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US-12617769-B2 - Chemical compound as thyroid hormone beta receptor agonist and use thereof

US12617769B2US 12617769 B2US12617769 B2US 12617769B2US-12617769-B2

Abstract

Provided is a chemical compound as a thyroid hormone Beta receptor agonist and a use thereof, further comprising a pharmaceutical composition containing the chemical compound. The chemical compound or pharmaceutical composition can be used in the preparation of drugs for preventing, treating or mitigation of diseases mediated by agonistic thyroid hormone β receptor, particularly for the preparation of drugs for treating non-alcoholic fatty liver diseases.

Inventors

  • Zheng Gu
  • Jianhao LI
  • Xinshan DENG
  • Zheng Li
  • Daoqian CHEN
  • Jianchao DENG
  • Aizhen LV
  • Jianyu LIU

Assignees

  • SUNSHINE LAKE PHARMA CO., LTD.

Dates

Publication Date
20260505
Application Date
20200923
Priority Date
20190924

Claims (9)

  1. 1 . A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof, wherein, Y is —O—, —S—, —NR c —, —CR a R b —, —S(═O) 2 —, —S(═O)— or —C(═O)—; L is absent, —O—, —S—, —NR c —, —CR d R e —, —S(═O) 2 —, —S(═O)— or —C(═O)—; each of R a , R b , R c , R d and R e 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 haloalkyl or C 1-6 haloalkoxy; 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; M is —C(═O)—, —C(═S)—, —S(═O) 2 — or —S(═O)—; E 1 is N or CH; E 2 is CR 2 ; E 3 is N or CR 3 ; each of R 2 and R 3 is independently H or deuterium; R 1 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(═O)—C 1-6 alkoxy, —C(═O)—C 1-6 alkylamino, —C(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered heterocyclyl, C 6-10 aryl or 5-8 membered heteroaryl, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(═O)—C 1-6 alkoxy, —C(═O)—C 1-6 alkylamino, —C(═O)—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 5-8 membered heterocyclyl, C 6-10 aryl and 5-8 membered heteroaryl is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from Deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —C(═O)NH 2 , —S(═O) 2 NH 2 , —SH, —OH, —NH 2 , ═O, —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy; W is R 4 is 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(═O)—C 1-6 alkoxy, —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkylamino, —C(═O)NH 2 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl or cyano C 1-6 alkyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)—C 1-6 alkoxy, —C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkylamino, —C(═O)NH 2 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 —C 1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl and cyano C 1-6 alkyl is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —OH, —NH 2 , —SH, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R 5 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.
  2. 2 . The compound of claim 1 , wherein 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 , trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl or cyanomethyl.
  3. 3 . The compound of claim 1 , wherein each of R a , R b , R c , R d and R e is independently H, deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —OH, NH 2 , —SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 or trifluoromethoxy.
  4. 4 . The compound of claim 1 , wherein R 1 is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —C(═O)—C 1-4 alkoxy, —C(═O)—C 1-4 alkylamino, —C(═O)—C 1-4 alkyl, —S(═O) 2 —C 1-4 alkyl, —S(═O) 2 —C 1-4 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heterocyclyl, wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, —C(═O)—C 1-4 alkoxy, —C(═O)—C 1-4 alkylamino, —C(═O)—C 1-4 alkyl, —S(═O) 2 —C 1-4 alkyl, —S(═O) 2 —C 1-4 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heterocyclyl is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from Deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —C(═O)NH 2 , —S(═O) 2 NH 2 , —SH, —OH, —NH 2 , ═O, —C(═O)—C 1-4 alkyl, —C(═O)—C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy.
  5. 5 . The compound of claim 1 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , trifluoromethoxy, difluoromethoxy, —C(═O)—OCH 3 , —C(═O)—OCH 2 CH 3 , —C(═O)—OCH(CH 3 ) 2 , —C(═O)—OCH 2 CH 2 CH 3 , —C(═O)—O(CH 2 ) 3 CH 3 , —C(═O)—OCH 2 CH(CH 3 ) 2 , —C(═O)—NHCH 3 , —C(═O)—N(CH 3 ) 2 , —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , —S(═O) 2 —CH 2 CH 2 CH 3 , —S(═O) 2 —NHCH 3 , —S(═O) 2 —N(CH 3 ) 2 , —CH═CH 2 , —CH 2 CH═CH 2 , —CH═C≡CH 3 , —C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl or oxazolyl, wherein each of the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, —CHF 2 , —CH 2 F, —CH 2 CF 3 , difluoromethoxy, —C(═O)—OCH 3 , —C(═O)—OCH 2 CH 3 , —C(═O)—OCH(CH 3 ) 2 , —C(═O)—OCH 2 CH 2 CH 3 , —C(═O)—O(CH 2 ) 3 CH 3 , —C(═O)—OCH 2 CH(CH 3 ) 2 , —C(═O)—NHCH 3 , —C(═O)—N(CH 3 ) 2 , —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , —S(═O) 2 —CH 2 CH 2 CH 3 , —S(═O) 2 —NHCH 3 , —S(═O) 2 —N(CH 3 ) 2 , —CH═CH 2 , —CH 2 CH═CH 2 , —CH≡CHCH 3 , —C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, dihydropyrrolyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxadiazolyl and oxazolyl is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —C(═O)NH 2 , —S(═O) 2 NH 2 , —SH, —OH, —NH 2 , ═O, —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , —C(═O)—OCH 3 , —C(═O)—OCH 2 CH 3 , —C(═O)—OCH(CH 3 ) 2 , —C(═O)—OCH 2 CH 2 CH 3 , —C(═O)—O(CH 2 ) 3 CH 3 , —C(═O)—OCH 2 CH(CH 3 ) 2 , —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, —CF 3 , —CHF 2 , —CH 2 CF 3 , trifluoromethoxy or difluoromethoxy.
  6. 6 . The compound of claim 1 , wherein R 4 is H, deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —OH, —NH 2 , —SH, methyl, ethyl, n-propyl, isopropyl, —CH═CH 2 , —CH 2 CH—CH 2 , —CH—CHCH 3 , —C═CH, —C(═O)—OCH 3 , —C(═O)—OCH 2 CH 3 , —C(═O)—OCH(CH 3 ) 2 , —C(═O)—OCH 2 CH 2 CH 3 , —C(═O)—O(CH 2 ) 3 CH 3 , —C(═O)—OCH 2 CH(CH 3 ) 2 , —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , —C(═O)—NHCH 3 , —C(═O)—N(CH 3 ) 2 , —C(═O)NH 2 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , —S(═O) 2 —NHCH 3 , methylamino, ethylamino, methoxy, ethoxy, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CH 2 CHF 2 , trifluoromethoxy, difluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl, wherein each of the methyl, ethyl, n-propyl, isopropyl, —CH═CH 2 , —CH 2 CH═CH 2 , —CH═CHCH 3 , —C═CH, —C(═O)—OCH 3 , —C(═O)—OCH 2 CH 3 , —C(═O)—OCH(CH 3 ) 2 , —C(═O)—OCH 2 CH 2 CH 3 , —C(═O)—O(CH 2 ) 3 CH 3 , —C(═O)—OCH 2 CH(CH 3 ) 2 , —C(═O)—CH 3 , —C(═O)—CH 2 CH 3 , —C(═O)—NHCH 3 , —C(═O)—N(CH 3 ) 2 , —C(═O)NH 2 , —S(═O) 2 —CH 3 , —S(═O) 2 —CH 2 CH 3 , —S(═O) 2 —NHCH 3 , methylamino, ethylamino, methoxy, ethoxy, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CH 2 CHF 2 , difluoromethoxy, hydroxymethyl, aminomethyl, carboxymethyl and cyanomethyl is independently unsubstituted or substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, —CN, —NO 2 , —COOH, —OH, —NH 2 , —SH, C1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.
  7. 7 . The compound of claim 1 , wherein R 5 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, —CH═CH 2 , —CH 2 CH═CH 2 , —CH═CHCH 3 , —C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6 membered heterocyclyl, phenyl, naphthyl or 5-6 membered heteroaryl.
  8. 8 . A compound having one of the following structures: or a stereoisomer, a tautomer, an N-oxide, a solvate, or a pharmaceutically acceptable salt thereof.
  9. 9 . A pharmaceutical composition comprising the compound of claim 1 , optionally, further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims the priorities and benefits of Chinese Patent Application No.s 201910901997.0, 202010164947.1 and 202010231242.7, filed with the State Intellectual Property Office of China on Sep. 24, 2019, Mar. 11, 2020, and Mar. 27, 2020 respectively, which are incorporated herein by reference in their entirety. FIELD The present invention belongs to the field of medicine, and specifically relates to a compound as a thyroid hormone Beta 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 mediated by activated thyroid hormone β receptors, especially in the manufacture of a medicament for treating non-alcoholic fatty liver disease. BACKGROUND Thyroid hormone (TH) 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. The physiological function of TH is mainly carried out through thyroid hormone receptor (TR). 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. There are two subtypes of TR: TRα and TRβ. TRα can be divided into TRα1 and TRα2, and TRβ can be divided into TRβ1 and TRβ2. Among them, only TRα1, TRβ1 and TRβ2 can bind to ligand T3. TRα mainly regulates heart rate, TRβ 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 TRβ in the liver and pituitary gland. If side effects can be minimized or eliminated, then 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)). For example, 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 (J J. 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. 62-66 (1982); J J. Abrams et. al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). In animal models, 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); G J. Grover et. al. Endocrinology, Vol. 145: pp. 1656-1661 (2004); G J. Grover et. al. Proc. Natl. Acad. Sci. USA, Vol. 100: pp. 10067-10072 (2003)). The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels. Through the regulation of LDL and HDL, thyroid hormones may also reduce the risk of atherosclerosis and other cardiovascular diseases. In addition, there is evidence that thyroid hormone can reduce lipoprotein (a), which is a risk factor for atherosclerosis, and increased in patients with atherosclerosis (Paul Webb et. al. Expert Opin. Investig. Drugs, Vol. 13(5): pp. 489-500 (2004); de Bruin et. al. J. Clin. Endo. Metab., Vol. 76: pp. 121-126 (1993)). In addition, non-alcoholic fatty liver disease (NAFLD) is also closely related to thyroid hormones. On the one hand, NAFLD have an effect on the conversion and inactivation of thyroid hormones in the patients, which can lead to a decrease in