CN112442013B - Compound serving as thyroid hormone beta receptor agonist and application thereof - Google Patents
Compound serving as thyroid hormone beta receptor agonist and application thereof Download PDFInfo
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- CN112442013B CN112442013B CN202010912749.9A CN202010912749A CN112442013B CN 112442013 B CN112442013 B CN 112442013B CN 202010912749 A CN202010912749 A CN 202010912749A CN 112442013 B CN112442013 B CN 112442013B
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The compound or the pharmaceutical composition can be used for preparing medicaments for preventing, treating or relieving diseases modulated by thyroid hormone beta receptors, and particularly can be used for preparing medicaments for treating non-alcoholic fatty liver diseases.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The invention further relates to application of the compound and the pharmaceutical composition in preparing medicines for preventing, treating or alleviating diseases modulated by thyroid hormone beta receptors, in particular to application in preparing medicines for treating non-alcoholic fatty liver diseases.
Background
Thyroid Hormone (TH) has an extremely important role in growth, differentiation, development and maintenance of metabolic balance. Thyroid hormones are synthesized by the thyroid gland and secreted into the circulation in two major forms, triiodothyronine (T3) and tetraiodothyronine (T4). While T4 is the predominant form secreted by the thyroid gland, T3 is the more physiologically active form. T4 was converted to T3 by a tissue-specific deiodinase, which is present in all tissues but primarily in the liver and kidney.
The physiological effects of TH are mainly performed by thyroid hormone receptors (TR). TR, a member of the nuclear receptor superfamily, is a transcription factor induced by ligand T3 and is central in mediating the action of ligand T3. TR is mainly located in the nucleus, forms a heterodimer with retinoic acid X receptor (RXR) and other nuclear receptors, binds to a thyroid hormone response element (TRE) in the promoter region of a target gene, and thus regulates gene transcription. There are two subtypes of TR: TR α and TR β. TR α is further classified into TR α 1 and TR α 2, and TR β is further classified into TR β 1 and TR β 2. Of these, only TR α 1, TR β 1 and TR β 2 are capable of binding ligand T3. TR α primarily regulates heart rate, and TR β plays a key role in controlling hepatic cholesterol metabolism and inhibiting Thyroid Stimulating Hormone (TSH) release, which may be associated with high expression of TR β in the liver and pituitary.
Thyroid hormones have certain therapeutic benefits if side effects can be minimized or eliminated (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 heat production, thereby reducing body weight. Reducing body weight will improve the co-morbidities associated with obesity with beneficial effects on obese patients, and may also have beneficial effects on glycemic control in obese patients with type 2 diabetes.
Thyroid hormones also lower serum Low Density Lipoprotein (LDL) (Eugene Morkin et al. journal of Molecular and Cellular diagnostics, Vol.37: pp.1137-1146 (2004)). Hyperthyroidism has been found to be associated with low total serum cholesterol, due to the thyroid hormones increasing hepatic LDL receptor expression and stimulating cholesterol metabolism to bile acids (jj. abrams et al. j. lipid res., vol.22: pp.323-38 (1981)). Hypothyroidism is in turn associated with hypercholesterolemia and reduction of total cholesterol by thyroid hormone replacement therapy has been reported (M.Aviram et al. Clin. biochem., Vol.15: pp.62-66 (1982); JJ.Abrams et al. J.lipid Res., Vol.22: pp.323-38 (1981)). In animal models, thyroid hormones have been shown to have beneficial effects of increasing HDL cholesterol and increasing the conversion rate of LDL to HDL by increasing the expression of apo A-1, one of the major apoproteins of HDL (Gene C.Ness et al. biochemical Pharmacology, Vol.56: pp.121-129 (1998); GJ.Grover et al. Endocrinology, Vol.145: pp.1656-1661 (2004); GJ.Grover et al. Proc.Natl.Acad.Sci.USA, Vol.100: pp.10067-10072 (2003)). The incidence of atherosclerotic vascular disease is directly related to LDL cholesterol levels, and by modulating LDL and HDL, thyroid hormones may also reduce the risk of atherosclerosis and other cardiovascular diseases. In addition, there is evidence that the thyroid hormone hypolipoprotein (a), an important risk factor, is elevated in atherosclerotic patients (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, nonalcoholic fatty liver disease (NAFLD) is also closely related to thyroid hormone. On one hand, patients with NAFLD have influence on the functions of thyroid hormone such as transformation, inactivation and the like, and can cause the reduction of serum thyroid hormone level; on the other hand, the decrease of thyroid hormone level further causes lipid metabolism disorder and carbohydrate metabolism disorder, and is involved in the occurrence of NAFLD. It has been shown that the induction of fatty liver formation in rats by a choline-methionine deficient diet, followed by feeding T3, is observed in the reversal of fatty liver (Perra A, et al. Faseeb, 2008,22(8): 2981).
However, endogenous thyroid hormones are non-selective and present side effects, such as hyperthyroidism, in particular side effects associated with cardiovascular toxicity. Thus, the development of thyroid hormone analogs (e.g., thyroid hormone beta receptor agonists) that avoid the adverse effects of hyperthyroidism while maintaining the beneficial effects of thyroid hormone will open new avenues for treating patients with the following disorders: such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic fatty liver disease, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, and related conditions and diseases.
Disclosure of Invention
The invention provides a compound with better agonistic activity to a thyroid hormone beta receptor, and the compound and a composition thereof can be used for preparing medicaments for preventing, treating or relieving non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolic disorder, 1A type glycogen storage disease, hypothyroidism or thyroid cancer of patients.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I), or prodrug thereof,
wherein the content of the first and second substances,
y is-O-, -NH-, -CH 2 -、-CH＝CH-、-C(＝O)-、-CH(OH)-、-CH(CH 3 )-、-C(CH 3 ) 2 -or-S-;
R 3a 、R 3b 、R 3c and R 3d Each independently is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 An alkyl group;
R 1 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, 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, -S (═ O) 2 NH 2 、C 1-6 Alkylamino radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or cyano radicals C 1-6 An alkyl group;
R 2 is H, deuterium, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C 6-10 Aryl or 5-6 atom heteroaryl;
ring A is
X is N or CH;
E 1 is- (CR) a R b ) q -、-C(＝O)-、-O-、-C(＝CR j R k )-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -; q is 0,1, 2 or 3;
E 2 is-CR c R d -、-C(＝O)-、-C(＝CR h R i )-、-O-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -；
E 3 is-CR e R f -、-C(＝O)-、-C(＝CR m R n )-、-O-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -；
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 Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 Alkylene, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-4 Alkylene is each independentlyIs unsubstituted or substituted by 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R c 、R d Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R e 、R f Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted;
each R 4 And R g Independently of one another H, deuterium, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C 1-4 Alkylene, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C 1-4 Each alkylene is independently unsubstituted or substituted by 1,2 or 3R y1 Substituted;
or R a 、R c And together with the carbon atom to which they are each attached form-C ═ C-;
or R c 、R e And together with the carbon atom to which they are each attached form-C ═ C-;
or R 4 、R e And together with the atom to which they are each attached form-N ═ C-;
each R y Independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy or C 1-6 An alkylamino group;
each R y1 Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In some embodiments, R 3a 、R 3b 、R 3c And R 3d Each independently of the other is 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.
In some embodiments, R 1 Is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 SH, methyl, ethyl, n-propyl, isopropyl and-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 、-S(＝O) 2 NH 2 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.
In some embodiments, R 2 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, heterocyclyl with 5-6 atoms, phenyl, naphthyl or heteroaryl with 5-6 atoms.
In some embodiments, each R is a 、R b 、R c 、R d 、R e 、R f 、R h 、R i 、R j 、R k 、R m And R n Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C 1-2 Alkylene, wherein said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C 1-2 Each alkylene is independently unsubstituted or substituted by 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R c 、R d Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring or heterocyclic ring of 5 to 6 atoms, or R e 、R f Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 And (4) substituting.
In some embodiments, each R is a 、R b 、R c 、R d 、R e 、R f 、R h 、R i 、R j 、R k 、R m And R n Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 -C.ident.CH, methoxy, ethoxy, methylamino, -CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 CHF 2 Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, pyridyl-CH 2 -or pyrrolyl-CH 2 -, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 -C.ident.CH, methoxy, ethoxy, methylamino、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 CHF 2 Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, pyridinyl-CH 2 -and pyrrolyl-CH 2 Each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or heterocyclic ring of 5 to 6 atoms, or R c 、R d Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a heterocyclic ring of 5 to 6 atoms, or R e 、R f Together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R y1 And (4) substitution.
In some embodiments, each R is 4 And R g Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 、-C≡CH、-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 Alkylene, wherein said methyl, ethyl, n-propyl, isopropyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 、-C≡CH、-CHF 2 、-CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-2 Alkylene is each independently unsubstituted or substituted by 1,2 or 3R y1 And (4) substitution.
In some embodiments, each R is y 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.
In some embodiments, each R is y1 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. In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.
In another aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for agonizing a thyroid hormone receptor; or for the prevention, treatment or alleviation of diseases modulated by thyroid hormone receptors.
In some embodiments, the thyroid hormone receptor of the invention is the thyroid hormone beta receptor.
In some embodiments, the disease modulated by a thyroid hormone receptor of the present invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.
In some embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis, or primary liver cancer.
The foregoing merely summarizes certain aspects of the invention, but is not limited to such aspects. These and other aspects will be more fully described below.
Detailed Description
The invention provides a compound with better agonistic activity to a thyroid hormone beta receptor, a preparation method thereof, a pharmaceutical composition thereof and application thereof. Those skilled in the art can modify the process parameters appropriately in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein, and in cases where one or more of the incorporated documents, patents, and similar materials is different from or contradictory to the present application (including but not limited to defined terms, application of terms, described techniques, and the like), the present application shall control.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with CAS version of the periodic Table of the elements, and with handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry may be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, the articles are used herein to refer to articles of one or more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
Unless otherwise indicated, the terms used in the specification and claims have the following definitions.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the above general formula, or as specified in the examples, subclasses,and a class of compounds encompassed by the present invention. It is understood that the term "optionally substituted" is used interchangeably with the term "unsubstituted or … … substituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, an optional substituent group may be substituted at each substitutable position of the group, unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is 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-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl-alkylene, heteroaryl-alkylene, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… … independently" and "… … independently" and "… … independently" used in the present invention are interchangeable, and should be understood in a broad sense, which means that the specific items expressed between the same symbols do not affect each other in different groups, or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C 1-6 Alkyl "especially refers to independently disclosed C 1 Alkyl (methyl), C 2 Alkyl (ethyl), C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group; "C 3-8 Cycloalkyl "especially refers to independently disclosed C 3 Cycloalkyl radical, C 4 Cycloalkyl radical, C 5 Cycloalkyl radical, C 6 Cycloalkyl radical, C 7 Cycloalkyl and C 8 A cycloalkyl group; "heterocyclic group consisting of 3 to 6 atoms" means a heterocyclic group consisting of 3 atoms, a heterocyclic group consisting of 4 atoms, a heterocyclic group consisting of 5 atoms and a heterocyclic group consisting of 6 ring atoms.
In the various parts of this specification, 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 this variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1 to 8 carbon atoms; in other embodiments, the alkylene group contains 1 to 6 carbon atoms, i.e., C 1-6 An alkylene group; in some embodiments, the alkylene group contains 1 to 4 carbon atoms, i.e., C 1-4 An alkylene group; in some embodiments, the alkylene group contains 1 to 3 carbon atoms, i.e., C 1-3 An alkylene group; in some embodiments, the alkylene group contains 1-2 carbon atoms, i.e., C 1-2 An alkylene group. Examples of this 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-propylidene (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-butylene (including-CH (CH) 3 ) 2 )-、-CH 2 CH(CH 3 )CH 2 -or-CH 2 C(CH 3 ) 2 -), pentylene (e.g. -CH 2 (CH 2 ) 3 CH 2 -), hexylene (e.g. -CH 2 (CH 2 ) 4 CH 2 -) and the like. Wherein said alkylene may be optionally substituted with one or more substituents as described herein.
The term "alkyl" or "alkyl group" refers to a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, the alkyl group contains 1-8 carbon atoms, i.e., C 1-8 An alkyl group; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 An alkyl group; in some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 An alkyl group; in some embodiments, the alkyl group contains 1-2 carbon atoms, i.e., C 1-2 An alkyl group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl group (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 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butanesRadical (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 )2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp 2 A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in some embodiments, alkenyl groups contain 2-6 carbon atoms, i.e., C 2-6 An alkenyl group; in some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C 2-4 An alkenyl group.
Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH) 2 ) Allyl (-CH) 2 CH＝CH 2 ) Propenyl (-CH ═ CHCH) 3 ) Butenyl (-CH ═ CHCH) 2 CH 3 、-CH 2 CH＝CHCH 3 、-CH 2 CH 2 CH＝CH 2 、-CH＝C(CH 3 ) 2 、-CH＝C(CH 3 ) 2 、-CH 2 C(CH 3 )＝CH 2 ) Pentenyl (-CH) 2 CH 2 CH 2 CH＝CH 2 、-CH 2 CH 2 CH＝CHCH 3 、-CH 2 CH 2 CH＝CHCH 3 、-CH 2 CH＝CHCH 2 CH 3 、-CH＝CHCH 2 CH 2 CH 3 、-CH 2 CH 2 C(CH 3 )＝CH 2 、-CH 2 CH＝C(CH 3 ) 2 、-CH＝CHCH(CH 3 ) 2 、-C(CH 2 CH 3 )＝CHCH 3 、-CH(CH 2 CH 3 )CH＝CH 2 ) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms wherein at least one site of unsaturation is a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in some embodiments, alkynyl groups contain 2-6 carbon atoms, i.e., C 2-6 An alkynyl group; in some embodiments, alkynyl groups contain 2-4 carbon atoms, i.e., C 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH) 3 ) Propargyl (-CH) 2 C.ident.CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, i.e., -O-alkyl, wherein the alkyl group has the meaning as described herein, wherein the alkoxy group may be optionally substituted with one or more substituents as described herein. In some embodiments, alkoxy groups contain 1 to 20 carbon atoms; in some embodiments, alkoxy groups contain 1 to 10 carbon atoms; in some embodiments, alkoxy groups contain 1 to 8 carbon atoms; in some embodiments, the alkoxy group contains 1-6 carbon atoms, i.e. C 1-6 An alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C 1-4 An alkoxy group; in some embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C 1-3 An alkoxy group.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) N-propyloxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) I-propyloxy (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-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH)) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino", meaning that the amino groups are each independently substituted with one or two alkyl groups having the definitions described herein. Wherein the alkylamino group may be optionally substituted with one or more substituents described herein. In some embodiments, alkylamino is one or two C 1-6 Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C 1-6 An alkylamino group; in some embodiments, alkylamino is one or two C 1-4 Alkyl is attached toAlkylamino radicals on nitrogen atoms, i.e. C 1-4 An alkylamino group; in some embodiments, alkylamino is one or two C 1-2 Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C 1-2 An alkylamino group. Examples of 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 the like.
The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, i.e., -S-alkyl, wherein the alkyl group has the meaning as described herein, wherein the alkylthio group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkylthio group contains 1 to 20 carbon atoms; in some embodiments, the alkylthio group contains 1 to 10 carbon atoms; in some embodiments, the alkylthio group contains 1 to 8 carbon atoms; in some embodiments, the alkylthio group contains 1-6 carbon atoms, i.e., C 1-6 An alkylthio group; in some embodiments, the alkylthio group contains 1-4 carbon atoms, i.e., C 1-4 An alkylthio group; in some embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., C 1-3 An alkylthio group. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, and the like.
The term "haloalkyl" refers to an alkyl group having one or more halo substituents, wherein the haloalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkyl groups contain 1 to 10 carbon atoms; in some embodiments, haloalkyl groups contain 1 to 8 carbon atoms; in some embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., C 1-4 A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 3 carbon atoms, i.e., C 1-3 A haloalkyl group; in some embodiments of the present invention, the substrate is,the haloalkyl group containing 1 to 2 carbon atoms, i.e. C 1-2 A haloalkyl group. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH) 2 F) Difluoromethyl (-CHF) 2 ) Trifluoromethyl (-CF) 3 ) Fluoroethyl group (-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-dichloroethyl, 1, 2-dichloropropyl, and the like.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen substituents, wherein the haloalkoxy group may be optionally substituted with one or more substituents described herein. In some embodiments, haloalkoxy groups contain 1-10 carbon atoms; in some embodiments, haloalkoxy groups contain 1-8 carbon atoms; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C 1-6 A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C 1-4 A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C 1-3 A haloalkoxy group; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C 1-2 A haloalkoxy group. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups (-OH), the alkyl group having the meaning described herein, wherein the hydroxyalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a hydroxyalkyl group as described herein is defined as being substituted with one or more hydroxyl groups (-OH)) Substituted C 1-6 Alkyl, i.e. hydroxy C 1-6 An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups 1-4 Alkyl, i.e. hydroxy C 1-4 An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups 1-2 Alkyl, i.e. hydroxy C 1-2 An alkyl group. Examples of 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.
The term "aminoalkyl" refers to a substituted amino group (-NH) 2 ) Substituted alkyl having the meaning described herein, wherein the aminoalkyl may be optionally substituted with one or more substituents described herein. In some embodiments, an aminoalkyl group, as described herein, is defined as being substituted with one or more amino (-NH) groups 2 ) Substituted C 1-6 Alkyl radicals, i.e. amino radicals C 1-6 An alkyl group; in some embodiments, aminoalkyl groups are referred to by one or more amino groups (-NH) 2 ) Substituted C 1-4 Alkyl radicals, i.e. amino radicals C 1-4 An alkyl group; in some embodiments, an aminoalkyl group is defined as being substituted with one or more amino (-NH) groups 2 ) Substituted C 1-2 Alkyl, i.e. amino C 1-2 An alkyl group. Examples of 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.
The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups (-CN), the alkyl group having the meaning described herein, wherein the cyanoalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a cyanoalkyl group as described herein refers to C substituted with one or more cyano (-CN) groups 1-6 Alkyl, i.e. cyano C 1-6 An alkyl group; in some embodiments, cyanoalkyl groups refer to C substituted with one or more cyano (-CN) groups 1-4 Alkyl, i.e. cyano C 1-4 An alkyl group; in some embodiments, cyanoalkyl groups refer to C substituted with one or more cyano (-CN) groups 1-2 Alkyl, i.e. cyano C 1-2 An alkyl group. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH) 2 CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxy groups (-COOH), said alkyl group having the meaning described herein, wherein said carboxyalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a carboxyalkyl group as described herein refers to C substituted with one or more carboxyl groups (-COOH) 1-6 Alkyl, i.e. carboxyl C 1-6 An alkyl group; in some embodiments, carboxyalkyl groups refer to C substituted with one or more carboxyl groups (-COOH) 1-4 Alkyl, i.e. carboxyl C 1-4 An alkyl group; in some embodiments, carboxyalkyl groups refer to C substituted with one or more carboxyl groups (-COOH) 1-2 Alkyl, i.e. carboxyl C 1-2 An alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and the like.
The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring carbon atoms, saturated with one or more points of attachment to the rest of the molecule, wherein the cycloalkyl group is optionally substituted as described herein. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, i.e., C 3-10 A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, i.e., C 3-8 A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, i.e., C 3-6 A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylCycloheptyl, cyclooctyl, and the like.
The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3 to 12 atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, oxygen, and phosphorus, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the rest of the molecule. Wherein said heterocyclyl group may be optionally substituted by one or more substituents as described herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise specified, a heterocyclic group may be carbon-or nitrogen-based, and-CH 2 A group-may be optionally replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-10 atoms; in some embodiments, heterocyclyl is a ring system of 5-10 atoms; in some embodiments, heterocyclyl is a ring system of 5-8 atoms; in some embodiments, heterocyclyl is a ring system of 6-8 atoms; in some embodiments, heterocyclyl is a 5-6 atom ring system, i.e., 5-6 atom heterocyclyl; in some embodiments, heterocyclyl is a ring system of 3-6 atoms, i.e., 3-6 atoms of heterocyclyl; in some embodiments, heterocyclyl is a system of 3 ring atoms; in some embodiments, heterocyclyl is a ring system of 4 atoms; in other embodiments, heterocyclyl is a 5 atom ring system; in other embodiments, heterocyclyl is a 6 atom ring system.
Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroleMorpholinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, and the like. In heterocyclic radicals-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group and 1, 1-dioxothiomorpholinyl group. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2 ] s]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like.
The term "m-atomic" where m is an integer typically describes the number of ring-forming atoms in the molecule, which is m. For example, piperidinyl is a heterocyclyl group of 6 atoms, and furanyl is a heteroaryl group of 5 atoms. As another example, "heterocyclyl of 3-6 atoms" refers to heterocyclyl groups of 3,4,5, or 6 atoms.
The term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein each ring contains 3 to 7 ring atoms and has one or more attachment points to the rest of the molecule. Wherein said aryl group may be optionally substituted with one or more substituents as described herein. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", and examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracenyl, and the like.
The term "heteroaryl" denotes monocyclic, bicyclic and bicyclic rings containing 5-10 ring atomsA tricyclic aromatic system in which at least one ring contains one or more heteroatoms, wherein each ring contains 5 to 7 ring atoms, wherein at least one ring system is aromatic, and wherein the heteroaryl group has one or more attachment points to the rest of the molecule. Wherein said heteroaryl group may be optionally substituted with one or more substituents as described herein. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the host structure in the formula) via any reasonable site (which may be C in CH, or N in NH). When a heteroaryl group is present-CH 2 When the radical is-CH 2 -a group may optionally be replaced by-C (═ O) -. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a 5-8 atom composed heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-7 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5 atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a 6 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl (2-furyl, 3-furyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g. 5H-tetrazolyl), 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), thienyl (2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic or tricyclic groups are also included, but in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), phenoxathiin, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl.
The term "carbocyclyl" refers to a non-aromatic carbocyclic ring system of 3 to 14 ring carbon atoms that is saturated or contains one or more units of unsaturation. The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein. In some embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 3 to 12; in other embodiments, the number of carbon ring carbon atoms of the carbocyclic ring is from 3 to 10; in other embodiments, the number of ring carbon atoms of a carbocyclic ring is from 3 to 8; in other embodiments, the number of ring carbon atoms in a carbocyclic ring is from 3 to 6, i.e., C 3-6 A carbocyclic group; in other embodiments, the number of ring carbon atoms in a carbocyclic ring is from 5 to 6, i.e., C 5-6 A carbocyclic group; in other embodiments, the number of ring carbon atoms in a carbocyclic ring is from 5 to 8. In other embodiments, the number of carbon ring carbon atoms in a carbocyclic ring is from 6 to 8. "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic rings may be fused to one or more non-aromatic carbocyclic rings or one or more aromatic rings or combinations thereof. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system comprises two rings that share 2 adjacent ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems having a common general formula 1A ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclyl groups include, 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.
The term "cycloalkyl-alkylene" means that the cycloalkyl group is linked to the rest of the molecule through an alkylene group, wherein cycloalkyl and alkylene have the meaning described herein. The cycloalkyl-alkylene groups may be optionally substituted with one or more substituents as described herein. The term "C" in the present invention 3-6 cycloalkyl-C 1-4 Alkylene "represents C 3-6 Cycloalkyl radicals through C 1-4 An alkylene group is attached to the rest of the molecule. The term "C" in the present invention 3-6 cycloalkyl-C 1-2 Alkylene "represents C 3-6 Cycloalkyl radicals through C 1-2 An alkylene group is attached to the rest of the molecule. 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 -and the like.
The term "heterocyclyl-alkylene" means that the heterocyclyl group is attached to the rest of the molecule through an alkylene group, wherein heterocyclyl and alkylene have the meaning described herein. The heterocyclyl-alkylene group may be optionally substituted with one or more substituents as described herein. (heterocyclic group consisting of 5 to 6 atoms) -C described in the present invention 1-4 Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C 1-4 The alkylene group is attached to the rest of the molecule. Hair brush(heterocyclic group consisting of 5 to 6 atoms) -C as described in 1-2 Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C 1-2 The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, tetrahydropyranyl-CH 2 -, tetrahydropyranyl-CH 2 CH 2 -, tetrahydrofuryl-CH 2 -, tetrahydrofuryl-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.
The term "aryl-alkylene" means that the aryl group is linked to the rest of the molecule through an alkylene group, where aryl and alkylene have the meaning described herein. The aryl-alkylene group may be optionally substituted with one or more substituents described herein. For example, "C" according to the invention 6-10 aryl-C 1-4 Alkylene "represents C 6-10 Aryl through C 1-4 An alkylene group is attached to the rest of the molecule. "C" according to the invention 6-10 aryl-C 1-2 Alkylene "represents C 6-10 Aryl through C 1-2 An alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, naphthyl-CH 2 -and the like.
The term "heteroaryl-alkylene" means that the heteroaryl group is linked to the rest of the molecule through an alkylene group, wherein heteroaryl and alkylene have the meaning described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents described herein. (5-6-membered heteroaryl) -C as described in the present invention 1-4 Alkylene "denotes a 5-6 atom heteroaryl group via C 1-4 An alkylene group is attached to the rest of the molecule. (5-6-atom-constituting heteroaryl) -C as defined in the invention 1-2 Alkylene "denotes a heteroaryl group of 5 to 6 atoms bonded via C 1-2 An alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, pyridyl-CH 2 -, pyrrolyl-CH 2 CH 2 -, quinolyl-CH 2 -, thienyl-CH 2 -, furyl-CH 2 -, pyrimidinyl-CH 2 -, pyridyl-CH 2 -and the like.
The term "heteroatom" refers to O, S, N, P and any oxidation state form of Si, including S, N and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or hydrogen on nitrogen atoms in the heterocycle substituted, e.g. N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR T (like NR in N-substituted pyrrolidinyl) T ，R T As a substituent on N).
The term "halogen" refers to F, Cl, Br or I.
The term "nitro" means-NO 2 。
The term "mercapto" refers to-SH.
The term "hydroxy" refers to-OH.
The term "amino" refers to-NH 2 。
The term "cyano" refers to — CN.
The term "carboxylic acid" or "carboxyl" refers to-C (═ O) OH or-COOH.
The term "carbonyl", whether used alone or in combination with other terms such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.
The term "deuterium" means deuteration, i.e. 2 H。
As described herein, the ring system formed by the substituent R being attached to the central ring by a bond represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring to which it is attached. For example, formula a represents that substituent R may be substituted at any possible substituted position on the C ring as shown in formulas a-1 to a-4:
the term "protecting group" or "PG" refers to a group that serves to block other functional groups in a compound when they are reactedA substituent group that cleaves or protects a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group, and typical carboxyl protecting groups include-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "leaving group" or "LG" refers to an atom or functional group that is removed from a larger molecule in a chemical reaction and is the term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azido groups, or hydroxyl groups, and the like.
The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency 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.
The term "carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences,18th Ed. Mack Printing Company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, Bioreversible Carriers in Drug Design, American Pharmaceutical Association andPergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345。
the term "metabolite" refers to the product of the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
The term "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, describe the description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmacol Sci,1997,66, 1-19.
The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (syn. Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as methylene chloride.
Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, 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. Substituents on atoms having unsaturated double bonds may, if possible, be present in cis- (Z) -or trans- (E) -form.
Thus, as described herein, the compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.
Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates on the basis of the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any resulting final products or intermediates can be resolved into the optical enantiomers by known methods, by methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, e.g., High Pressure Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by Asymmetric Synthesis (e.g., Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972))。
The present invention also includes isotopically-labelled compounds of the present invention which are identical to those recited herein, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H， 3 H， 13 C， 14 C， 15 N， 16 O， 17 O， 31 P， 32 P， 36 S， 18 F and 37 Cl。
compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of this invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g. 3 H and 14 incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 h, and carbon-14, i.e. 14 C, an isotope is particularly preferred. Furthermore, with isotopes having a larger mass number, e.g. deuterium, i.e. with 2 H substitution may provide some therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; definitions and conventions described by and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomer, and geometric (or conformational)) forms of such structures; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the present invention are within the scope of the invention.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (value tautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "geometric isomer," also known as "cis-trans isomer," is an isomer resulting from the inability of double bonds (including olefinic double bonds, C ═ N double bonds, and N ═ N double bonds) or single bonds of ring carbon atoms to rotate freely.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
The terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a domestic animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.
Additionally, unless otherwise indicated, the structural formulae for the compounds described herein include isotopically enriched versions of one or more different atoms.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
Description of the Compounds of the invention
The invention provides a compound with better agonistic activity to a thyroid hormone beta receptor, which is used for preparing a medicament for treating nonalcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolic disorder, 1A type glycogen storage disease, hypothyroidism or thyroid cancer. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of using these compounds and pharmaceutical compositions in the manufacture of medicaments for the treatment of the above-mentioned diseases in mammals, especially in humans. Compared with the existing similar compounds, the compound of the invention not only has good pharmacological activity and selectivity, but also has excellent in vivo metabolic kinetics property and in vivo pharmacodynamics property. The preparation method of the compound is simple and feasible, has stable process method, and is suitable for industrial production. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
wherein, ring A, Y, R 1 、R 2 、R 3a 、R 3b 、R 3c And R 3d Having the definitions as described in the present invention.
In some embodiments, Y is-O-, -NH-, -CH 2 -、-CH＝CH-、-C(＝O)-、-CH(OH)-、-CH(CH 3 )-、-C(CH 3 ) 2 -or-S-.
In some embodiments, R 3a 、R 3b 、R 3c And R 3d Each independently of the other is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or cyano radicals C 1-6 An alkyl group.
In some embodiments, R 1 Is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, 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, -S (═ O) 2 NH 2 、C 1-6 Alkylamino radical, C 1-6 Alkoxy radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, carboxyl C 1-6 Alkyl or cyano radicals C 1-6 An alkyl group.
In some embodiments, R 2 Is H, deuterium, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms.
In some embodiments, ring a is
Said E 1 、E 2 、E 3 、R 4 X and R y Having the definitions set out in the present invention.
In some embodiments, X is N or CH.
In some embodiments, E 1 Is- (CR) a R b ) q -、-C(＝O)-、-O-、-C(＝CR j R k )-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -; the R is a 、R b 、R j 、R k 、R g And q has the definitions set forth herein.
In some embodiments, E 2 is-CR c R d -、-C(＝O)-、-C(＝CR h R i )-、-O-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -, said R c 、R d 、R h 、R i And R g Having the definitions set out in the present invention.
In some embodiments, E 3 is-CR e R f -、-C(＝O)-、-C(＝CR m R n )-、-O-、-S-、-S(＝O)-、-S(＝O) 2 -or-NR g -, said R e 、R f 、R m 、R n And R g Having the definitions set out in the present invention.
In some embodiments, each R is a 、R b 、R c 、R d 、R e 、R f 、R h 、R i 、R j 、R k 、R m And R n Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C 1-4 Alkylene, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C 1-4 Alkylene is each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set forth herein.
In some embodiments, any two R are a 、R b 、R c 、R d 、R e 、R f Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, wherein said C 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set out in the present invention.
In some embodiments, R a 、R b Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, in whichSaid C is 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted, said R y1 Having the definitions set forth herein.
In some embodiments, R c 、R d Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, wherein said C 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set forth herein.
In some embodiments, R e 、R f Together with the carbon atom to which they are attached form C 3-8 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, wherein said C 3-8 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted with R y1 Having the definitions set forth herein.
In some embodiments, each R is 4 And R g Independently of one another is H, deuterium, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 Alkylene, wherein said C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-4 Each alkylene is independently unsubstituted or substituted by 1,2 or 3R y1 Substituted with R y1 Having the structure of the inventionAnd (4) defining.
In some embodiments, R a 、R c And together with the carbon atom to which they are each attached form-C ═ C-.
In some embodiments, R c 、R e And together with the carbon atom to which they are each attached form-C ═ C-.
In some embodiments, R 4 、R e And together with the atoms to which they are each attached form-N ═ C-.
In some embodiments, q is 0,1, 2, or 3.
In some embodiments, each R is y Independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In some embodiments, each R is y1 Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In some embodiments, R 3a 、R 3b 、R 3c And R 3d Each independently is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylthio radical, C 1-4 Alkylamino radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl or cyano radicals C 1-4 An alkyl group.
In some embodiments, R 3a 、R 3b 、R 3c And R 3d Each independently of the other is 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.
In some embodiments, R 1 Is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, -C (═ O) -C 1-4 Alkoxy, -C (═ O) -C 1-4 Alkyl, -C (═ O) -C 1-4 Alkylamino, -C (═ O) NH 2 、-S(＝O) 2 -C 1-4 Alkyl, -S (═ O) 2 -C 1-4 Alkylamino, -S (═ O) 2 NH 2 、C 1-4 Alkylamino radical, C 1-4 Alkoxy radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, hydroxy C 1-4 Alkyl, amino C 1-4 Alkyl, carboxyl C 1-4 Alkyl or cyano radicals C 1-4 An alkyl group.
In some embodiments, R 1 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 、-S(＝O) 2 NH 2 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.
In some casesIn embodiments, R 2 Is H, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C 6-10 Aryl or heteroaryl of 5 to 6 atoms.
In some embodiments, R 2 Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 -C.ident.CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a heterocyclic group of 5 to 6 atoms, phenyl, naphthyl or a heteroaryl group of 5 to 6 atoms.
In some embodiments, each R is a 、R b 、R c 、R d 、R e 、R f 、R h 、R i 、R j 、R k 、R m And R n Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C 1-2 Alkylene, wherein said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-2 Each alkylene is independently not substituted bySubstituted or substituted by 1,2 or 3R y1 Substituted with R y1 Having the definitions set forth herein.
In some embodiments, each R is a 、R b 、R c 、R d 、R e 、R f 、R h 、R i 、R j 、R k 、R m And R n Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 -C.ident.CH, methoxy, ethoxy, methylamino, -CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 CHF 2 Trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, pyridyl-CH 2 -or pyrrolyl-CH 2 -, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 -C.ident.CH, methoxy, ethoxy, methylamino, -CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 CHF 2 Difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl-CH 2 -, phenyl-CH 2 CH 2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, pyridyl-CH 2 -and pyrrolyl-CH 2 Each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set out in the present invention.
In some embodiments, any two R are a 、R b 、R c 、R d 、R e 、R f Together with the carbon atom to which they are attached form C 3-6 Carbocyclic ring or heterocyclic ring of 5 to 6 atoms in which the ring forms C 3-6 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, any two R are a 、R b 、R c 、R d 、R e 、R f Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or 5-6 atom heterocycle wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, R a 、R b Together with the carbon atom to which they are attached form C 3-6 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C 3-6 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set out in the present invention.
In some embodiments, R a 、R b Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a heterocyclic ring of 5 to 6 atoms, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylCycloheptyl and a heterocycle of 5 to 6 atoms each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, R c 、R d Together with the carbon atom to which they are attached form C 3-6 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C 3-6 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted, said R y1 Having the definitions set forth herein.
In some embodiments, R c 、R d Together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R y1 Substituted, said R y1 Having the definitions set out in the present invention.
In some embodiments, R e 、R f Together with the carbon atom to which they are attached form C 3-6 A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, wherein said C 3-6 The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, R e 、R f Together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or a 5-6 atom heterocycle wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 5-6 atom heterocycle are each independently unsubstituted or substituted with 1,2, or 3R y1 Substituted with R y1 Having the definitions set forth herein.
In some embodiments, each R is 4 And R g Independently of one another H, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C 1-2 Alkylene, wherein said C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C 1-2 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-2 Alkylene is each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, each R is 4 And R g Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 、-C≡CH、-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 Alkylene, wherein the methyl, ethyl, n-propyl, isopropyl, -CH ═ CH 2 、-CH 2 CH＝CH 2 、-CH＝CHCH 3 、-C≡CH、-CHF 2 、-CH 2 F、-CH 2 CHF 2 、-CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C 1-2 Alkylene, phenyl, alkyl, aryl, heteroaryl, and heteroaryl,phenyl-C 1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C 1-2 Alkylene is each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted with R y1 Having the definitions set out in the present invention.
In some embodiments, each R is y Independently H, deuterium, F, Cl, Br, I, CN, OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy or C 1-4 An alkylamino group.
In some embodiments, each R is y1 Independently deuterium, F, Cl, Br, I, CN, OH, NH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy or C 1-4 An alkylamino group.
In some embodiments, each R is y 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.
In some embodiments, each R is y1 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.
In another aspect, the invention relates to a structure of one of the following, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In some embodiments, the pharmaceutical composition of the present invention, optionally, further comprises any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.
In another aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for agonizing a thyroid hormone receptor; or for the prevention, treatment or alleviation of diseases mediated by thyroid hormone receptors.
In another aspect, the invention relates to a method of agonizing a thyroid hormone receptor, or a method for preventing, treating or ameliorating a disease modulated by a thyroid hormone receptor, using a compound or a pharmaceutical composition of the invention, by administering a therapeutically effective amount of the compound or the pharmaceutical composition to a subject in need thereof. Also, the above-described compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for agonizing a thyroid hormone receptor, or for the prevention, treatment or alleviation of a disease modulated by a thyroid hormone receptor.
In some embodiments, the thyroid hormone receptor of the present invention is the thyroid hormone beta receptor.
In some embodiments, the disease modulated by a thyroid hormone receptor agonist according to the invention is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism, or thyroid cancer.
In some embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis, or primary liver cancer.
The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay-acting effect, etc., will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, route and frequency of administration, etc., and will need to be determined on a case-by-case basis by the attending physician. For example, when a compound or pharmaceutical composition provided by the present invention is administered by intravenous route, administration may be performed once per week or at even longer intervals.
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of the enantiomers of the compounds of the present invention.
Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The invention relates to a pharmaceutical composition which comprises a compound of the invention or a compound of the structure shown in the examples, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite and a pharmaceutically acceptable salt thereof or a prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of the invention and at least one pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle. The amount of compound in the pharmaceutical composition of the invention is effective to detectably agonize thyroid hormone beta receptors in a biological sample or patient.
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, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.
As described herein, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, as used herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York disclose various carriers for use in formulating pharmaceutically acceptable compositions and methods for their preparation. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.
Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methyl cellulose, hydroxypropyl methyl cellulose, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), celluloses and derivatives thereof (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), Powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (e.g., propylene glycol or polyethylene glycols), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), and coloring agents, detackifying agents, coating agents, sweetening and flavoring agents, preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator.
The pharmaceutical compositions of the present invention may be administered directly or in the form of pharmaceutical compositions or medicaments, along with suitable carriers or excipients, as is well known in the art. The methods of treatment of the present invention may comprise administering to a subject in need thereof an effective compound of the present invention. In some embodiments, the subject is a mammalian subject, and in other embodiments, the subject is a human subject.
Effective amounts of the compounds, pharmaceutical compositions or medicaments of the present invention can be readily determined by routine method tests, as can the most effective and convenient route of administration and the most appropriate formulation.
The compounds or compositions of the present invention may be administered by any suitable means, and the compounds and pharmaceutically acceptable compositions described above may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), or by nasal spray, etc., depending on 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. In addition to the active compounds, the liquid dosage forms may contain inert diluents 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, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections.
For example, injectable formulations can be sterilized by filtration through a bacteria retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, for example 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.
Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 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 arts. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
The active compound may also be in microencapsulated form with one or more of the above-mentioned excipients. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain, in addition to the inert diluent, additional substances such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also be of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably in a portion of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a dermal patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated forms. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers that are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions may be prepared by mixing the agents and non-irritating excipients, such materials including, but not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical instillation to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical skin patches may also be used.
For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
Application of compound and pharmaceutical composition of the invention
The compound or the pharmaceutical composition provided by the invention can be used for preparing medicaments for stimulating thyroid hormone receptors or medicaments for preventing, treating or alleviating diseases modulated by the thyroid hormone receptors.
The compounds or pharmaceutical compositions provided by the present invention are useful for agonizing thyroid hormone receptors or for preventing, treating or ameliorating diseases modulated by thyroid hormone receptors.
The present invention provides a method for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disease modulated by a thyroid hormone receptor, which comprises administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need of treatment. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
The thyroid hormone receptor is a thyroid hormone beta receptor.
The diseases are non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, 1A type 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 liver cirrhosis or primary liver cancer.
In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Other examples of animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
An "effective amount", "therapeutically effective amount" or "effective dose" of a compound or pharmaceutically acceptable pharmaceutical composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, administered in one or more divided doses. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
General Synthesis and detection methods
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.
In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known drugs other than those described herein, or by some routine modification of the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The structure of the compound is determined by nuclear magnetic resonance 1 H-NMR、 13 C-NMR or/and 19 F-NMR). 1 H-NMR、 13 C-NMR、 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR、 13 C-NMR、 19 F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer using deuterated chloroform (CDCl) as the solvent 3 ) Deuterated methanol (CD) 3 OD or MeOH-d 4 ) Or deuterated dimethyl sulfoxide (DMSO-d) 6 ). TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), dt (doublets of triplets, doublets), td (triplets of doublets, triplet), brs (broad singlets). Coupling constant J, in Hertz (Hz).
Preparative purification or preparative resolution generally uses a Novasep pump 250 high performance liquid chromatograph.
LC-MS was measured using an Agilen-6120Quadrupole LC/MS mass spectrometer.
The column chromatography generally uses 300-400 mesh silica gel in Qingdao ocean chemical industry as a carrier.
The starting materials of the present invention are known and commercially available, from Shanghai Accela Company, Energy Company, Bailingwei Company (J & K), Tianjin Afaheasha Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.
In the examples, the reaction was carried out in a nitrogen atmosphere unless otherwise specified;
the nitrogen atmosphere refers to the condition that a reaction bottle is connected with a nitrogen balloon or a steel kettle with the volume of about 1L;
the hydrogen atmosphere refers to that a reaction bottle is connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L;
in the examples, unless otherwise specified, the solution refers to an aqueous solution;
in the examples, the reaction temperature is room temperature unless otherwise specified;
in the examples, the room temperature is 20 ℃ to 40 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is regulated according to different polarities of the compounds.
The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.
HPLC refers to high performance liquid chromatography;
HPLC was carried out using an Agilent 1260 high pressure liquid chromatograph (column: Agilent ZORBAX Eclipse Plus C184.6 mm. times.150 mm,3.5 μm);
HPLC test conditions: operating time: column temperature 25 min: detection wavelength at 35 ℃: 210 nm; 245 nm;
mobile phase: phase A: 0.05% phosphoric acid solution phase B: acetonitrile; flow rate: 1.0 ml/min;
mobile phase gradients are shown in table a:
TABLE A
| Time | Gradient of mobile phase A | Gradient of mobile phase B |
| 0min | 90％ | 10％ |
| 15min | 10％ | 90％ |
| 20min | 10％ | 90％ |
| 25min | 90％ | 10％ |
The analytical LC/MS/MS system in the biological test experiment comprises an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate automatic sampler, a column thermostat, and an Agilent G6430 three-stage quadrupole mass spectrometer with an Electric Spray Ionization (ESI) source. The quantitative analysis was performed in MRM mode, with the parameters of the MRM transition as shown in table B:
table B
| Full scan | 50～1400 |
| Fragmentation voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350℃ |
| Atomizer | 0.28MPa |
| Flow rate of dryer | 10L/min |
Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm,3.5 μm column. The analysis conditions are as follows: the mobile phases were 0.1% aqueous formic acid (A) and 0.1% methanoic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table C:
watch C
| Time | Gradient of mobile phase B |
| 0.5min | 5％ |
| 1.0min | 95％ |
| 2.2min | 95％ |
| 2.3min | 5％ |
| 5.0min | Terminate |
Low resolution Mass Spectrometry (MS)) The test conditions for the data were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O)) at 210nm/254nm by UV detection using electrospray ionization mode (ESI).
The following acronyms are used throughout the invention:
| DMSO-d 6 ： | deuterated dimethyl sulfoxide; | Boc： | a tert-butoxycarbonyl group; |
| DCC： | dicyclohexylcarbodiimide; | DMSO： | dimethyl sulfoxide; |
| CDCl 3 ： | deuterated chloroform; | ％wt,mass％： | the weight percentage is as follows; |
| CD 3 OD： | deuterated methanol; | mL,ml： | milliliters of the solution; |
| μL,μl： | microliter; | mol/L,mol/l： | moles per liter; |
| mol： | mole; | mmol/L,mmol/l,mM： | millimole/liter; |
| μmol/L,μmol/l,μM： | micromoles per liter; | nmol/L,nmol/l,nM： | nanomole/liter; |
| g： | g; | h： | hours; |
| mg： | mg; | μg： | microgram; |
| ng： | nanogram; | nm： | nano; |
| μm： | micron size; | mm： | millimeter; |
| H 2 ： | hydrogen gas; | N 2 ： | nitrogen gas; |
| min： | the method comprises the following steps of (1) taking minutes; | MPa： | megapascals; |
| Me： | a methyl group; | ACN： | acetonitrile; |
| TFA： | trifluoroacetic acid; | H 2 O： | and (3) water. |
General synthetic methods
Typical synthetic procedures for preparing the disclosed compounds are shown in the following synthetic schemes. Unless otherwise stated, each E 1 、E 2 、E 3 、R 3a 、R 3d And R 1 Having the definition as described in the present invention, X is halogen.
Synthesis scheme 1:
the compounds having the structure shown in the general formula (I-A) can be prepared by the general synthetic method described in FIG. 1. Firstly, reacting a compound (I-a) with a compound (I-b) under the action of a base (such as potassium carbonate and sodium hydride) to obtain a compound (I-c); reducing the nitro group of the compound (I-c) to obtain a compound (I-d); diazotizing the amino group of the compound (I-d) and reacting with the compound (I-e) to obtain a compound (I-f); and (3) closing the ring of the compound (I-f) under the action of alkali (such as potassium acetate) to obtain the target compound shown in the general formula (I-A).
Preparation examples
EXAMPLE 12- [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 1)
Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b
6-hydroxy-3, 4-dihydro-1H-quinolin-2-one 1a (2.0g,12.3mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (2.57g, 18.4mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (3.90g,12.3mmol) were added and reacted at 120 ℃ for 5.5 hours under nitrogen substitution. The reaction was cooled to room temperature, water (30mL) was added, stirred for 5min, filtered, and the filter cake was collected and dried under vacuum to give the title compound 1b (4.0g, 93% yield) as an off-white solid.
1 HNMR(400MHz,CDCl 3 )δ(ppm)8.43(s,1H),8.31(s,2H),6.73(d,J＝8.5Hz,1H),6.67(s,1H),6.63(dd,J＝8.5,2.6Hz,1H),2.93(t,J＝7.5Hz,2H),2.67-2.58(m,2H)。
Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -3, 4-dihydroquinolin-2-one 1c
Reacting 6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-diHydrogenQuinolin-2-one 1b (1.7g,4.81mmol) was dissolved in ethanol (10mL), and sodium sulfide (3.79g,48.1mmol) was added to the solution, followed by reaction at 80 ℃ for 4 hours. The reaction was cooled to room temperature, poured into water (30mL), stirred for 15 minutes, filtered, and the collected filter cake was dried under vacuum to give the title compound 1c (1.20g, 77% yield) as a yellow solid.
MS(ESI,pos.ion)m/z:323.2[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)9.94(s,1H),6.77(d,J＝8.6Hz,1H),6.69(s,2H),6.62(d,J＝2.4Hz,1H),6.54(dd,J＝8.6,2.7Hz,1H),5.60(s,2H),2.81(t,J＝7.5Hz,2H),2.42-2.37(m,2H)。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Benzene and its derivatives
Base of]Hydrazine fork]Acetyl group]Urethane 1d
6- (4-amino-2, 6-dichloro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1c (0.80g,2.5mmol), N-cyanoacetylurethane (0.43g,2.7mmol) and concentrated hydrochloric acid (0.63mL) were added to acetic acid (5mL), and an aqueous solution (2mL) of sodium nitrite (0.19g,2.7mmol) was added dropwise at 3 deg.C, followed by continuing the reaction for 7 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 1d (0.40g, yield 33%) as a yellow solid.
MS(ESI,pos.ion)m/z:491.1[M+H] + 。
Step 4)2- [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Phenyl radical]-3, 5-bis
Oxo-1, 2, 4-triazine-6-carbonitrile 1
Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-3, 4-dihydro-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 1d (0.40g,0.82mmol) was dissolved in N, N-dimethylacetamide (1mL), potassium acetate (0.32g,3.3mmol) was added, and the reaction was carried out at 120 ℃ for 12 hours. Cooling the reaction solution to room temperature, filtering, and separating and purifying the filtrate by [ 50% ACN/50% H ] 2 O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 1(88mg, yield 24%, HPLC purity: 99.86%) as a white solid.
MS(ESI,neg.ion)m/z:442.0[M-H] - ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)10.01(s,1H),7.80(s,2H),6.82(d,J＝8.7Hz,1H),6.75(d,J＝2.5Hz,1H),6.64(dd,J＝8.6,2.7Hz,1H),2.84(t,J＝7.4Hz,2H),2.44-2.37(m,2H)。
Example 22- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 2)
Step 1) N- (4-methoxyphenyl) -3-methyl-but-2-enamide 2b
P-methoxyaniline 2a (4.00g,32.5mmol), 3-methyl-but-2-ene-oic acid (3.69g,35.8mmol), triethylamine (6.8mL,49mmol) and 2- (7-azobisbenzotrifluoride) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (15.6g,39.0mmol) were dissolved in N, N-dimethylformamide (10mL) and reacted at room temperature for 30 minutes. Water (100mL) was added to the reaction, stirred for 10min, filtered, the filter cake was washed with ethanol (10mL), collected and dried under vacuum to give the title compound 2b (4.6g, 69% yield) as a white solid.
Step 2) N- (4-hydroxyphenyl) -3-methyl-but-2-enamide 2c
N- (4-methoxyphenyl) -3-methyl-but-2-enamide 2b (4.6g,22.4mmol) was dissolved in dichloromethane (15mL), and boron tribromide (4.2mL,44mmol) was added dropwise at 5 ℃ after 2.5 hours of reaction. The reaction was poured into an ice-water mixture (30g), saturated sodium bicarbonate solution (30mL) was added, stirred for 10 minutes, extracted with dichloromethane (10mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 2c (4.0g, yield 93%) as a white solid.
MS(ESI,pos.ion)m/z:192.3[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)9.54(s,1H),9.13(s,1H),7.39(d,J＝8.7Hz,2H),6.67(d,J＝8.8Hz,2H),5.81(s,1H),2.12(s,3H),1.83(s,3H)。
Step 3) 6-hydroxy-4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2d
N- (4-hydroxyphenyl) -3-methyl-but-2-enamide 2c (4.0g,20.9mmol) was dissolved in chlorobenzene (10mL), and aluminum trichloride (5.58g,41.8mmol) was added and reacted at 120 ℃ for 22 hours. The reaction solution was poured into ice water (40mL), extracted with ethyl acetate (20mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 2d (1.4g, yield 35%) as a pale gray solid.
MS(ESI,pos.ion)m/z:192.3[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)9.84(s,1H),9.03(s,1H),6.67(d,J＝8.3Hz,2H),6.53(dd,J＝8.4,2.5Hz,1H),2.26(s,2H),1.17(s,6H)。
Step 4)6- (2, 6-dichloro-4-nitro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2e
6-hydroxy-4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2d (0.80g, 4.2mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (1.5g, 10mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (1.3g,4.2mmol) were added and reacted at 120 ℃ for 5.5 hours with nitrogen blanket. The reaction was cooled to room temperature, water (30mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 2e (1.2g, 75% yield) as a grey solid.
MS(ESI,pos.ion)m/z:381.0[M+H] + 。
Step 5)6- (4-amino-2, 6-dichloro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2f
6- (2, 6-dichloro-4-nitro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2e (1.2g,3.15mmol) was dissolved in ethanol (5mL), and sodium sulfide (2.48g,31.5mmol) was added and the reaction was allowed to proceed at 80 ℃ for 12 hours. The reaction mixture was cooled to room temperature, water (30mL) was poured into the mixture, the mixture was stirred for 15 minutes, and the mixture was filtered, collected and purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 2f (0.50g, yield 45%) as an off-white solid.
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)10.02(s,1H),6.81(d,J＝2.7Hz,1H),6.77(d,J＝8.6Hz,1H),6.70(s,2H),6.43(dd,J＝8.6,2.7Hz,1H),5.61(s,2H),2.32(s,2H),1.17(s,6H)。
Step 6) N- [ 2-cyano-2 [ [3, 5-dichloro-4- [ (4, 4-methyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy
Base (C)]Phenyl radical]Hydrazine fork]Acetyl group]Urethane (meth) acrylate2g
6- (4-amino-2, 6-dichloro-phenoxy) -4, 4-dimethyl-1, 3-dihydroquinolin-2-one 2f (0.45g,1.3mmol), N-cyanoacetylurethane (0.22g,1.4mmol) and concentrated hydrochloric acid (0.33mL) were added to acetic acid (4mL), and an aqueous solution (2mL) of sodium nitrite (0.098g,1.4mmol) was added dropwise at 3 ℃ followed by reaction for 6 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give 2g (0.2g, yield 30%) of the title compound as a yellow solid.
MS(ESI,pos.ion)m/z:518.1[M+H] + 。
Step 7)2- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy]Phenyl radical]-
3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 2
Reacting N- [ 2-cyano-2 [ [3, 5-dichloro-4- [ (4, 4-methyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate (2 g, 0.20g,0.39mmol) was dissolved in N, N-dimethylacetamide (1mL), and potassium acetate (0.15g,1.5mmol) was added to react at 120 ℃ for 24 hours. Cooling the reaction solution to room temperature, filtering, and separating and purifying the filtrate by preparation and purification [ 50% ACN/50% H ] 2 O (0.1% TFA), Firmor ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 2(8mg, yield 4%, HPLC purity: 98.92%) as a white solid.
MS(ESI,pos.ion)m/z:472.0[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)9.01(s,1H),7.63(s,2H),7.03(d,J＝2.4Hz,1H),6.70(d,J＝8.6Hz,1H),6.44(dd,J＝8.6,2.5Hz,1H),2.05(s,6H)。
EXAMPLE 32- [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 3)
Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1, 4-dihydro-3, 1-benzoxazine-2-one 3b
Under the protection of nitrogen, 6-hydroxy-1, 4-dihydro-3, 1-benzoxazine-2-one 3a (1.0g,6.1mmol) was dissolved in N, N-dimethylacetamide (7mL), and potassium carbonate (1.24g,8.97mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (1.9g,6.0mmol) were added in this order to react at 100 ℃ for 4.5 hours. The reaction solution was cooled to room temperature, water (30mL) was added, the mixture was stirred for 5 minutes, and the mixture was filtered, collected and purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 3b (1.33g, yield 62%) as a brown solid.
MS(ESI,neg.ion)m/z:353.0[M-H] - 。
1 HNMR(400MHz,CDCl 3 )δ(ppm)8.73(s,1H),8.31(s,2H),6.82(d,J＝12.0Hz,1H),6.73(d,J＝12.0Hz,1H),6.64(d,J＝4.0Hz,1H),5.27(s,2H)。
Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1, 4-dihydro-3, 1-benzoxazine-2-one 3c
6- (2, 6-dichloro-4-nitro-phenoxy) -1, 4-dihydro-3, 1-benzoxazin-2-one 3b (1.2g,3.4mmol) was added to ethanol (20mL), sodium sulfide nonahydrate (8.29g,33.9mmol) was added, and the reaction was carried out at room temperature for 12 hours. The reaction was quenched by addition of water (40mL), extracted with ethyl acetate (50 × 3), the combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 3c (0.20g, yield 18%) as a yellow solid.
MS(ESI,pos.ion)m/z:325.0[M+H] + ；
1 HNMR(400MHz,DMSO-d 6 )δ(ppm)6.77(s,2H),6.59(s,J＝4.0Hz,1H),6.54(d,J＝8.0Hz,1H),6.43-6.40(m,1H),5.54(s,2H),4.56(s,2H)。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy ] carbonyl
Base (C)]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 3d
6- (4-amino-2, 6-dichloro-phenoxy) -1, 4-dihydro-3, 1-benzoxazin-2-one 3c (0.16g,0.49mmol) was dissolved in water (6mL) and concentrated hydrochloric acid (1mL), an aqueous solution (1mL) of sodium nitrite (40mg,0.57mmol) was added dropwise at 0 ℃, the reaction solution was then rapidly filtered, and the filtrate was added dropwise to a mixed solution of pyridine (3mL) and water (9mL) of N-cyanoacetamiurethane (84mg,0.54mmol) at 0 ℃ and the mixture was allowed to react at 0 ℃ for 30 minutes. The reaction was filtered, the collected filter cake was dissolved in dichloromethane (20mL), the organic phase was washed successively with water (10mL) and saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 3d (0.15g, 61% yield) as a red solid.
MS(ESI,neg.ion)m/z:489.9[M-H] - 。
Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy]Phenyl radical]-3,
5-dioxo-1, 2, 4-triazine-6-carbonitrile 3
Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 4-dihydro-3, 1-benzoxazin-6-yl) oxy ] group]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 3d (0.15g,0.30mmol) and sodium acetate (25mg,0.30mmol) were added to acetic acid (2.5mL) and reacted at 120 ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, water (7mL) was added dropwise to the residue, a red solid precipitated, filtered, and the filter cake was collected to isolate and purify [ 40% ACN/60% H ] 2 O (0.1% TFA), Kromasil: C1810 μm X50 mm X250 mm, flow rate: 100mL/min]To obtain the title compound 3(17mg, yield 13%, HPLC purity: 95.95%) as a yellow solid.
MS(ESI,pos.ion)m/z:446.0[M+H] + ；
1 H NMR(400MHz,CD 3 OD)δ(ppm)7.81(s,2H),7.37(d,J＝8.0Hz,1H),7.09(d,J＝4.0Hz,1H),6.92-9.89(m,1H),4.53(s,2H)。
Example 42- [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 4)
Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -4H-1, 4-benzeneAnd oxazin-3-one 4b
7-hydroxy-4H-1, 4-benzoxazin-3-one 4a (3.6g,22mmol) was dissolved in N, N-dimethylacetamide (10mL), and potassium carbonate (4.56g,33mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (6.99g,22mmol) were added in this order to react at 120 ℃ for 12 hours. The reaction was cooled to room temperature, quenched by the addition of water (30mL), stirred for 5 minutes, filtered, the filter cake washed with water (10mL), collected and dried under vacuum to give the title compound 4b (6.7g, 87% yield) as a brown solid.
MS(ESI,neg.ion)m/z:354.1[M-H] - 。
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.66(s,1H),8.51(s,2H),6.84(d,J＝8.0Hz,1H),6.58(d,J＝4.0Hz,1H),6.50-6.47(m,1H),4.57(s,2H)。
Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -4H-1, 4-benzoxazine-3-one 4c
7- (2, 6-dichloro-4-nitro-phenoxy) -4H-1, 4-benzoxazin-3-one 4b (3.0g,8.4mmol) and sodium sulfide nonahydrate (5.6g,23.3mmol) were added to ethanol (20mL) and reacted at 80 ℃ for 15 hours. The reaction was quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake collected and dried in vacuo to give the title compound 4c (1.84g, 67% yield) as a brown solid.
MS(ESI,pos.ion)m/z:325.0[M+H] + 。
1 HNMR(400MHz,CD 3 OD)δ(ppm)6.80(d,J＝8.0Hz,1H),6.73(s.2H),6.41-6.36(m,2H),4.54(s,2H)。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy ] group]Benzene and its derivatives
Base of]Hydrazine fork]Acetyl group]Urethane 4d
7- (4-amino-2, 6-dichloro-phenoxy) -4H-1, 4-benzoxazin-3-one 4c (1.0g,3.08mmol) was added to water (36mL) and concentrated hydrochloric acid (6mL), an aqueous solution (1mL) of sodium nitrite (0.24g,3.39mmol) was added dropwise at-5 deg.C, the reaction was allowed to react for 15 minutes, and the reaction solution was rapidly filtered. To the filtrate was added a mixed solution of N-cyanoacetylurethane (0.53g,3.38mmol) in pyridine (18mL) and water (42mL) at-5 ℃ to react for 30 minutes. The reaction was filtered and the filter cake was collected to give the title compound 4d (0.60g, 40% yield) as an orange solid.
MS(ESI,neg.ion)m/z:488.5[M-H] - 。
Step 4)2- [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy group]Phenyl radical]-3, 5-dioxo
Substituted-1, 2, 4-triazine-6-carbonitrile 4
Acetic acid (10mL) was added to N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (3-oxo-4H-1, 4-benzoxazin-7-yl) oxy ] group]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 4d (0.60g,1.22mmol) and sodium acetate (100mg,1.2073mmol) were reacted at 120 ℃ for 3 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was added with acetic acid (3mL) and water (15mL), stirred for 15 minutes, filtered, washed with water (5mL), and the filter cake was collected to isolate and purify [ 20% ACN/80% H ] 2 O (0.1% ammonia), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 90mL/min]To obtain the title compound 4(61mg, yield 11%, HPLC purity: 97.95%) as a yellow solid.
MS(ESI,neg.ion)m/z:443.9[M-H] - ；
1 H NMR(400MHz,CD 3 OD)δ(ppm)7.76(s,2H),6.85(d,J＝12.0Hz,1H),6.51(d,J＝2.6Hz,1H),6.46(dd,J＝8.6,2.7Hz,1H),4.57(s,2H)。
Example 52- [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 5)
Step 1)5- (2, 6-dichloro-4-nitro-phenoxy) -3, 3-dimethyl-indolin-2-one 5b
5-hydroxy-3, 3-dimethyl-indolin-2-one 5a (0.48g,2.7mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (0.56g,4.05mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (0.86g,2.7mmol) were added and reacted at 120 ℃ for 18 hours. The reaction was cooled to room temperature, water (20mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried to give the title compound 5b (0.62g, yield 62%) as a yellow solid.
MS(ESI,pos.ion)m/z:367.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.29(s,1H),8.51(s,2H),7.06(d,J＝4.0Hz,1H),6.77(d,J＝8.0Hz,1H),6.61(dd,J＝8.4,2.6Hz,1H),1.23(s,6H)。
Step 2)5- (4-amino-2, 6-dichloro-phenoxy) -3, 3-dimethyl-indolin-2-one 5c
Reacting 5- (2, 6-dichloro-4-nitro-phenoxy) -3, 3-dimethyl-indoleQuinoline (III)-2-keto-5 b (0.62g,1.69mmol) was dissolved in ethanol (10mL), and sodium sulfide nonahydrate (1.20g,4.90mmol) was added and reacted at 80 ℃ for 11 hours. The reaction was cooled to room temperature, quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake was collected and dried to give the title compound 5c (0.33g, 57% yield) as a yellow solid.
MS(ESI,pos.ion)m/z:337.0[M+H] + 。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-benzene
Base of]Hydrazine fork]Acetyl group]Urethane 5d
5- (4-amino-2, 6-dichloro-phenoxy) -3, 3-dimethyl-indolin-2-one 5c (0.15g,0.45mmol) was dissolved in water (5mL) and concentrated hydrochloric acid (2.3mL), and an aqueous solution (1mL) of sodium nitrite (31mg,0.45mmol) was added dropwise at 0 ℃ followed by addition of a mixed solution of N-cyanoacetylurethane (78mg,0.50mmol) in pyridine (2.3mL) and water (5.4mL) and allowed to react at 0 ℃ for 30 minutes. The reaction was filtered, the filter cake was collected and dried to give the title compound 5d (0.13g, 56% yield) as a red solid.
MS(ESI,Pos.ion)m/z:504.0[M+H] + ；
1 H NMR(400MHz,CD 3 OD)δ(ppm)7.81(s,2H),6.84(dd,J＝7.5,5.6Hz,2H),6.58(dd,J＝8.4,2.5Hz,1H),4.28(q,J＝7.0Hz,2H),1.36-1.32(m,9H)。
Step 4)2- [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indolin-5-yl) oxy-phenyl]-3, 5-bis
Oxo-1, 2, 4-triazine-6-carbonitrile 5
Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- (3, 3-dimethyl-2-oxo-indole)Quinoline (III)-5-yl) oxy-phenyl]Hydrazine fork]Acetyl group]Ethyl carbamate 5d (126mg,0.25mmol) was dissolved in acetic acid (3.5mL), and sodium acetate (20mg,0.24mmol) was added to react at 120 ℃ for 4 hours. Concentrating the reaction solution, adding water (30mL), filtering, collecting filter cake, drying, and purifying by preparative separation [ 47% ACN/53% H ] 2 O (0.1% TFA), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To give the title compound 5(52mg, yield 45%, HPLC purity: 98.82%) as a pale yellow solid.
MS(ESI,neg.ion)m/z:455.9[M-H] - ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm)10.29(s,1H),7.80(s,2H),7.07(s,1H),6.78(d,J＝8.2Hz,1H),6.51(d,J＝7.4Hz,1H),1.24(s,6H)。
EXAMPLE 62- [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indolin ] -5-yl) oxy-phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 6)
Step 1)5'- (2, 6-dichloro-4-nitro-phenoxy) spiro [ cyclopropane-1, 3' -indoline]-2' -Ketone 6b
5' -Hydroxyspiro [ cyclopropane-1, 3' -indolin ] -2' -one 6a (0.55g,3.14mmol) was dissolved in N, N-dimethylacetamide (5mL), and potassium carbonate (0.65g,4.65mmol) and 3-dichloro-2-iodo-5-nitrobenzene (0.99g,3.1mmol) were added and reacted at 120 ℃ for 14 hours. The reaction was cooled to room temperature, water (40mL) was added, stirred for 5 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 6b (0.88g, 77% yield) as a black solid.
MS(ESI,neg.ion)m/z:363.0[M-H] - 。
Step 2)5'- (4-amino-2, 6-dichloro-phenoxy) spiro [ cyclopropane-1, 3' -indoline]-2' -keto 6c
5- (2, 6-dichloro-4-nitro-phenoxy) spiro [ cyclopropane-1, 3' -indolin ] -2-one 6b (0.88g,2.3mmol) was dissolved in ethanol (12mL), and sodium sulfide nonahydrate (1.47g,6.00mmol) was added and reacted at 80 ℃ for 1 hour. The reaction was cooled to room temperature and quenched by the addition of water (40mL), stirred for 5 minutes, filtered, and the filter cake collected and dried in vacuo to give the title compound 6c (0.39g, 50% yield) as a brown solid.
MS(ESI,pos.ion)m/z:335.0[M+H] + 。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline)]-5' -yl)
Oxy-phenyl]Hydrazine fork]Acetyl group]Urethane 6d
5' - (4-amino-2, 6-dichloro-phenoxy) spiro [ cyclopropane-1, 3' -indolin ] -2' -one 6c (0.39g,1.16mmol) was dissolved in water (12mL) and concentrated hydrochloric acid (6mL), an aqueous solution (2mL) of sodium nitrite (80mg,1.15mmol) was added dropwise at 0 ℃, the reaction solution was then rapidly filtered, and the filtrate was added dropwise to a mixed solution of N-cyanoacetylurethane (200mg,1.28mmol) at 0 ℃ in pyridine (6mL) and water (14mL), and the mixture was allowed to react at 0 ℃ for 30 minutes. The reaction was filtered, the collected filter cake was dried in vacuo to give the title compound 6d (0.112g, 19% yield) as a red solid.
MS(ESI,neg.ion)m/z:499.9[M-H] - 。
Step 4)2- [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoleQuinoline (I)]-5' -yl) oxy-phenyl]- 3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 6
To N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2 '-oxospiro [ cyclopropane-1, 3' -indoline)]-5' -yl) oxy-phenyl]Hydrazine fork]Acetyl group]To ethyl carbamate 6d (112mg,0.223mmol) and sodium acetate (18.5mg,0.223mmol) was added acetic acid (3mL) and reacted at 120 ℃ for 4 hours. The reaction was cooled to room temperature, water (10mL) was added, stirred for 10min, filtered, the filter cake was collected and dried under vacuum to give a red solid which was purified by preparative separation [ 25% ACN/75% H 2 O (0.1% ammonia), Kromasil: C1810. mu. m.times.50 mm.times.250 mm, flow rate: 100mL/min]To obtain the title compound 6(22mg, yield 21%, HPLC purity: 97.98%) as a pale yellow solid.
MS(ESI,pos.ion)m/z:455.9[M+H] + ；
1 H NMR(400MHz,CD 3 OD)δ(ppm)7.75(s,2H),6.89(d,J＝8.0Hz,1H),6.60(m,2H),1.65-1.56(m,4H)。
Example 72- [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl) oxy-benzene Base (C)]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile(Compound 7)
Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane]-2-one 7b
6-Hydroxyspiro [1, 4-dihydroquinolin-3, 1' -cyclopropane ] -2-one 7a (0.57g,3.01mmol) was dissolved in N, N-dimethylacetamide (3.5mL), and potassium carbonate (0.62g,4.49mmol) and 1, 3-dichloro-2-iodo-5-nitrobenzene (0.95g,2.7mmol) were added in this order and reacted at 120 ℃ for 6 hours. The reaction was cooled to room temperature, water (20mL) was added, stirred for 30 minutes, filtered, and a yellow filter cake was collected to give the title compound 7b (1.1g, 96% yield) as a yellow solid.
MS(ESI,pos.ion)m/z:379.0[M+H] + 。
Step 2)6- (4-amino-2, 6-dichloro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane]-2-one 7c
6- (2, 6-dichloro-4-nitro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane ] -2-one 7b (1.1g,2.9mmol) was dissolved in ethanol (20mL), and sodium sulfide nonahydrate (2.3g,9.4mmol) was added and reacted at 80 ℃ for 10 hours. The reaction was cooled to room temperature, quenched by addition of water (40mL), stirred for 5 minutes, filtered, and collected to give the title compound 7c (0.68g, 67% yield) as a brown solid.
MS(ESI,pos.ion)m/z:349.1[M+H] + 。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-
Yl) oxy-phenyl]Hydrazine fork]Acetyl group]Urethane 7d
6- (4-amino-2, 6-dichloro-phenoxy) spiro [1, 4-dihydroquinoline-3, 1' -cyclopropane ] -2-one 7c (0.68g,1.94mmol) was dissolved in water (20mL) and concentrated hydrochloric acid (10mL), an aqueous solution (3mL) of sodium nitrite (135mg,1.94mmol) was added dropwise at 0 ℃, the reaction solution was then rapidly filtered, and the filtrate was added dropwise to a mixed solution of N-cyanoacetylurethane (334mg,2.13mmol) in pyridine (10mL) and water (23mL) at 0 ℃ and reacted at 0 ℃ for 30 minutes. The reaction was filtered, the collected filter cake was dried under vacuum to give the title compound 7d (83mg, yield 8.3%) as a yellow solid.
MS(ESI,pos.ion)m/z:516.0[M+H] + 。
Step 4)2- [3, 5-dichloro-4- (2-oxaspiro (1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl-) oxy-benzene
Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 7
To N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxospiro [1, 4-dihydroquinoline-3, 1' -cyclopropane)]-6-yl) oxy-phenyl]Hydrazine fork]Acetyl group]To ethyl carbamate 7d (83.1mg,0.161mmol) and sodium acetate (13.3mg,0.161mmol) was added acetic acid (3mL) and the reaction was carried out at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (10mL) was added, stirring was carried out for 10 minutes, filtration was carried out, the filter cake was collected and dried under vacuum, and the obtained red solid was isolated and purified [ 47% ACN/53% H ] 2 O (0.1% TFA), Kromasil: C1810 μm X50 mm X250 mm, flow rate: 100mL/min]To obtain the title compound 7(37mg, yield 49%, HPLC purity: 95.95%) as a pale yellow solid.
MS(ESI,neg.ion)m/z:470.0[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.07(s,1H),7.78(s,2H),6.85(d,J＝8.9Hz,1H),6.65(s,2H),2.81(s,2H),1.04(s,2H),0.69(s,2H)。
Example 82- [3, 5-dichloro-4- [ (2-oxo-1H-quinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 8)
Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1H-quinolin-2-one 8a
6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b (0.74g,2.09mmol), 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (0.79g,3.14mmol) and N, O-bis (trimethylsilyl) trifluoroacetamide were dissolved in 1, 4-dioxane (15mL) and reacted at 100 ℃ for 21 hours. The reaction solution was cooled to room temperature, water (30mL) was poured into the reaction solution, extracted with ethyl acetate (10mL × 2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 8a (0.21g, yield 29%) as a yellow solid.
MS(ESI,neg.ion)m/z:348.9[M-H] - ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)11.15(s,1H),8.34(s,2H),7.66(d,J＝9.6Hz,1H),7.32(d,J＝9.0Hz,1H),7.18(dd,J＝8.9,2.7Hz,1H),6.86(d,J＝2.7Hz,1H),6.71(d,J＝9.6Hz,1H)。
Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1H-quinolin-2-one 8b
6- (2, 6-dichloro-4-nitro-phenoxy) -1H-quinolin-2-one 8a (0.21g, 0.60mmol) and sodium sulfide (0.24g,3.00mmol) were dissolved in ethanol (3mL) and reacted at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (30mL) was added, stirred for 15min, filtered, and the filter cake was collected and dried under vacuum to give the title compound 8b (0.10g, 52% yield) as a yellow solid.
MS(ESI,pos.ion)m/z:321.0[M+H] + 。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Second step
Acyl radical]Urethane 8c
6- (4-amino-2, 6-dichloro-phenoxy) -1H-quinolin-2-one 8b (0.10g, 0.31mmol), N-cyanoacetylurethane (0.05g,0.34mmol) and concentrated hydrochloric acid (0.08mL) were added to acetic acid (2mL), and an aqueous solution (2mL) of sodium nitrite (0.02g,0.34mmol) was added dropwise at 3 ℃ followed by reaction for 2 hours. The reaction was concentrated to give the title compound 8c (0.15g, yield 99%) as a yellow solid.
MS(ESI,pos.ion)m/z:488.0[M+H] + 。
Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]-3, 5-dioxo-1, 2,
4-triazine-6-carbonitrile 8
Reacting N- [ 2-cyano-2- [ [3, 5-dichloro-4- (2-oxo-1H-quinolin-6-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 8c (0.15g,0.31mmol) was dissolved in N, N-dimethylacetamide (1mL), and potassium acetate (0.12g,1.2mmol) was added to react at 120 ℃ for 5 hours. Cooling the reaction solution to room temperature, filtering, concentrating the filtrate, and separating and purifying the residue [ 39% ACN/61% H ] 2 O (0.1% TFA), Firmor ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 8(20mg, yield 15%, HPLC purity: 98.34%) as a white solid.
MS(ESI,neg.ion)m/z:440.3[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.30(s,1H),11.75(s,1H),7.87(d,J＝9.5Hz,1H),7.82(s,2H),7.34(d,J＝8.8Hz,1H),7.26(d,J＝9.6Hz,1H),7.09(s,1H),6.50(d,J＝9.4Hz,1H)。
Example 92- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxamide (Compound 9)
Compound 2(0.15g,0.32mmol) was dissolved in concentrated hydrochloric acid (3mL) and reacted at 75 ℃ for 3.5 hours. The reaction was cooled to room temperature, quenched with water (10mL), adjusted to pH 9 with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (15mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration to give the title compound 9(62mg, yield 40%, HPLC purity: 95.00%) as a brown solid.
MS(ESI,pos.ion)m/z:490.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.00(s,1H),10.11(s,1H),9.56(d,J＝3.7Hz,1H),7.87(d,J＝2.5Hz,2H),7.67(d,J＝3.6Hz,1H),7.00-6.91(m,1H),6.82(d,J＝8.6Hz,1H),6.50(dd,J＝8.5,2.7Hz,1H),2.35(s,2H),1.21(s,6H)。
Example 102- [3, 5-dichloro-4- [ (4, 4-dimethyl-2-oxo-1, 3-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxylic acid (Compound 10)
Compound 2(0.15g,0.32mmol) was dissolved in concentrated hydrochloric acid (3mL) and reacted at 75 ℃ for 3.5 hours. The reaction was cooled to room temperature, quenched by addition of water (10mL), adjusted to pH 9 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (15mL × 3); the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (3mol/L,30mL), then extracted with ethyl acetate (15mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15mL × 2), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 10(50mg, yield 32%, HPLC purity: 99.26%) as a pale yellow solid. MS (ESI, neg. ion) M/z 488.9[ M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)12.72(s,1H),10.09(s,1H),7.84(s,2H),6.98(d,J＝2.6Hz,1H),6.82(d,J＝8.7Hz,1H),6.50(dd,J＝8.6,2.7Hz,1H),2.35(s,2H),1.22(s,6H)。
EXAMPLE 112- [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 11)
Step 1)6- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11a
Sodium hydride (0.57g,14mmol,60 mass%) was added portionwise to a solution of 6- (2, 6-dichloro-4-nitro-phenoxy) -3, 4-dihydro-1H-quinolin-2-one 1b (2.00g,5.66mmol) in tetrahydrofuran (30mL) under nitrogen blanket in an ice-water bath, and iodomethane (0.47mL,7.4mmol) was added dropwise, followed by reaction at room temperature for 12 hours. The reaction mixture was quenched with water (30mL) in an ice-water bath, extracted with ethyl acetate (30mL × 3), the combined organic phases were washed with saturated sodium chloride solution (30mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 11a (1.15g, yield 55%) as a pale yellow solid.
MS(ESI,pos.ion)m/z:367.0[M+H] + 。
Step 2)6- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11b
6- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11a (0.70g,1.90mmol) was dissolved in acetic acid (15mL), and iron powder (0.43g,7.5mmol) was added and reacted at 60 ℃ for 4 hours. The reaction was cooled to room temperature, the iron powder was removed, water (40mL) was added, stirring was carried out for 30 minutes, filtering was carried out, and the filter cake was collected and dried under vacuum to give the title compound 11b (0.52g, yield 81%) as an off-white solid.
MS(ESI,pos.ion)m/z:337.1[M+H] + 。
Step 3) [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy]
Phenyl radical]Hydrazine fork]Acetyl group]Urethane 11c
6- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-3, 4-dihydroquinolin-2-one 11b (0.50g,1.48mmol) and N-cyanoacetylurethane (0.26g,1.63mmol) were dissolved in acetic acid (10mL), and an aqueous solution (1.5mL) of sodium nitrite (0.16g,2.23mmol) was added at 0 ℃ to react for 4.5 hours. Water (30mL) was added to the reaction, stirred for 30 min, filtered, and the filter cake was collected and dried under vacuum to give the title compound 11c (0.64g, 86% yield) as a yellow solid.
MS(ESI,neg.ion)m/z:502.1[M-H] - 。
Step 4)2- [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy]Phenyl radical]-3,5-
Dioxygen1,2, 4-triazine-6-carbonitrile 11
Ethyl [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-3, 4-dihydroquinolin-6-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 11c (0.75g,1.49mmol) was dissolved in N, N-dimethylacetamide (10mL), and sodium acetate (0.62g,7.43mmol) was added and reacted at 120 ℃ for 4.5 hours. The reaction was cooled to room temperature, water (40mL) was added, the pH was adjusted to 7 with dilute hydrochloric acid (2mol/L), stirring was carried out for 30 minutes, filtration was carried out, the collected cake was dried in vacuo, and the resulting reddish brown solid was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/2] to give the title compound 11(0.12g, yield 17%, HPLC purity: 98.14%) as a pale yellow solid.
MS(ESI,neg.ion)m/z:456.1[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.28(s,1H),7.82(s,2H),7.05(d,J＝8.9Hz,1H),6.85(d,J＝1.8Hz,1H),6.75-6.69(m,1H),3.23(s,3H),2.85(t,J＝7.0Hz,2H),2.52(t,J＝7.0Hz,2H)。
Example 122- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 12)
Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b
7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.50g,2.8mmol), 1, 3-dichloro-2-iodo-5-nitro-benzene (0.99g,3.1mmol) were dissolved in N, N-dimethylformamide (8mL), and potassium carbonate (0.79g,5.7mmol) was added to react at 100 ℃ for 16 hours. The reaction was cooled to room temperature, water (15mL) was added, stirred for 15 minutes, filtered, the filter cake was collected, and the resulting yellow solid was recrystallized at 85 ℃ (ethanol/ethyl acetate/petroleum ether ═ 1/5/10,16mL), filtered, and the filter cake was dried to give the title compound 12b (0.70g, yield 68%) as a gray solid.
Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12c
7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b (0.70g,1.9mmol) was dissolved in acetic acid (8mL), and iron powder (0.43g,7.7mmol) was added and reacted at 70 ℃ for 4 hours. The reaction was cooled to room temperature, water (30mL) was added, stirred for 10 minutes, filtered, rinsed with water (10mL), and the solid collected and dried under vacuum to give the title compound 12c (0.64g, 100% yield) as a brown solid. MS (ESI, pos.ion) M/z 337.0[ M + H ]] + 。
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine-7-
Radical) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 12d
7- (4-amino-2, 6-dichloro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12c (0.20g,0.54mmol), N-cyanoacetylurethane (94mg,0.59mmol) was dissolved in acetic acid (4mL) and a solution of sodium nitrite (75mg,1.08mmol) in water (2mL) was added at 0 ℃. Water (10mL) was added to the reaction mixture at 0 deg.C, stirred for 10min, filtered, rinsed with water (2mL), and the collected cake was dried under vacuum to give the title compound 12d (0.27g, 100% yield) as a brown solid.
Step 4)2- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy]Benzene and its derivatives
Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 12
Ethyl N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 12d (0.27g,0.54mmol) was dissolved in N, N-dimethylacetamide (3mL), and sodium acetate (48mg,0.59mmol) was added and reacted at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20mL) was added, extraction was performed with ethyl acetate (20mL × 5), the combined organic phases were washed with a saturated sodium chloride solution (10mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (100% ethyl acetate), and the resulting red solid was recrystallized (ethanol/ethyl acetate/petroleum ether ═ 1/6/12,9.5mL) at 85 ℃ to give the title compound 12(36mg, yield 15%, HPLC purity: 85.61%) as a red brown solid.
MS(ESI,neg.ion)m/z:456.5[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.29(s,1H),9.42(s,1H),7.81(s,2H),6.94(d,J＝8.7Hz,1H),6.87(d,J＝2.6Hz,1H),6.70(dd,J＝8.6,2.8Hz,1H),2.67(t,J＝6.4Hz,2H),2.11(dd,J＝17.3,4.6Hz,4H)。
EXAMPLE 132- [3, 5-dichloro-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carboxylic acid methyl ester (Compound 13)
A methanol solution of hydrogen chloride (2mL,4.5mol/L) was added to a methanol solution (2mL) of Compound 12(0.10g,0.22mmol), and the mixture was reacted at 50 ℃ for 4.5 hours. Cooling the reaction solution to room temperature, concentrating, and separating and purifying the residue [ 40% ACN/60% H ] 2 O (0.1% TFA), Philomena ACE specification C1810 μm X50 mm X250 mm, flow rate 100mL/min]To obtain the title compound 13(62mg, yield 58%, HPLC purity: 98.48%) as an off-white solid.
MS(ESI,neg.ion)m/z:490.0[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.81(s,2H),7.05(d,J＝7.9Hz,1H),6.77(s,1H),6.67(d,J＝7.5Hz,1H),3.59(s,3H),2.54(d,J＝4.2Hz,2H),2.41-2.29(m,2H),1.85-1.65(m,2H)。
EXAMPLE 142- [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 14)
Step 1)7- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one
14a
7- (2, 6-dichloro-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 12b (0.80g,2.2mmol) was dissolved in tetrahydrofuran (15mL), and sodium hydride (0.17g,4.3mmol,60 mass%) was added at 0 ℃ to react for 10 minutes, followed by methyl iodide (0.20mL,3.2mmol) and reacted at room temperature for 1 hour. The reaction was quenched by the addition of water (10mL), extracted with ethyl acetate (50mL × 2), the combined organic phases were washed with saturated sodium chloride (20mL), dried over anhydrous sodium sulfate, concentrated with suction filtration, and the resulting yellow solid was recrystallized (petroleum ether/ethyl acetate ═ 3/2,15mL) at 85 ℃ to give the title compound 14a (0.60g, yield 72%) as a yellow solid.
Step 2)7- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one
14b
7- (2, 6-dichloro-4-nitro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14a (0.72g,1.9mmol) was dissolved in acetic acid (8mL), iron powder (0.21g,3.8mmol) was added, and the reaction was carried out at 60 ℃ for 2 hours. The reaction was cooled to room temperature, water (48mL) was added, stirred for 10min, filtered, rinsed with water (10mL), and the solid was collected and dried under vacuum to give 14b as a yellow solid (0.66g, 99% yield).
Step 3) N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepine [ ] -
Zepin-7-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 14c
7- (4-amino-2, 6-dichloro-phenoxy) -1-methyl-4, 5-dihydro-3H-1-benzazepin-2-one 14b (0.56g,1.6mmol) was dissolved in acetic acid (11mL), a solution of sodium nitrite (0.22g,3.2mmol) in water (5.6mL) was added at 0 ℃ and reacted for 1 hour, N-cyanoacetylurethane (0.33g,2.1mmol) was added and the reaction was continued for 3.5 hours. Water (10mL) was added to the reaction solution at 0 ℃, stirred for 10 minutes, filtered, rinsed with water (10mL), the filter cake was collected and dried under vacuum to give the title compound 14c (0.83g, 100% yield) as a yellow solid.
Step 4)2- [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy
Base (C)]Phenyl radical]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 14
Ethyl N- [ 2-cyano-2- [ [3, 5-dichloro-4- [ (1-methyl-2-oxo-4, 5-dihydro-3H-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 14c (0.86g,1.7mmol) was dissolved in N, N-dimethylformamide (8mL), and sodium acetate (0.20g,2.4mmol) was added and reacted at 120 ℃ for 4 hours. The reaction solution was cooled to room temperature, water (20mL) was added, stirred for 10 minutes, filtered, washed with water (10mL), and the collected solid was slurried with ethanol/ethyl acetate/petroleum ether (5/5/10,20mL) to give the title compound 14(0.41g, yield 52%, HPLC purity: 88.67%) as a yellow solid.
MS(ESI,neg.ion)m/z:469.9[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.82(s,2H),7.30(d,J＝8.8Hz,1H),6.88(d,J＝2.8Hz,1H),6.79(dd,J＝8.7,2.9Hz,1H),3.20(s,3H),2.64(t,J＝6.8Hz,2H),2.13(t,J＝6.6Hz,2H),2.02(t,J＝11.5Hz,2H)。
Example 152- [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 15)
Step 1)7- (2, 6-dimethyl-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15a
7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.30g,1.7mmol), 2-fluoro-1, 3-dimethyl-5-nitro-benzene (0.32g,1.9mmol) were dissolved in N, N-dimethylformamide (2.4mL), and potassium carbonate (0.47g,3.4mmol) was added and reacted at 70 ℃ for 16 hours. After the reaction solution was cooled to room temperature, water (10mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and dried to give the title compound 15a (0.55g, yield 100%) as an off-white solid.
Step 2)7- (4-amino-2, 6-dimethyl-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15b
7- (2, 6-dimethyl-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15a (0.55g,1.7mmol) was dissolved in acetic acid (3.3mL), and iron powder (0.28g,5.0mmol) was added to the solution to react at 60 ℃ for 5 hours. The reaction was cooled to room temperature, water (10mL) was added, extraction was performed with ethyl acetate (20 mL. times.3), the combined organic phases were washed with saturated sodium chloride (10 mL. times.3), dried over anhydrous sodium sulfate, concentrated by suction filtration, slurried with petroleum ether/ethyl acetate (1/1,10mL), filtered, the cake was collected and dried to give the title compound 15b (0.50g, 100% yield) as an off-white solid.
Step 3) N- [ 2-cyano-2- [ [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine-
7-yl) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 15c
7- (4-amino-2, 6-dimethyl-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 15b (0.50g,1.7mmol) was dissolved in acetic acid (10mL), a solution of sodium nitrite (0.24g,3.4mmol) in water (5mL) was added at 0 deg.C, and after half an hour of reaction, N-cyanoacetylurethane (0.35g,2.2mmol) was added and the reaction was continued for 3 hours. Water (10mL) was added to the reaction mixture at 0 deg.C, stirred for 10 minutes, filtered, rinsed with water (10mL), and the filter cake was collected and dried to give the title compound 15c (0.47g, 60% yield) as a yellow solid.
Step 4)2- [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy]Benzene (III)
Base of]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 15
Ethyl N- [ 2-cyano-2- [ [3, 5-dimethyl-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] hydrazono ] acetyl ] carbamate 15c (0.47g,1.0mmol) was dissolved in N, N-dimethylformamide (4mL), and sodium acetate (0.12g,1.5mmol) was added and reacted at 120 ℃ for 5 hours. The reaction was cooled to room temperature, water (10mL) was added, filtered, the filter cake was collected and dried, and the resulting solid was recrystallized at 85 ℃ (ethanol/ethyl acetate/petroleum ether ═ 2.5/5/10,17.5mL), filtered, the filter cake was collected and dried in vacuo to give the title compound 15(0.23g, 54% yield, 98.59% HPLC purity) as a yellow solid.
MS(ESI,neg.ion)m/z:416.2[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)9.35(s,1H),7.29(s,2H),6.90(d,J＝8.6Hz,1H),6.74(d,J＝2.6Hz,1H),6.57(dd,J＝8.6,2.8Hz,1H),3.42(s,2H),2.63(t,J＝6.6Hz,2H),2.11(s,6H),2.10-2.03(m,2H)。
Example 162- [3, 5-bromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy ] phenyl ] -3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile (Compound 16)
Step 1)7- (2, 6-dibromo-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16a
7-hydroxy-1, 3,4, 5-tetrahydro-1-benzazepin-2-one 12a (0.10g,0.56mmol), 1, 3-dibromo-2-fluoro-5-nitro-benzene (0.20g,0.67mmol) were dissolved in N, N-dimethylformamide (5mL), and potassium carbonate (0.16g,1.2mmol) was added and reacted at 60 ℃ for 10 hours. After the reaction solution was cooled to room temperature, water (5mL) was added, stirred for 10 minutes, filtered, and the filter cake was collected and dried to give the title compound 16a (0.25g, yield 97%) as a pale yellow solid.
Step 2)7- (4-amino-2, 6-dibromo-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16b
7- (2, 6-dibromo-4-nitro-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16a (0.25g,0.55mmol) was dissolved in acetic acid (3mL), and iron powder (0.10g,1.6mmol) was added and reacted at 60 ℃ for 5 hours. The reaction was cooled to room temperature, water (5mL) was added, stirred for 10min, filtered, washed with water (3mL × 2), and the filter cake was collected and dried to give the title compound 16b (0.19g, yield 81%) as a yellow solid.
Step 3) N- [ 2-cyano-2- [ [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepine-7-
Radical) oxy]Phenyl radical]Hydrazine fork]Acetyl group]Urethane 16c
7- (4-amino-2, 6-dibromo-phenoxy) -1,3,4, 5-tetrahydro-1-benzazepin-2-one 16b (0.19g,0.45mmol) was dissolved in acetic acid (3mL), a solution of sodium nitrite (46mg,0.67mmol) in water (1mL) was added at 0 ℃, and after 10 minutes of reaction, N-cyanoacetylurethane (90mg,0.56mmol) was added, followed by further reaction at 0 ℃ for 1 hour. To the reaction was added water (3mL), stirred for 10min, filtered, washed with water (3mL), and the filter cake was collected and dried to give the title compound 16c (0.20g, 76% yield) as a yellow solid.
Step 4)2- [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy) benzene
Base (C)]-3, 5-dioxo-1, 2, 4-triazine-6-carbonitrile 16
Reacting N- [ 2-cyano-2- [ [3, 5-dibromo-4- [ (2-oxo-1, 3,4, 5-tetrahydro-1-benzazepin-7-yl) oxy group]Phenyl radical]Hydrazine fork]Acetyl group]Ethyl carbamate 16c (0.20g,0.34mmol) was dissolved in N, N-dimethylformamide (3mL), and sodium acetate (33mg,0.40mmol) was added to react at 120 ℃ for 5 hours. The reaction solution was cooled to room temperature, water (5mL) was added, stirring was carried out for 10 minutes, filtration was carried out, and the collected solid was separated and purified by preparative liquid chromatography [ 47% ACN/53% H ] 2 O (0.1% TFA), Kromasil standard: C1810 μm. times.50 mm. times.250 mm, flow rate: 100mL/min]To obtain the title compound 16(50mg, yield 27%, HPLC purity: 98.04%) as a white solid.
MS(ESI,neg.ion)m/z:546.0[M-H] - ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)13.25(s,1H),9.42(s,1H),7.95(s,2H),6.94(d,J＝8.8Hz,1H),6.85(d,J＝2.4Hz,1H),6.64(dd,J＝2.8,2.8Hz,1H),2.67(t,J＝6.4Hz,2H),2.72-2.62(m,4H)。
Activity test examples
Firstly, the compounds of the invention detect the agonist activity of TR alpha or TR beta in a dual-luciferase reporter gene experiment
Test materials:
HEK293 cells, purchased from ATCC, Cat No. CRL-1573;
fugene HD transformation reagent, available from Promega, Cat No. E231A;
DMEM, available from Gibco, Cat No. 11995;
FBS, purchased from Biosera, Cat No. FB-1280/500;
0.25% Trypsin-EDTA, available from Gibco, Cat No. 25200-072;
Dual-Luciferase Reporter Assay System, available from Promega, Cat No. E1960;
96-well plate (round bottom) available from Corning, Cat No. 3365.
The test method comprises the following steps:
HEK293 cells were cultured in 10% FBS + DMEM in whole medium. pBind-TR alpha or pBind-TR beta (100 ng/. mu.l), pG5Luc (100 ng/. mu.l), FuGENE HD and Opti-MEM were mixed well and incubated at room temperature for 15min, while HEK293 cells were digested with 0.25% Trypsin-EDTA, resuspended in whole medium, the cell density was calculated, adjusted to 500,000cells/ml, the transcription mixture was added to mix well with the cell suspension, plated in 96-well plates (100. mu.L/well), and cultured at 37 ℃ for 24 h. After 24h, test compounds were dissolved in DMSO and diluted 3-fold for 10 concentrations, then the compounds were diluted with DMEM into 10% DMSO in compound solution, 5 μ L of compound was taken in a 96-well plate at a final DMSO concentration of 0.5% compound, and the compounds were co-cultured with the cells for 18 h. After 18h, firefly fluorescence signals and Renilla fluorescence signals were detected using the Dual-Luciferase Reporter Assay System. Dividing the firefly fluorescence signal (F) by the Renilla fluorescence signal (R) to calculate the F/R ratio, plotting using Graph Pad Prism software and calculating EC 50 The value is obtained.
The test results show that: the compound has obvious agonistic activity and selectivity on TR beta.
Secondly, the in vitro binding activity detection of the compound of the invention to TR alpha or TR beta
Test materials:
LanthaScreen TR-FRET thyoid Receptor beta Coactivator Assay kit available from Invitrogen, Cat. No. PV4686;
LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit was purchased from Invitrogen, Cat.No. PV4687.
The test method comprises the following steps:
the method uses the LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit to perform the experiment. Test compounds were dissolved in DMSO and diluted 3-fold for 10 concentrations, and then diluted with TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO. mu.L of compound solution containing 2% DMSO was placed in a 384 well plate, then 5. mu.L of 4 XTR beta/alfa-LBD, 5. mu.L of a mixture containing 0.4. mu.M fluoroescein-SRC 2-2 and 8nM Tb anti-GST antibody was added to each well, mixed well and incubated for 1h at room temperature in the dark. After 1h, fluorescence values (RFU) were read at excitation 520nm and emission 495nm using the PHERAstar FSX microplate reader from BMG LABTECH. The TR-FRET ratio was calculated by dividing the emission signal at 520nm by the emission signal at 495 nm. Curves were drawn using Graph Pad Prism 5 software and EC was calculated 50 The value is obtained. The results of the experiment are shown in table 1.
Table 1:
the test results show that: the compound has stronger binding affinity and selectivity to TR beta.
Third, pharmacokinetic determination of the Compounds of the invention
For purposes of the test the following method was used to determine the pharmacokinetics of the compounds of the present invention.
Test materials:
the experimental reagents and the samples to be tested: propranolol (internal standard), methanol, ammonium acetate, K 2 EDTA (potassium ethylenediaminetetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), KolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;
SD rat: male, 180-.
The test method comprises the following steps:
1. preparation of test article
The test solutions were prepared from 5% DMSO + 5% KolliphorHS15+ 90% physiological saline, and were adjusted to completely dissolve each compound.
2. Design of animal experiment
3. Animal administration dose meter
| Group of | Sex | Number of animals | Dosage to be administered | Concentration of drug administration | Volume of administration |
| I.v. was injected intravenously. | Male(s) | 3 | 1mg/kg | 1mg/mL | 1mL/kg |
| P.O is administered orally. | Male sex | 3 | 5mg/kg | 1mg/mL | 5mL/kg |
4. Solution preparation
(1) Preparation of a stock solution of a test article: accurately weighing a proper amount of a test sample, dissolving the test sample in DMSO, diluting the test sample to 1mg/mL by using acetonitrile, and shaking up the test sample to obtain the test sample. Storing at-20 deg.C.
(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL of the stock solution of Propranol was precisely aspirated, and the solution was diluted to 100ng/mL with water.
5. Sample analysis
Processing a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis on the sample by a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode, and calculating the concentration of the result by using instrument quantitative software.
6. Plasma sample pretreatment
Accurately sucking 30 mu L of plasma sample, adding 250 mu L of internal standard, and uniformly mixing by vortex. The extract was extracted once with 1mL of MTBE, centrifuged at 13,000rpm for 2min at 4 ℃, 800. mu.L of the supernatant was aspirated, evaporated in a 96-well nitrogen blower, and the residue was reconstituted with 150. mu.L of methanol/water (v/v. 50/50), vortexed, and injected in an amount of 8. mu.L.
7. Preparation of Standard samples
Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with plasma concentrations of 3,5, 10, 30, 100, 300, 1,000, 3,000, 5,000 and 10,000ng/mL, performing double-sample analysis according to the operation of 'plasma sample pretreatment', and establishing a standard curve.
8. Analytical method
The LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.
9. Data processing
Pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.
The test results show that the compound of the invention shows excellent pharmacokinetic properties when administered by intravenous injection or oral administration.
Fourthly, pharmacodynamic evaluation of the compound
Test materials:
western diet: purchased from Research die, cat # code: D12079B;
MCD die: purchased from southbound telofil fodder science ltd, cat #: TP 3006R;
ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: purchased from Roche, and the respective cargo numbers are: 20764957322, 20764949322, 03333701190, 20767107322, 0303973190, 04399803190, 03038866322 and 04404483190;
male OB/OB mice at 8 weeks of age: purchased from Jiangsu Jiejiaokang Biotech limited;
8 week old male db/db mice: purchased from Jiangsu Jiejiaokang Biotech limited.
A. Compound in Western diet induced OB/OB mouse non-alcoholic steatohepatitis (NASH) model
Evaluation of pharmacodynamics of (1)
OB/OB mice are mice with leptin gene deletion, and OB/OB mouse NASH model induced by Western diet is a common NASH in vivo efficacy evaluation model. The experiment was started 1 week after the animals were acclimated. OB/OB mice were fed Western diet, which was changed three times a week (Monday, three, five), and mice were dosed starting at the fifth week after feeding, once a day orally for 6 weeks, for a total experimental period of 10 weeks. The animals were monitored daily for baseline and mouse body weights were recorded weekly during the experiment. After the experiment, the test was performed overnight, and the mice were anesthetized, subjected to orbital bleeding to collect whole blood, centrifuged at 4 ℃ and 4,000rpm for 10min to obtain serum, and stored at-80 ℃. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, livers were removed and weighed. Liver midlobes were stored at-80 ℃ in EP tubes and used for intrahepatic TG and CHO content determination. Left lobe of liver was fixed in 10% formalin, HE stained and NAS scored.
B. Pharmacodynamic of compound in MCD diet-induced db/db mouse non-alcoholic steatohepatitis (NASH) model
Evaluation of science
The db/db mouse is a leptin receptor gene deletion mouse, and the db/db mouse NASH model induced by MCD diet is a commonly used NASH in-vivo efficacy evaluation model. The experiment was started 1 week after the animals were acclimated. db/db mice were fed with MCD feed, which was changed three times a week (monday, wednesday, friday), and the mice were tested by dosing while molding, once a day for 8 weeks, with the entire test period of 8 weeks. The animals were monitored daily for baseline performance during the experiment and mouse body weights were recorded weekly. After the experiment is finished, the rat is fasted overnight, and after the mouse is anesthetized, the whole blood is collected by orbital blood collection and is centrifuged at 4 ℃ and 4,000rpm for 10min to obtain serum, and the serum is stored at-80 ℃. The serum was used for the detection of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. The mice were dissected, livers were removed and weighed. Liver midlobes were stored at-80 ℃ in EP tubes and used for intrahepatic TG and CHO content determination. Left lobe of liver was fixed in 10% formalin, HE stained and scored for NAS.
Test results show that the compound can effectively reduce fat accumulation in liver, relieve inflammation and improve hepatic fibrosis.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (12)
1. A compound which is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound represented by formula (I),
wherein the content of the first and second substances,
y is-O-;
R 3a 、R 3b 、R 3c and R 3d Each independently is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH or C 1-6 An alkyl group;
R 1 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 、-SH、C 1-6 Alkyl, -C (═ O) -C 1-6 Alkoxy, -C (═ O) -C 1-6 Alkyl, -C (═ O) -C 1-6 Alkylamino or-C (═ O) NH 2 ；
R 2 Is H or deuterium;
ring A is
X is CH;
E 1 is- (CR) a R b ) q -or-O-; q is 0,1, 2 or 3;
E 2 is-CR c R d -、-C(＝CR h R i ) -or-O-;
E 3 is-C (═ O) -;
each R a 、R b 、R c 、R d 、R h And R i Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH or C 1-6 Alkyl radical, wherein said C 1-6 Alkyl is independently unsubstituted or substituted with 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring, or R c 、R d Together with the carbon atom to which they are attached form C 3-8 Carbocycle wherein said C 3-8 The carbocycles being independently unsubstituted or substituted by 1,2 or 3R y1 Substituted;
R 4 is H, deuterium, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein said C 1-6 Alkyl and C 1-6 Haloalkyl is each independently unsubstituted or substituted with 1,2 or 3R y1 Substituted;
each R y Independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 Or C 1-6 An alkyl group;
each R y1 Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 Or C 1-6 An alkyl group.
2. The compound of claim 1, wherein R is 3a 、R 3b 、R 3c And R 3d Each independently of the other is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 SH, methyl, ethyl, n-propyl or isopropyl.
3. The compound of claim 1, wherein R is 1 Is H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH, methyl, ethyl, n-propyl, isopropyl, -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 or-C (═ O) NH 2 。
4. The compound of claim 1, wherein each R is a 、R b 、R c 、R d 、R h And R i Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH or C 1-4 Alkyl radical, wherein said C 1-4 Alkyl is independently unsubstituted or substituted with 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form C 3-8 Carbocyclic ring, or R c 、R d Together with the carbon atom to which they are attached form C 3-8 Carbocycle wherein said C 3-8 The carbocycles being independently unsubstituted or substituted by 1,2 or 3R y1 And (4) substituting.
5. The compound of claim 4, wherein each R is a 、R b 、R c 、R d 、R h And R i Independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 、-COOH、-OH、-NH 2 -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl are each independently unsubstituted or substituted by 1,2 or 3R y1 Substituted;
or R a 、R b Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, or R c 、R d Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups are each independently not takenIs substituted or substituted by 1,2 or 3R y1 And (4) substitution.
6. The compound of claim 1, wherein said R 4 Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, -CF 3 、-CHF 2 、-CH 2 F、-CH 2 CHF 2 or-CH 2 CF 3 Wherein the methyl, ethyl, n-propyl, isopropyl, -CHF 2 、-CH 2 F、-CH 2 CHF 2 and-CH 2 CF 3 Each independently of the others being unsubstituted or substituted by 1,2 or 3R y1 And (4) substituting.
7. The compound of claim 1, each R y Independently H, deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 Methyl, ethyl, n-propyl or isopropyl;
each R y1 Independently deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 Methyl, ethyl, n-propyl or isopropyl.
8. The compound of claim 1, having one of the following structures:
9. A pharmaceutical composition comprising a compound of any one of claims 1-8, optionally further comprising any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or any combination thereof.
10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for agonizing a thyroid hormone receptor; or for the prevention, treatment or alleviation of diseases mediated by thyroid hormone receptors.
11. The use of claim 10, wherein the thyroid hormone receptor is thyroid hormone beta receptor.
12. The use according to claim 10, wherein the disease modulated by thyroid hormone receptors is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity, diabetes, lipid metabolism disorders, glycogen storage disease type 1A, 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.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801960A (en) * | 2007-09-20 | 2010-08-11 | 霍夫曼-拉罗奇有限公司 | prodrugs to thyroid hormone analogs |
| CN102459185A (en) * | 2009-04-20 | 2012-05-16 | 田边三菱制药株式会社 | Novel thyroid hormone beta receptor agonist |
| JP2012106996A (en) * | 2010-10-19 | 2012-06-07 | Mitsubishi Tanabe Pharma Corp | NOVEL THYROID HORMONE β-RECEPTOR AGONIST |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6787652B1 (en) * | 1999-09-30 | 2004-09-07 | Pfizer, Inc. | 6-Azauracil derivatives as thyroid receptor ligands |
| JPWO2003064369A1 (en) * | 2002-01-30 | 2005-05-26 | キッセイ薬品工業株式会社 | Novel thyroid hormone receptor ligands, pharmaceutical compositions containing them, and uses thereof |
| CA2614529C (en) * | 2005-07-21 | 2011-06-28 | F. Hoffmann-La Roche Ag | Pyridazinone derivatives as thyroid hormone receptor agonists |
| DK3689853T3 (en) * | 2012-09-17 | 2022-03-07 | Madrigal Pharmaceuticals Inc | PROCEDURE FOR SYNTHESIS OF THYREOIDE AHORMON ANALOGS AND THEIR POLYMORPHERES |
| CN108727344A (en) * | 2018-05-14 | 2018-11-02 | 嘉兴特科罗生物科技有限公司 | A kind of compound and its synthetic method and application |
| US20210355110A1 (en) * | 2018-10-12 | 2021-11-18 | InventisBio Co., Ltd. | Thyroid hormone receptor agonists |
| WO2020169069A1 (en) * | 2019-02-21 | 2020-08-27 | Nanjing Ruijie Pharma Co., Ltd. | Novel compounds and their uses as thyroid hormone receptor agonists |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101801960A (en) * | 2007-09-20 | 2010-08-11 | 霍夫曼-拉罗奇有限公司 | prodrugs to thyroid hormone analogs |
| CN102459185A (en) * | 2009-04-20 | 2012-05-16 | 田边三菱制药株式会社 | Novel thyroid hormone beta receptor agonist |
| JP2012106996A (en) * | 2010-10-19 | 2012-06-07 | Mitsubishi Tanabe Pharma Corp | NOVEL THYROID HORMONE β-RECEPTOR AGONIST |
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| WO2021043185A1 (en) | 2021-03-11 |
| CN112442013A (en) | 2021-03-05 |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |