring members, wherein each ring in the system contains 3 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule. Wherein the aryl may be optionally substituted with one or more substituents disclosed herein.
  • aryl may be used interchangeably with the term “aryl ring” or “aromatic ring” .
  • Some non-limiting examples of the aryl group include phenyl, indenyl, naphthyl and anthracenyl.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems having a total of five to ten ring members, wherein at least one ring in the system is aromatic, and in which at least one ring member is selected from heteroatom, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • the heteroaryl may be optionally substituted with one or more substituents disclosed herein.
  • the heteroaryl group may be connected to the rest of the molecule (such as the parent nucleus structure in the general formula) through any reasonable position (which may be C in CH or N in NH) .
  • heteroaryl and “heteroaromatic ring” or “heteroaromatic compound” can be used interchangeably herein.
  • heteroaryl is a heteroaryl group of 5-8 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl group of 5-7 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl group of 5-6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl group of 5 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl group of 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl include the following monocyclic groups: furyl (2-furanyl, 3-furanyl) , 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) , pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl) , thiazolyl (2-thiazolyl)
  • Carbocyclyl refers to a nonaromatic carbon ring system having 3 to 14 ring carbon atoms, which is saturated or contains one or more units of unsaturation.
  • carbon ring refers to a nonaromatic carbon ring system having 3 to 14 ring carbon atoms, which is saturated or contains one or more units of unsaturation.
  • carbon ring refers to a nonaromatic carbon ring system having 3 to 14 ring carbon atoms, which is saturated or contains one or more units of unsaturation.
  • carbon ring , “carbocyclyl” or “carbocyclic” can be used interchangeably here.
  • the ring carbon atom number of the carbocyclyl is 3 to 12; in other embodiments, the ring carbon atom number of the carbocyclyl is 3 to 10; in other embodiments, the ring carbon atom number of the carbocyclyl is 3 to 8; in other embodiments, the ring carbon atom number of the carbocyclyl is 3 to 6, i.e., C 3-6 carbocyclyl; in other embodiments, the ring carbon atom number of the carbocyclyl is 5 to 6, i.e., C 5-6 carbocyclyl; in other embodiments, the ring carbon atom number of the carbocyclyl is 5 to 8.
  • the ring carbon atom number of the carbocyclyl is 6 to 8.
  • the “carbocyclyl” includes a monocyclic, bicyclic, or polycyclic fused ring, spiro ring or bridged ring system, and a polycyclic ring system containing one carbocyclic ring fused with one or more non-aromatic carbocyclic ring, or one or more aromatic ring, or a combination thereof.
  • the bicyclic carbocyclyl groups includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spiro bicyclic carbocyclyl group, and fused bicyclic system contains two rings which share two adjacent ring atoms.
  • Bridged bicyclic group contains two rings which share three or four adjacent ring atoms.
  • Spiro bicyclic system contains two ring which share one ring atom.
  • Some non-limiting examples of the carbocyclyl group include cycloalkyl, cycloalkenyl and cycloalkynyl.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like
  • Bridged carbocyclyl group includes, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.
  • cycloalkyl-alkylene refers to a cycloalkyl group attached to the rest of the molecule through an alkylene group, wherein the cycloalkyl and alkylene are as defined herein.
  • the cycloalkyl-alkylene may be optionally substituted with one or more substituents disclosed herein.
  • the “C 3-6 cycloalkyl-C 1-4 alkylene” in the present invention means that the C 3-6 cycloalkyl group is attached to the rest of the molecule through the C 1-4 alkylene group.
  • C 3-6 cycloalkyl-C 1-2 alkylene in the present invention means that the C 3-6 cycloalkyl group is attached to the rest of the molecule through the C 1-2 alkylene group.
  • Such examples include, but are not limited to, cyclopropyl-CH 2 -, cyclopropyl-CH 2 CH 2 -, cyclobutyl-CH 2 -, cyclobutyl-CH 2 CH 2 -, cyclopentyl-CH 2 -, cyclopentyl-CH 2 CH 2 -, cyclohexyl-CH 2 -, cyclohexyl-CH 2 CH 2 -, etc.
  • heterocyclyl-alkylene refers to a heterocyclyl group attached to the rest of the molecule through an alkylene group, wherein the heterocyclyl and alkylene are as defined herein.
  • the “heterocyclyl-alkylene” group may be optionally substituted with one or more substituents disclosed herein.
  • the “ (5-6 membered heterocyclyl) -C 1-4 alkylene” in the present invention means that the 5-6 membered heterocyclyl is attached to the rest of the molecule through the C 1-4 alkylene group.
  • the “ (5-6 membered heterocyclyl) -C 1-2 alkylene” in the present invention means that the 5-6 membered heterocyclyl is attached to the rest of the molecule through the C 1-2 alkylene group.
  • Such examples include, but are not limited to, tetrahydropyranyl-CH 2 -, tetrahydropyranyl-CH 2 CH 2 -, tetrahydrofuranyl-CH 2 -, tetrahydrofuranyl-CH 2 CH 2 -, pyrrolidinyl-CH 2 -, piperidinyl-CH 2 -, piperidinyl-CH 2 CH 2 -, morpholinyl-CH 2 -, morpholinyl-CH 2 CH 2 -and so on.
  • aryl-alkylene refers to an aryl group attached to the rest of the molecule through an alkylene group, wherein the aryl and alkylene are as defined herein.
  • the “aryl-alkylene” group may be optionally substituted with one or more substituents disclosed herein.
  • the “C 6-10 aryl-C 1-4 alkylene” in the present invention means that the C 6-10 aryl group is attached to the rest of the molecule through the C 1-4 alkylene group.
  • the “C 6-10 aryl-C 1-2 alkylene” in the present invention means that the C 6-10 aryl group is attached to the rest of the molecule through the C 1-2 alkylene group.
  • Such examples include, but are not limited to, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, naphthyl-CH 2 -, and the like.
  • heteroaryl-alkylene refers to an heteroaryl group attached to the rest of the molecule through an alkylene group, wherein the heteroaryl and alkylene are as defined herein.
  • the heteroaryl-alkylene group may be optionally substituted with one or more substituents disclosed herein.
  • the “ (5-6 membered heteroaryl) -C 1-4 alkylene” in the present invention means that the 5-6 membered heteroaryl is attached to the rest of the molecule through the C 1-4 alkylene group.
  • the “(5-6 membered heteroaryl) -C 1-2 alkylene” in the present invention means that the 5-6 membered heteroaryl is attached to the rest of the molecule through the C 1-2 alkylene group.
  • Such examples include, but are not limited to, pyridyl-CH 2 -, pyrrolyl-CH 2 CH 2 -, quinolinyl-CH 2 -, thienyl-CH 2 -, furyl-CH 2 -, pyrimidinyl-CH 2 -, pyridyl-CH 2 -, etc.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus and silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR T (as in N-substituted pyrrolidinyl, R T is a substituent on N) .
  • halogen refers to fluoro (F) , chloro (Cl) , bromo (Br) , or iodo (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 D, i.e., 2 H.
  • a bond drawn from a substituent R to the center of one ring within a ring system represents substitution of the substituent R at any substitutable position or any reasonable position on the ring to which it is connected.
  • formula a represents that the substituent R may be substituted at any position on the ring C that may be substituted, as shown in formulas a-1 to a-4.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991; and P. J. 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 reactions and elimination reactions.
  • a nucleophilic substitution reaction a reactant attacked by a nucleophilic reagent is called a substrate, and an atom or atomic group that breaks out with a pair of electrons from a substrate molecule is called a leaving group.
  • Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, or hydroxy groups.
  • pharmaceutically acceptable refers to that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier includes any solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents) , isotonic agents, salt, drug stabilizers, binders, excipients, dispersants, lubricants, sweetening agents, flavoring agents, coloring agents, or a combination thereof, all of which are well kown to the skilled in the art. (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, all of which are incorporated herein by reference) . Except any conventional carrier is incompatible with the active ingredient, the pharmaceutically acceptable carriers are effectively used in the treatment or pharmaceutical compositions.
  • pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and other additional therapeutic agents, such as anti-diabetic agents, antihyperglycemic agents, antiadipositas agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering agents, etc.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism.
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • phosphates such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche, et al. ed., 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, all of which are incorporated herein by reference in their entireties.
  • metabolite refers to a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
  • pharmaceutically acceptable salt refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail in Berge et al., J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference in its entirety.
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid and ethanolamine.
  • DMSO dimethylsulfoxide
  • hydrate refers to the complex where the solvent molecule is water.
  • N-oxide refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chlor
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (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 in the (R) -or (S) -configuration.
  • the substituent on the atom having an unsaturated double bond may exist in the form of cis- (Z) -or trans- (E) -.
  • the compound disclosed herein may exsit in the form of any possible isomer, rotamer, atropisomer, tautomer, or a mixture thereof, e.g., substantially pure geometric (cis-or trans-) isomer, diastereoisomer, optical isomer (enantiomer) , racemate or a mixture thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2nd 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 atoms whose atomic mass or mass number is different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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, respectively.
  • isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Because of easy preparation and detection, isotopes such as tritiated, i.e., 3 H, and carbon-14, i.e., 14 C are preferred. Further, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Therefore, the heavier isotopes may be preferred in somewhere.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • different optically active compounds are called stereoisomers and are identical except that they are mirror images of one another.
  • a specific stereoisomer is referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, 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 cycloalkyl substituent may have a cis-or trans-configuration.
  • the Formula described herein also contains all the isomers thereof (such as, enantiomers, diastereomers, atropisomers and geometric (conformational) isomers; such as all (R) -and (S) -isomers, (Z) and (E) isomers around the double bond, (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric mixtures (or conformers) of the present compounds are within the scope disclosed herein.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • the specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4 (1H) -one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • subject can be used interchangeablely with “patient” in the invention.
  • subject and patient refer to animals (e.g., birds such as chicken, quail or turkey, or mammals) , specially mammals including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, dogs, cats and mice) and primates (e.g., monkeys, chimpanzees and humans) , more specially 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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • the present invention provides a class of compounds with good agonistic activity on thyroid hormone ⁇ receptors. Such compounds can be used in the manufacture of a medicament for treating non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism disorders, type 1A glycogen storage disease, hypothyroidism or thyroid cancer in a subject.
  • the present invention also provides methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions to prepare medicaments for the above-mentioned diseases in mammals, especially humans.
  • the compounds of the present invention Compared with the existing similar compounds, the compounds of the present invention not only have better pharmacological activity and selectivity, but also have better in vivo metabolic kinetic properties and in vivo pharmacodynamic properties.
  • the preparation method of the compound of the present invention is simple and easy, and the technological method is stable, which is suitable for industrial production. Therefore, the compound provided by the present invention has better druggability compared with the existing similar compounds.
  • the invention relates to a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • ring A, Y, R 1 , R 2 , R 3a , R 3b , R 3c and R 3d have the definition as described in the present invention.
  • each of R 3a , R 3b , R 3c and R 3d is 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.
  • R 2 is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • ring A is wherein E 1 , E 2 , E 3 , R 4 , X, and R y have the definitions described herein.
  • X is N or CH.
  • each R a , R b , R c , R d , R e , R f , R h , R i , R j , R k , R m and R n is independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH , -NH 2 , -SH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-6 membered heteroaryl or
  • R a and R b together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, wherein each C 3-8 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R c and R d together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, wherein each C 3-8 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R e and R f together with the carbon atom to which they are attached, form a C 3-8 carbocycle or a 5-6 membered heterocycle, wherein each C 3-8 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • each R 4 and R g is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl) -C 1-4 alkylene, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-4 alkylene, C 6-10
  • q is 0, 1, 2 or 3.
  • each R y is independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino.
  • each R y1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino.
  • each of R 3a , R 3b , R 3c and R 3d is 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.
  • each of R 3a , R 3b , R 3c , and R 3d is 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 , -CH 2 CHF 2 , trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.
  • R 2 is H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.
  • each R a , R b , R c , R d , R e , R f , R h , R i , R j , R k , R m and R n is independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -COOH, -OH , -NH 2 , -SH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, 5-6 membered heteroaryl or
  • R a and R b together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 5-6 membered heterocycle, wherein each C 3-6 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R a and R b together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R c and R d together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 5-6 membered heterocycle, wherein each C 3-6 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R c and R d together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R e and R f together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 5-6 membered heterocycle, wherein each C 3-6 carbocycle and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • R e and R f together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a 5-6 membered heterocycle, wherein each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 5-6 membered heterocycle is independently unsubstituted or substituted with 1, 2 or 3 R y1 , and R y1 has the definition described in the present invention.
  • each R 4 and R g is independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, 5-6 membered heteroaryl or (5-6 membered heteroaryl) -C 1-2 alkylene, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, 5-6 membered heterocyclyl, (5-6 membered heterocyclyl) -C 1-2 alkylene, C 6-10
  • each R y is independently H, deuterium, F, Cl, Br, I, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino.
  • each R y1 is independently deuterium, F, Cl, Br, I, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino.
  • each R y is independently H, deuterium, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CF 3 , -CHF 2 , trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or methylamino.
  • each R y1 is independently deuterium, F, Cl, Br, I, CN, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, -CF 3 , -CHF 2 , trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, or methylamino.
  • the present invention relates to one of the following structures, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • composition comprising the compound disclosed herein.
  • the pharmaceutical composition disclosed herein optionally, further comprises any one of pharmaceutically acceptable carriers, excipients, adjuvants, vehicles or a combination thereof.
  • the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in the manufacture of a medicament for agonizing thyroid hormone receptors; or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject.
  • provided herein is a method of agonizing thyroid hormone receptors; or preventing, treating or alleviating diseases regulated by thyroid hormone receptors comprising administering to the subject in need a therapeutically effective amount of the compound or the the pharmaceutical composition disclosed herein.
  • the compound provided by the present invention or the pharmaceutical composition thereof 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 compound of the present invention or the pharmaceutical composition of the present invention for use in agonizing thyroid hormone receptors; or in preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the thyroid hormone receptor of the present invention is a thyroid hormone ⁇ receptor.
  • the disease regulated by thyroid hormone receptors of the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorders, lipid metabolism 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, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.
  • the dosage of the compound or pharmaceutical composition required for the implementation of treatment, prevention or delay is usually dependent 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 based on the specific situation.
  • the compound or pharmaceutical composition provided by the present invention when administered by an intravenous route, it can be administered once a week or even at longer intervals.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • 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 intermediates of the enantiomers of 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, it is intended that the invention embrace both solvated and unsolvated forms.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or the compound of the structure shown in the examples, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof, and optionally, other therapeutic and/or prophylactic ingredients.
  • the pharmaceutical composition comprises an 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 is effective to detectably excite thyroid hormone ⁇ receptors in biological specimens or patients.
  • Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound.
  • the pharmaceutically acceptable carrier should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic or once administered to the patient without other adverse reactions or side effects. 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, which, as used herein, includes any solvents, diluents, liquid excipients, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any solvents, diluents, liquid excipients, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams &Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methyl cellulose, hydroxypropyl methyl cellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose a
  • the pharmaceutical composition of the present invention can be administered directly or in a pharmaceutical composition or pharmaceutical form along 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 routine test, and the most effective and convenient route of administration and the most suitable formulation can also be determined by routine test.
  • the compound or composition of the present invention may be administered by any suitable means, and the above-mentioned compounds and pharmaceutically acceptable compositions can be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment or drops) or by nasal sprays, etc., according to the severity of the disease.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions may also contain adjuvants such as
  • Injectable formulations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable water or oil suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly (orthoesters) and poly (anhydrides) .
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compounds are mixed with at least one pharmaceutically acceptable inert excipients or carriers, such as sodium citrate or dicalcium phosphate and /or (a) fillers or swelling agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) adhesives such as carboxymethylcellulose, alginates, gelatin, polyethylene pyrrole ketone, sucrose and gum arabic; (c) moisturizing agents such as glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (e) blocker solution, such as paraffin; (f) absorption promoter such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents such as
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the 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 formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • the active compound may also take the form of a micro-seal 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.
  • this dosage form 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 can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carrier compounds for topical administration of the present invention include, but are not limited to, mineral oil, petrolatum oil, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active components 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 compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, specifically, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the compound or the pharmaceutical composition provided by the present invention can be used in the manufacture of a medicament for agonizing thyroid hormone receptors, or preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the compound or the pharmaceutical composition provided by the present invention can be used for agonizing thyroid hormone receptors, or preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
  • the present invention provides a method of agonizing thyroid hormone receptors, or preventing, treating or alleviating diseases regulated by thyroid hormone receptors comprising administering to the subject in need a therapeutically effective amount of the compound or the the pharmaceutical composition disclosed herein.
  • the compound provided by the present invention or the pharmaceutical composition thereof can be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at certain time intervals.
  • the thyroid hormone receptor of the present invention is a 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, lipid metabolism 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, non-alcoholic fatty liver disease-related cryptogenic cirrhosis or primary liver cancer.
  • these compounds are also useful for veterinary treatment of animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • the animals disclosed herein include horses, dogs, and cats.
  • the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and pharmaceutically acceptable compositions are effective administered in a fairly wide dose range.
  • the daily dose is from about 0.1 mg to 1000 mg per person, the compounds or pharmaceutically acceptable compositions can be administered in a single dose or in several divided doses a day.
  • the compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • a compound or composition can also be administered with one or more other therapeutic agents as discussed above.
  • the compound is characterized by the corresponding structure.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • the structures of the compounds were identified by nuclear magnetic resonance (e.g., 1 H-NMR, 13 C-NMR and/or 19 F-NMR) .
  • 1 H-NMR, 13 C-NMR and 19 F-NMR chemical shifts ( ⁇ ) were recorded as ppm (10 -6 ) .
  • Measure of 1 H-NMR, 13 C-NMR, 19 F-NMR are performed, respectively, on Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer using deuterated chloroform (CDCl3) , deuterated methanol (CD 3 OD and MeOH-d 4 ) or deuterated DMSO (DMSO-d 6 ) as a solvent.
  • TMS (0 ppm) or chloroform (7.25 ppm) is as the reference standard.
  • peak multiplicities were reported, the following abbreviations were used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , dt (doublet of triplets) , td (triplet of doublets) , brs (broadened singlet) .
  • Coupling constants J when given, were reported in Hertz (Hz) .
  • Novasep pump 250 high performance liquid chromatography is generally used for preparation, purification or separation.
  • the silica gel used in column chromatography generally was Qingdao Ocean Chemical Factory 300 to 400 mesh silica gel.
  • the staring materials of the present invention were known or purchased from Shanghai Accela Company, Energy Company, J&K, Alfa Company and the like, or they could be prepared by the conventional synthesis methods in the prior art.
  • nitrogen atmosphere refers to such an atmosphere that a reaction flask was equipped with a balloon or a stainless steel autoclave filled with about 1 L nitrogen.
  • hydrogen atmosphere refers to such an atmosphere that a reaction flask was equipped with a balloon or a stainless steel autoclave filled with about 1 L hydrogen.
  • the solution used in the examples disclosed herein was an aqueous solution.
  • reaction temperature was room temperature.
  • the room temperature was from 20°C to 40°C.
  • the reaction process in the examples was monitored by thin layer chromatography (TLC) .
  • TLC thin layer chromatography
  • the solvent system for development of a TLC plate comprised dichloromethane and methanol, dichloromethane and ethyl acetate, petroleum ether and ethyl acetate.
  • the volume ratio of the solvents in the solvent system was adjusted according to the polarity of the compounds.
  • the elution system of column chromatography comprised: A: petroleum ether and ethyl acetate, B: dichloromethane and ethyl acetate, C: dichloromethane and methanol.
  • A petroleum ether and ethyl acetate
  • B dichloromethane and ethyl acetate
  • C dichloromethane and methanol.
  • the volume ratio of the solvents in the elution system was adjusted according to the polarity of the compounds, and sometimes it was also adjusted by adding a basic agent such as aqueous ammonia or an acidic agent such as acetic acid.
  • HPLC refers to High Performance Liquid Chromatography
  • HPLC was determined on Agilent 1260 high pressure liquid chromatography spectrometer (chromatographic column: Agilent ZORBAX Eclipse Plus C18 4.6mm ⁇ 150mm, 3.5 ⁇ m) ;
  • the test condition of HPLC the run time was 25 minutes (min) ; the column temperature was 35 °C; the detection was carried out at the wavelength of 210 nm and 245 nm using PDA detector;
  • phase A 0.05%phosphoric acid solution
  • phase B acetonitrile
  • flow rate 1.0ml/min
  • the LC/MS/MS system used in biological analysis test comprises Agilent 1200 series vacuum degassing furnace, binary pumps, well-plate autosampler, thermostatted column compartment, the Agilent G6430 Triple Quadru pole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions were in the Table B.
  • MS data were determined on an Agilent 6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 3.5 ⁇ m) .
  • the flow rate was 0.6 mL/min; the mobile phases consisted of a combination of A (0.1%formic acid in CH 3 CN) and B (0.1%formic acid in H 2 O) in gradient mode (5%to 95%) , and an ESI source was used, the peak of HPLC was recorded with UV-Vis detection at 210 nm/254 nm.
  • DMSO-d 6 dimethylsulfoxide-d 6 ; Boc: tert-butoxycarbonyl; DCC: dicyclohexylcarbodiimide DMSO: dimethylsulfoxide; CDCl 3 : chloroform-d; %wt, mass%: weight percent; CD 3 OD: methanol-d; mL, ml: milliliter ⁇ L, ⁇ l: microliter; mol/L, mol/l: mole per liter; mol: mole; mmol/L, mmol/l, mM: millimole/liter; ⁇ mol/L, ⁇ mol/l, ⁇ M: micromole/liter; nmol/L, nmol/l, nM: nanomole/liter; g: gram; h: hour; mg: milligram; ⁇ g: microgram; ng: nanogram; nm: nanometer; ⁇ m: micrometer; mm: millimeter; H 2
  • the compound having formula (I-A) can be prepared by the general synthesis method described in synthesis scheme 1.
  • compound (I-a) can react with compound (I-b) under alkaline conditions (such as potassium carbonate or Sodium hydride) to give compound (I-c) ;
  • compound (I-c) can be subjected to a nitro reduction reaction to give compound (I-d) ;
  • compound (I-d) can be subjected to an amino diazotization reaction, and then can react with compound (I-e) to give compound (I-f) ;
  • compound (I-f) can be ring closed under alkaline conditions (such as potassium acetate) to give the target compound (I-A) .
  • Step 4) 2- (3, 5-dichloro-4- ( (2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo- 2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 1
  • reaction solution was cooled to room temperature, filtered, and the filtrate was purified on a preparative chromatography column [50%ACN /50%H2O (0.1%TFA) , Phenomenex ACE specifications: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100 mL/min] to obtain the title compound 1 (88 mg, yield 24%, HPLC purity: 99.86%) as a white solid.
  • Example 2 3-, 5-dichloro-4- ( (4, 4-dimethyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile (compound 2)
  • N- (4-Methoxyphenyl) -3-methylbut-2-enamide 2b (4.6 g, 22.4 mmol) was dissolved in dichloromethane (15 mL) , and then boron tribromide (4.2 mL, 44 mmol) was added dropwise at 5 °C. The mixture was reacted for 2.5 hours. The reaction solution was poured into an ice-water mixture (30 g) , and saturated sodium bicarbonate solution (30 mL) was added. The resulting mixture was stirred for 10 minutes, and extracted with dichloromethane (10 mL ⁇ 2) . The combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration to obtain the title compound 2c (4.0 g, yield 93%) as a white solid.
  • Step 4 (2, 6-dichloro-4-nitrophenoxy) -4, 4-dimethyl-3, 4-dihydroquinolin-2 (1H) -one 2e
  • Step 6) (Z) -ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ( (4, 4-dimethyl-2-oxo-1, 2, 3, 4- tetrahydroquinolin-6-yl) oxy) phenyl) hydrazono) acetyl) carbamate 2g
  • Step 7) 2- (3, 5-dichloro-4- ( (4, 4-dimethyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 2
  • reaction solution was cooled to room temperature, filtered, and the filtrate was purified on a preparative chromatography column [50%ACN /50%H2O (0.1%TFA) , Phenomenex ACE specifications: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100 mL/min] to obtain the title compound 2 (8 mg, yield 4%, HPLC purity: 98.92%) as a white solid.
  • the mixture was kept at 0 °C and reacted for 30 minutes.
  • the reaction solution was filtered, and the collected filter cake was dissolved with dichloromethane (20 mL) .
  • the organic phases were washed with water (10 mL) and saturated sodium chloride solution (10 mL) in turn, dried over anhydrous sodium sulfate, and concentrated by suction filtration to obtain the title compound 3d (0.15 g, yield 61%) as a red solid.
  • Step 2) 7- (4-amino-2, 6-dichlorophenoxy) -2H-benzo [b] [1, 4] oxazin-3 (4H) -one 4c
  • Example 6 3- (3, 5-dichloro-4- ( (2'-oxospiro [cyclopropane-1, 3'-indolin] -5'-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile (compound 6)
  • Step 2) 5'- (4-amino-2, 6-dichlorophenoxy) spiro [cyclopropane-1, 3'-indolin] -2'-one 6c
  • Step 4) 2- (3, 5-dichloro-4- ( (2'-oxospiro [cyclopropane-1, 3'-indolin] -5'-yl) oxy) phenyl) -3, 5- dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 6
  • the obtained red solid was purified on a preparative chromatography column [25%ACN-/75%H 2 O (0.1%ammonia water) , Kromasil: C18 10 ⁇ m ⁇ 50 mm ⁇ 250 mm, flow rate: 100 mL/min] to obtain the title compound 6 (22 mg, yield 21%, HPLC purity: 97.98%) as a pale yellow solid.
  • Example 7 2- (3, 5-dichloro-4- ( (2'-oxo-2', 4'-dihydro-1'H-spiro [cyclopropane-1, 3'-quinolin] -6'-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile (compound 7)
  • Step 4) 2- (3, 5-dichloro-4- ( (2'-oxo-2', 4'-dihydro-1'H-spiro [cyclopropane-1, 3'-quinolin] -6'-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 7
  • Example 8 2- (3, 5-dichloro-4- ( (2-oxo-1, 2-dihydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile (compound 8)
  • reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated, the residue was purified on a preparative chromatography column [39%ACN /61%H 2 O (0.1%TFA) , Phenomenex ACE specifications: C18 10 ⁇ m ⁇ 50mm ⁇ 250mm, flow rate: 100 mL/min] to obtain the title compound 8 (20 mg, yield 15%, HPLC purity: 98.34%) as a white solid.
  • Example 10 3- (3, 5-dichloro-4- ( (4, 4-dimethyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carboxylic acid (compound 10)
  • Step 4) 2- (3, 5-dichloro-4- ( (1-methyl-2-oxo-1, 2, 3, 4-tetrahydroquinolin-6-yl) oxy) phenyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-carbonitrile 11
  • Step 2) 7- (4-amino-2, 6-dichlorophenoxy) -4, 5-dihydro-1H-benzo [b] azepin-2 (3H) -one 12c
  • Step 2) 7- (4-amino-2, 6-dichlorophenoxy) -1-methyl-4, 5-dihydro-1H-benzo [b] azepin- 2 (3H) -one 14b
  • Step 2) 7- (4-amino-2, 6-dimethylphenoxy) -4, 5-dihydro-1H-benzo [b] azepin-2 (3H) -one 15b
  • the mixture was filtered, and the filter cake was collected and dried in vacuo to obtain the title compound 15 (0.23 g, yield 54%, HPLC purity 98.59%) as a yellow solid.
  • Step 2) 7- (4-amino-2, 6-dibromophenoxy) -4, 5-dihydro-1H-benzo [b] azepin-2 (3H) -one 16b
  • 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;
  • 0.25%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 whole medium.
  • pBind-TR ⁇ or pBind-TR ⁇ (100 ng/ ⁇ l) , pG5Luc (100 ng/ ⁇ l) , FuGENE HD and Opti-MEM were mixed well and then incubated at room temperature for 15 min.
  • HEK293 cells were digested with 0.25%Trypsin-EDTA, then resuspended in the whole medium. The cell density was calculated, the cell density was adjusted to 500,000 cells/ml, then the transcription mixture was added and mixed well with the cell suspension, and plated in a 96-well plate (100 ⁇ L/well) .
  • the mixture was incubated at 37 °C for 24 h. After 24 h, the test compound was dissolved in DMSO and diluted three-fold to obtain a total of 10 concentrations, and then the compounds were diluted into solutions containing 10%DMSO with DMEM. 5 ⁇ L Of the compounds were taken to a 96-well plate. The final DMSO concentration of the compounds was 0.5%, and the compounds were co-cultured with cells for 18 h. After 18 h, the Dual-Luciferase Reporter Assay System was used to detect the firefly fluorescence signal and Renilla fluorescence signal. The firefly fluorescence signal (F) was divided by the Renilla fluorescence signal (R) to calculate the F/R ratio, and the graph was drawn using Graph Pad Prism software to calculate the EC 50 value.
  • F firefly fluorescence signal
  • R Renilla fluorescence signal
  • test results show that the compounds of the present invention have obvious agonistic activity and selectivity for TR ⁇ .
  • LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit was purchased from Invitrogen, Cat. No. PV4686;
  • This method was tested using LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit.
  • the test compound was dissolved in DMSO and diluted three-fold to obtain a total of 10 concentrations, then the compounds were diluted into solutions containing 2%DMSO with TR-FRET Coregulator Buffer C in the kit. 10 ⁇ L Of the compounds containing 2%DMSO were taken to a 384-well plate. Then 5 ⁇ L of 4 ⁇ TR beta/alfa-LBD and 5 ⁇ L of a mixture containing 0.4 ⁇ M fluorescein-SRC2-2 and 8 nM Tb anti-GST antibody were added to each well.
  • test results show that the compounds of the present invention have strong binding affinity and selectivity for TR ⁇ .
  • Test purpose The following method is used to determine the pharmacokinetics of the compounds of the present invention.
  • SD rat male, 180-220 g, 7-8 weeks old, purchased from Hunan Slake Experimental Animal Co., Ltd.
  • test compound prepared was completely dissolved in a mixture of 5%DMSO + 5%KolliphorHS 15 + 90%Saline according solubility property thereof.
  • test compound stock solution an appropriate amount of test compound was precisely weighed, dissolved in DMSO, diluted to 1 mg/mL with acetonitrile, and shaken well to obtain the test compound stock solution, which was stored at -20°C for use.
  • the liquid-liquid extraction method was used to process the samples for chromatographic separation.
  • quantitative analysis was performed using multiple reactive ion monitoring (MRM) , and the concentration were calculated using instrument quantitative software.
  • MRM multiple reactive ion monitoring
  • the content of the test compound in the plasma of rats after administration of different compounds was determined by LC/MS/MS method.
  • Pharmacokinetic parameters were calculated using a noncompartmental method by WinNonLin 6.1 software.
  • test results show that the compounds provided by the present invention exhibit excellent pharmacokinetic properties when administered intravenously or orally.
  • MCD diet purchased from Nantong Trophy Feed Technology Co., Ltd., article number: TP3006R;
  • ALT, AST, ALP, TG, CHO, HDL, LDL and GLU purchased from Roche, article numbers are: 20764957322, 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 0440483190;
  • NASH non-alcoholic steatohepatitis
  • OB/OB mice were leptin gene-deficient mice, and the OB/OB mouse NASH model induced by Western diet is a commonly used NASH in vivo drug efficacy evaluation model.
  • the animals experiment began after 1 week of acclimation. OB/OB mice were fed with Western diet, and the feed was changed three times a week (Monday, Wednesday, and Friday) . The mice began to be administered with the drug in the fifth week after feeding, and they were administered orally once a day for 6 weeks. The entire experiment period was 10 weeks. During the experiment, the basic conditions of the animals were monitored every day, and the weight of the mice was recorded once a week. After the experiment, the rats were fasted overnight.
  • mice After anesthetizing the mice, blood was collected from the orbit to collect whole blood.
  • the serum was obtained by centrifugation at 4°C, 4,000 rpm for 10 min, and stored at -80°C.
  • the serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU.
  • the mice were dissected to take the livers and weighed. The middle lobes of the livers were placed in EP tubes and stored at -80°C for the determination of TG and CHO content in the livers. After the left lobes of livers were fixed in 10%formalin, HE staining was performed and NAS score was performed.
  • NASH non-alcoholic steatohepatitis
  • db/db Mice were leptin receptor gene-deficient mice, and the db/db mouse NASH model induced by MCD diet is a commonly used NASH in vivo drug efficacy evaluation model.
  • the animals experiment began after 1 week of acclimation. db/db Mice were fed with MCD diet, and the feed was changed three times a week (Monday, Wednesday, and Friday) . The mice were administered the drug while modeling, and they were administered orally once a day for 8 weeks. The entire experiment period was 8 weeks. During the experiment, the basic conditions of the animals were monitored every day, and the weight of the mice was recorded once a week. After the experiment, the rats were fasted overnight.
  • mice After anesthetizing the mice, whole blood was collected from the orbit. The serum was obtained by centrifugation at 4 °C, 4,000 rpm for 10 min, and stored at -80°C. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected to take the livers and weighed. The middle lobes of the livers were placed in EP tubes and stored at -80°C for the determination of TG and CHO content in the livers. After the left lobes of livers were fixed in 10%formalin, HE staining was performed and NAS score was performed.
  • test results show that the compounds of the present invention can effectively reduce the accumulation of fat in the liver, reduce inflammation, and improve liver fibrosis.

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Abstract

L'invention concerne un composé utilisé comme agoniste du récepteur bêta des hormones thyroïdiennes et son utilisation. L'invention concerne en outre une composition pharmaceutique comprenant le composé. Le composé ou la composition pharmaceutique peut être utilisé dans la fabrication d'un médicament pour prévenir, traiter ou atténuer des maladies régulées par les récepteurs bêta des hormones thyroïdiennes, en particulier dans la fabrication d'un médicament pour le traitement d'une stéatose hépatique non alcoolique.
PCT/CN2020/113115 2019-09-04 2020-09-03 Composé utilisé comme agoniste du récepteur bêta des hormones thyroïdiennes et son utilisation WO2021043185A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US11091467B2 (en) 2019-05-08 2021-08-17 Aligos Therapeutics, Inc. Modulators of THR-β and methods of use thereof
WO2022099066A1 (fr) * 2020-11-06 2022-05-12 Aligos Therapeutics, Inc. Oxindoles et leurs procédés d'utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3192169A1 (fr) * 2020-09-17 2022-03-24 Sunshine Lake Pharma Co., Ltd. Compose servant d'agoniste du recepteur ? de l'hormone thyroidienne et utilisations du compose
CN116925045A (zh) * 2020-12-15 2023-10-24 中国科学院上海药物研究所 甲状腺素受体β选择性激动剂化合物、其药物组合物和用途
CN113979963B (zh) * 2021-12-24 2022-03-11 凯思凯旭(上海)医药科技有限公司 一种作为甲状腺激素β受体激动剂的化合物及其用途
CN116354934A (zh) * 2021-12-28 2023-06-30 中国科学院上海药物研究所 一类喹啉类化合物及其制备方法、药物组合物和用途

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