CN113045551A - Compound as thyroid hormone beta receptor agonist and application thereof - Google Patents

Compound as thyroid hormone beta receptor agonist and application thereof Download PDF

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CN113045551A
CN113045551A CN202011552018.4A CN202011552018A CN113045551A CN 113045551 A CN113045551 A CN 113045551A CN 202011552018 A CN202011552018 A CN 202011552018A CN 113045551 A CN113045551 A CN 113045551A
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alkylene
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顾峥
黎健豪
邓新山
邓建超
陈道乾
彭飞
袁炜辉
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Sunshine Lake Pharma Co Ltd
Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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 mediated by thyroid hormone beta receptor activation, and particularly can be used for preparing medicaments for treating non-alcoholic fatty liver diseases.

Description

Compound as thyroid hormone beta receptor agonist and application thereof
Technical Field
The invention belongs to the field of medicines, 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 mediated by thyroid hormone beta receptor activation, 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, T3 is the more physiologically active form. T4 was converted to T3 by a tissue-specific deiodinase, which is present in all tissues but mainly 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 divided into TR α 1 and TR α 2, and TR β is further divided 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)). Studies have found that hyperthyroidism is associated with low total serum cholesterol, due to 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 atherosclerosis 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 reduces lipoprotein (a), an important risk factor for atherosclerosis, which 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 metabolism 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,
Figure BDA0002858004110000021
wherein the content of the first and second substances,
y is-O-, -C (═ O) -, -CH (OH) -, -CH (CH)3)-、-C(CH3)2-or-S-;
R4a、R4b、R4cand R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl or cyano C1-6An alkyl group;
ring Cy is
Figure BDA0002858004110000022
U1Is CRaOr N; u shape2Is CRbOr N; u shape3Is CRcOr N;
R1、R2and together with the atoms to which they are attached form a 3-8 atom heterocycle, wherein said 3-8 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdSubstituted;
R0and R3Each independently is H, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, 5-6 atom consisting of heteroaromaticRadical or (5-6-atom-constituting heteroaryl) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-8A carbocyclic ring or a heterocyclic ring of 3 to 8 atoms in which said C3-8The carbocycle and the heterocycle of 3 to 8 atoms are each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Haloalkoxy, C1-6Alkoxy or C1-6An alkylamino group;
w is
Figure BDA0002858004110000031
Figure BDA0002858004110000032
Each R5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C (═ O) -C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl or cyano C1-6An alkyl group;
n is 0, 1,2,3 or 4.
In some embodiments, W is
Figure BDA0002858004110000033
Figure BDA0002858004110000034
In some embodiments, R1、R2And together with the atoms to which they are attached form a 5-6 atom heterocycle, wherein the 5-6 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdAnd (4) substituting.
In some embodiments, R1、R2And together with the atoms to which they are each attached form pyrrolidine, pyrazolidine, 1, 3-oxazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazine-2-one, 1-dioxo-1, 2-thiazine, or 4H-1, 3-oxazin-6- (5H) -one, wherein said pyrrolidine, pyrazolidine, 1, 3-oxazolidine, morpholine, piperazine, piperidine, morpholine, piperazine, piperidine, piperazine, piperidine, 2-, Piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazinan-2-one, 1-dioxo-1, 2-thiazine and 4H-1, 3-oxazin-6- (5H) -one are each independently unsubstituted or substituted with 1,2,3 or 4RdAnd (4) substituting.
In some embodiments, each R is5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3And a method for preparing the sameRadical, ethylamino, methoxy, ethoxy, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.
In some embodiments, R0And R3Each independently is H, deuterium, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3RyAnd (4) substituting.
In some embodiments, R0And R3Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinepyridyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl group,Thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinylPiperazinyl, (5-6-membered heterocyclyl) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdAnd together with the carbon atom to which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane or heterocycle of 5-6 atoms, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane and heterocycle of 5-6 atoms are each independently unsubstituted or substituted with 1,2 or 3RyAnd (4) substituting.
In some embodiments, each R isyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Methoxy, ethoxy, methylamino or ethylamino.
In some embodiments, R4a、R4b、R4cAnd R4dEach of which isIndependently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl or cyanomethyl.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, optionally further comprising pharmaceutically acceptable adjuvants.
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 preventing, treating or ameliorating a disease mediated by thyroid hormone receptor activation.
In some embodiments, the thyroid hormone receptor of the present invention is the thyroid hormone beta receptor.
In some embodiments, the disease mediated by thyroid hormone receptor activation 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 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 to achieve the desired results with reference to 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 the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 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, as used herein, the articles refer to articles of one or more than one (i.e., 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.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the 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. Generally, 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, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino, alkylOxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, 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 to mean 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 "C1-6Alkyl "in particular denotes independently disclosed C1Alkyl (methyl), C2Alkyl (ethyl), C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group; "heterocyclic group consisting of 3 to 8 atoms" means a heterocyclic group consisting of 3 atoms, a heterocyclic group consisting of 4 atoms, a heterocyclic group consisting of 5 atoms, a heterocyclic group consisting of 6 atoms, a heterocyclic group consisting of 7 atoms and a heterocyclic group consisting of 8 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 that 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" denotes a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon radicalA radical group. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms, i.e. C1-12An alkylene group. In some embodiments, the alkylene group contains 1 to 8 carbon atoms, i.e., C1-8An alkylene group; in other embodiments, the alkylene group contains 1 to 6 carbon atoms, i.e., C1-6An alkylene group; in some embodiments, the alkylene group contains 1 to 4 carbon atoms, i.e., C1-4An alkylene group; in some embodiments, the alkylene group contains 1 to 3 carbon atoms, i.e., C1-3An alkylene group; in some embodiments, the alkylene group contains 1-2 carbon atoms, i.e., C1-2An alkylene group. Examples include, but are not limited to, methylene (-CH)2-, ethylene (including-CH)2CH2-or-CH (CH)3) -, isopropylidene (including-CH (CH)3)CH2-or-C (CH)3)2-), n-propylidene (including-CH)2CH2CH2-、-CH(CH2CH3) -or-CH2CH(CH3) -) n-butylene (including-CH)2(CH2)2CH2-、-CH(CH2CH2CH3)-、-CH2CH(CH2CH3)-、-CH2CH2CH(CH3) -or-CH (CH)3)CH(CH3) -), tert-butylidene (including-CH (CH)3)2)-、-CH2CH(CH3)CH2-or-CH2C(CH3)2-), pentylene (e.g., -CH)2(CH2)3CH2-), hexylene (e.g. -CH2(CH2)4CH2-) 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 1-10 carbon atoms, i.e., C1-10An alkyl group; in some embodiments, the alkyl group contains1 to 8 carbon atoms, i.e. C1-8An alkyl group; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C1-6An alkyl group; in some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C1-4An alkyl group; in some embodiments, the alkyl group contains 1-2 carbon atoms, i.e., C1-2An alkyl group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2)3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)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 carbon-carbon sp is present2A 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, the alkenyl group contains 2 to 8 carbon atoms, i.e., C2-8An alkenyl group; in some embodiments, the alkenyl group contains 2 to 6 carbon atoms, i.e., C2-6An alkenyl group; in some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C2-4An alkenyl group.
Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) Propenyl (-CH ═ CHCH)3) Butenyl (-CH ═ CHCH)2CH3、-CH2CH＝CHCH3、-CH2CH2CH＝CH2、-CH＝C(CH3)2、-CH＝C(CH3)2、-CH2C(CH3)＝CH2) Pentenyl (-CH)2CH2CH2CH＝CH2、-CH2CH2CH＝CHCH3、-CH2CH2CH＝CHCH3、-CH2CH＝CHCH2CH3、-CH＝CHCH2CH2CH3、-CH2CH2C(CH3)＝CH2、-CH2CH＝C(CH3)2、-CH＝CHCH(CH3)2、-C(CH2CH3)＝CHCH3、-CH(CH2CH3)CH＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp triple bond, whereinThe alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms, i.e., C2-8An alkynyl group; in some embodiments, alkynyl groups contain 2-6 carbon atoms, i.e., C2-6An alkynyl group; in some embodiments, alkynyl groups contain 2-4 carbon atoms, i.e., C2-4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH)3) Propargyl (-CH)2C.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, the alkoxy group contains 1 to 20 carbon atoms, i.e., C1-20An alkoxy group; in some embodiments, the alkoxy group contains 1 to 10 carbon atoms, i.e., C1-10An alkoxy group; in some embodiments, the alkoxy group contains 1 to 8 carbon atoms, i.e., C1-8An alkoxy group; in some embodiments, the alkoxy group contains 1 to 6 carbon atoms, i.e., C1-6An alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C1-4An alkoxy group; in some embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C1-3An alkoxy group; in some embodiments, the alkoxy group contains 1-2 carbon atoms, i.e., C1-2An alkoxy group.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) N-propyloxy (n-PrO, n-propoxy, -OCH)2CH2CH3) i-Propyloxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy)Radical, -OCH2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-isopropyloxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) 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 C1-6Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C1-6An alkylamino group; in some embodiments, alkylamino is one or two C1-4Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C1-4An alkylamino group; in some embodiments, alkylamino is one or two C1-2Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C1-2An 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, whichThe alkylthio group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkylthio group contains 1-20 carbon atoms, i.e., C1-20An alkylthio group; in some embodiments, the alkylthio group contains 1-10 carbon atoms, i.e., C1-10An alkylthio group; in some embodiments, the alkylthio group contains 1-8 carbon atoms, i.e., C1-8An alkylthio group; in some embodiments, the alkylthio group contains 1-6 carbon atoms, i.e., C1-6An alkylthio group; in some embodiments, the alkylthio group contains 1-4 carbon atoms, i.e., C1-4An alkylthio group; in some embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., C1-3An 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, the haloalkyl group contains 1 to 10 carbon atoms, i.e., C1-10A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 8 carbon atoms, i.e., C1-8A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., C1-6A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., C1-4A haloalkyl group; in some embodiments, the haloalkyl group contains 1 to 3 carbon atoms, i.e., C1-3A haloalkyl group; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C1-2A haloalkyl group. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH)2F) Difluoromethyl (-CHF)2) Trifluoromethyl (-CF)3) Fluoroethyl (-CHFCH)3,-CH2CH2F) Difluoroethyl (-CF)2CH3,-CFHCFH2,-CH2CHF2) Perfluoroethyl, fluoropropyl (-CHFCH)2CH3,-CH2CHFCH3,-CH2CH2CH2F) DifluoropropanRadical (-CF)2CH2CH3,-CFHCFHCH3,-CH2CH2CHF2,-CH2CF2CH3,-CH2CHFCH2F) 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 to 10 carbon atoms; in some embodiments, haloalkoxy groups contain 1 to 8 carbon atoms; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C1-6A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C1-4A haloalkoxy group; in some embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C1-3A haloalkoxy group; in some embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C1-2A 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 refers to C substituted with one or more hydroxyl (-OH) groups1-6Alkyl, i.e. hydroxy C1-6An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups1-4Alkyl, i.e. hydroxy C1-4An alkyl group; in some embodiments, a hydroxyalkyl group refers to C substituted with one or more hydroxyl (-OH) groups1-2Alkyl, i.e. hydroxy C1-2An alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH)2OH), hydroxyethyl (e.g. 2-hydroxyethyl), hydroxy-n-propyl(e.g., -CH)2CH2CH2OH), 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) groups2) Substituted C1-6Alkyl radicals, i.e. amino radicals C1-6An alkyl group; in some embodiments, an aminoalkyl group is defined as being substituted with one or more amino (-NH) groups2) Substituted C1-4Alkyl radicals, i.e. amino radicals C1-4An alkyl group; in some embodiments, an aminoalkyl group is defined as being substituted with one or more amino (-NH) groups2) Substituted C1-2Alkyl radicals, i.e. amino radicals C1-2An alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH)2NH2) Diamino methyl (-CH (NH)2)2) Aminoethyl (e.g., -2-aminoethyl), amino-n-propyl (e.g., -CH)2CH2CH2NH2) 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) groups1-6Alkyl, i.e. cyano C1-6An alkyl group; in some embodiments, cyanoalkyl refers to C substituted with one or more cyano (-CN) groups1-4Alkyl, i.e. cyano C1-4An alkyl group; in some embodiments, cyanoalkyl refers to C substituted with one or more cyano (-CN) groups1-2Alkyl, i.e. cyano C1-2An alkyl group. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH)2CN), 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)1-6Alkyl, i.e. carboxyl C1-6An alkyl group; in some embodiments, a carboxyalkyl group refers to C substituted with one or more carboxyl groups (-COOH)1-4Alkyl, i.e. carboxyl C1-4An alkyl group; in some embodiments, a carboxyalkyl group refers to C substituted with one or more carboxyl groups (-COOH)1-2Alkyl, i.e. carboxyl C1-2An 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 saturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms having one or more points of attachment to the rest of the molecule, wherein the cycloalkyl group is optionally substituted with the substituents described herein. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, i.e., C3-10A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, i.e., C3-8A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, i.e., C3-6A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 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 consisting of 3 to 8 atoms" refers to a heterocyclyl group consisting of 3,4, 5,6, 7, or 8 atoms.
The term "heterocyclyl" refers to a saturated or partial moiety containing 3 to 12 atomsUnsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus, wherein said heterocyclic group is non-aromatic and does not contain any aromatic rings, and wherein said 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, heterocyclyl may be carbon-or nitrogen-based, and-CH2The-group may optionally be 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 ring atoms; in some embodiments, heterocyclyl is a ring system of 5-10 ring atoms; in some embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in some embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in some embodiments, heterocyclyl is a ring system of 5-6 ring atoms, i.e., heterocyclyl of 5-6 atoms; in some embodiments, heterocyclyl is a ring system of 3-6 ring atoms, i.e., heterocyclyl of 3-6 atoms.
Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, 1, 3-oxazolidinyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidine, piperazinyl, and mixtures thereofExamples of the substituent include, but are not limited to, phenyl, oxacycloheptyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl (e.g., 1,2,3, 6-tetrahydropyridine), 5, 6-dihydro-4H-1, 3-oxazine, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, 1, 3-oxazolidinyl, and the like. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, oxo-1, 3-thiazolidinyl, 3, 5-dioxopiperidinyl, pyrimidinedione, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazine-2-one, 4H-1, 3-oxazin-6- (5H) -one. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl, 1, 1-dioxo-1, 2-thiazinoalkyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like.
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 anthryl, and the like.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic aromatic systems containing 5 to 10 ring atoms, wherein 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 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., of the formula) via any reasonable site (which may be C in CH, or N in NH)The host structure). When a heteroaryl group is present-CH2When said radical is-CH2-the 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 heteroaryl consisting of 5 to 8 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-7 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 heteroaryl consisting of 6 atoms 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 "cycloalkyl-alkylene" means that the cycloalkyl group is attached 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 invention3-6cycloalkyl-C1-4Alkylene "represents C3-6Cycloalkyl radicals through C1-4The alkylene group is attached to the rest of the molecule. The term "C" in the present invention3-6cycloalkyl-C1-2Alkylene "represents C3-6Cycloalkyl radicals through C1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, cyclopropyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2-, cyclohexyl-CH2CH2-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 invention1-4Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C1-4The alkylene group is attached to the rest of the molecule. (heterocyclic group consisting of 5 to 6 atoms) -C described in the present invention1-2Alkylene "denotes a heterocyclic radical of 5 to 6 atoms bonded via C1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, tetrahydropyranyl-CH2-, tetrahydropyranyl-CH2CH2-, tetrahydrofuryl-CH2-, IVHydrogen furyl-CH2CH2-, pyrrolidinyl-CH2-, piperidinyl-CH2-, piperidinyl-CH2CH2-, morpholinyl-CH2-, morpholinyl-CH2CH2-and so on.
The term "aryl-alkylene" means that the aryl group is attached to the rest of the molecule through an alkylene group, wherein aryl and alkylene have the meaning described herein. The aryl-alkylene groups may be optionally substituted with one or more substituents as described herein. For example, "C" according to the invention6-10aryl-C1-4Alkylene "represents C6-10Aryl radicals through C1-4The alkylene group is attached to the rest of the molecule. "C" according to the invention6-10aryl-C1-2Alkylene "represents C6-10Aryl radicals through C1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, phenyl-CH2-, phenyl-CH2CH2-, naphthyl-CH2-and the like.
The term "heteroaryl-alkylene" means that the heteroaryl group is attached 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-atom-constituting heteroaryl) -C as defined in the invention1-4Alkylene "denotes a heteroaryl group of 5 to 6 atoms bonded via C1-4The alkylene group is attached to the rest of the molecule. (5-6-atom-constituting heteroaryl) -C as defined in the invention1-2Alkylene "denotes a heteroaryl group of 5 to 6 atoms bonded via C1-2The alkylene group is attached to the rest of the molecule. Examples include, but are not limited to, pyridyl-CH2-, pyrrolyl-CH2-, pyrrolyl-CH2CH2-, quinolyl-CH2-, thienyl-CH2-, furyl-CH2-, pyrimidinyl-CH2-, pyridinyl-CH2-, imidazolyl-CH2-, isoxazolyl-CH2-and the like.
The term "hetero atom"means 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 NRT(like NR in N-substituted pyrrolidinylT，RTAs a substituent on N).
The term "halogen" refers to F, Cl, Br or I.
The term "nitro" means-NO2。
The term "mercapto" refers to-SH.
The term "hydroxy" refers to-OH.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "carboxylic acid" or "carboxyl" refers to-C (═ O) OH or-COOH.
The term "carbonyl" denotes- (C ═ O) -.
The term "deuterium" means deuterated, i.e.2H。
As described herein, the ring system formed by a ring with a substituent R bonded to the center 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 any potentially substituted position on the pyrimidine ring may be optionally substituted with t R; as another example, formula b represents that substituent R may be substituted at any possible substituted position on the pyrimidine ring, as shown in formulas b-1 to b-3:
Figure BDA0002858004110000121
as described herein, a ring system formed by a bond to the center of the ring represents that the bond can be attached to the rest of the molecule at any point on the ring system that is attachable. For example, formula d represents a pyrimidine ring which may be attached to the remainder of the molecule via any possible attachment position, as shown in formulae d-1 to d-3:
Figure BDA0002858004110000122
the term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. 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. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, 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, a term used in nucleophilic substitution reactions 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 away 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, azide groups, hydroxyl groups, or 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 "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 an 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 and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews Discovery,2008,7, 255-.
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 assay methods 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 that is 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-oxide (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 dichloromethane.
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 of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using 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 differing from the natural normal by atomic mass or mass numberSee atomic mass or mass number. 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 as2H，3H，13C，14C，15N，16O，17O，31P，32P，36S，18F and37Cl。
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 the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g.3H and14incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e.,3h, and carbon-14, i.e14C, an isotope is particularly preferred. Furthermore, with isotopes having a larger mass number, e.g. deuterium, i.e. with2H substitution may provide some of the 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 included 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, the structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomer, and geometric (or conformational)) forms of the structure; 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 (valenctautomers) 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" as used herein are used interchangeably. 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 farm 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.
In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
Description of the Compounds of the invention
The invention provides a compound with better activation activity on thyroid hormone beta receptor, which is used for preparing medicaments for treating nonalcoholic 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. 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 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 prodrug thereof,
Figure BDA0002858004110000151
wherein, ring Cy, Y, W, R4a、R4b、R4cAnd R4dHaving the definitions as described in the present invention.
In some embodiments, Y is-O-, -C (═ O) -, -CH (oh) -, -CH (CH)3)-、-C(CH3)2-or-S-.
In some embodiments, R4a、R4b、R4cAnd R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl or cyano C1-6An alkyl group.
In some embodiments of the present invention, the substrate is,
Figure BDA0002858004110000152
wherein said R0、R1、R2、R3、U1、U2And U3Having the definitions set out in the present invention.
In some embodiments, U is1Is CRaOr N, wherein R isaHaving the definitions set out in the present invention.
In some embodiments, U is2Is CRbOr N, wherein R isbHaving the definitions set out in the present invention.
In some embodiments, U is3Is CRcOr N, wherein R iscHaving the definitions set out in the present invention.
In some embodiments, R1、R2And together with the atoms to which they are attached form a 3-8 atom heterocycle, wherein said 3-8 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdWherein each R isdHaving the definitions set out in the present invention.
In some embodiments, R0And R3Each independently is H, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10Aryl radicals-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, Ra、RbAnd RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RyGet itWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, each R isdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-8A carbocyclic ring or a heterocyclic ring of 3 to 8 atoms in which said C3-8The carbocycle and the heterocycle of 3 to 8 atoms are each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, each R isyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6An alkylamino group,-S(＝O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Haloalkoxy, C1-6Alkoxy or C1-6An alkylamino group.
In some embodiments, W is
Figure BDA0002858004110000161
Figure BDA0002858004110000162
Figure BDA0002858004110000171
Wherein each R5And n has the definitions set forth herein.
In some embodiments, each R is5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C (═ O) -C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl or cyano C1-6An alkyl group.
In some embodiments, n is 0, 1,2,3, or 4.
In some embodiments, W is
Figure BDA0002858004110000172
Figure BDA0002858004110000173
In some embodiments, W is
Figure BDA0002858004110000174
Figure BDA0002858004110000175
In some embodiments, R1、R2And together with the atoms to which they are attached form a 5-6 atom heterocycle, wherein the 5-6 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdSubstituted, each R isdHaving the definitions set out in the present invention.
In some embodiments, R1、R2And together with the atoms to which they are each attached form pyrrolidine, pyrazolidine, 1, 3-oxazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazine-2-one, 1-dioxo-1, 2-thiazine, or 4H-1, 3-oxazin-6- (5H) -one, wherein said pyrrolidine, pyrazolidine, 1, 3-oxazolidine, morpholine, piperazine, piperidine, morpholine, piperazine, piperidine, piperazine, piperidine, 2-, Piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazinan-2-one, 1-dioxo-1, 2-thiazine and 4H-1, 3-oxazin-6- (5H) -one are each independently unsubstituted or substituted with 1,2,3 or 4RdSubstituted, each R isdHaving the definitions set out in the present invention.
In some embodiments, each R is5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, -C (═ O) -C1-4Alkoxy, -C (═ O) -C1-4Alkyl, -C (═ O) -C1-4Alkylamino, -S (═ O)2-C1-4Alkyl, -S (═ O)2-C1-4Alkylamino radical, C1-4Alkylamino radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl or cyano C1-4An alkyl group.
In some embodiments, each R is5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3Methylamino, ethylamino, methoxy, ethoxy, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.
In some embodiments, R0And R3Each independently is H, deuterium, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, Ra、RbAnd RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, each R isdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4A halogenated alkoxy group,C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3RySubstituted, each R isyHaving the definitions set out in the present invention.
In some embodiments, R0And R3Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, Ra、RbAnd RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyridineOxazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5-6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RyWherein each R isyHaving the definitions set out in the present invention.
In some embodiments, each R isdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane or 5-6 atomsA heterocyclic ring of (a), wherein said cyclopropane, cyclobutane, cyclopentane, cyclohexane and 5-6 atom heterocyclic ring are each independently unsubstituted or substituted with 1,2 or 3RySubstituted, each R isyHaving the definitions set out in the present invention.
In some embodiments, each R isyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-4Alkoxy, -C (═ O) -C1-4Alkyl, -C (═ O) -C1-4Alkylamino, -S (═ O)2-C1-4Alkyl, -S (═ O)2-C1-4Alkylamino radical, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkoxy or C1-4An alkylamino group.
In some embodiments, each R isyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Methoxy, ethoxy, methylamino or ethylamino.
In some embodiments, R4a、R4b、R4cAnd R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C1-4Alkoxy radical、C1-4Alkylthio radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, hydroxy C1-4Alkyl, amino C1-4Alkyl or cyano C1-4An alkyl group.
In some embodiments, R4a、R4b、R4cAnd R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl or cyanomethyl.
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,
Figure BDA0002858004110000201
Figure BDA0002858004110000211
Figure BDA0002858004110000221
in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention.
In some embodiments, the pharmaceutical compositions of the present invention, optionally, further comprise a pharmaceutically acceptable adjuvant.
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 preventing, treating or ameliorating a disease mediated by thyroid hormone receptor activation.
In another aspect, the invention relates to a method of using a compound or pharmaceutical composition described herein to agonize a thyroid hormone receptor, or to prevent, treat or ameliorate a disease mediated by thyroid hormone receptor activation, by administering a therapeutically effective amount of the compound or the pharmaceutical composition to a subject in need thereof. 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.
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 mediated by thyroid hormone receptor activation.
In some embodiments, the thyroid hormone receptor of the present invention is the thyroid hormone beta receptor.
In some embodiments, the disease mediated by thyroid hormone receptor activation described herein 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 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 adjuvant, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of the present invention and at least one pharmaceutically acceptable adjuvant. 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 adjuvants may contain inert ingredients that do not unduly inhibit the biological activity of the compound. Pharmaceutically acceptable adjuvants should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or have no 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 pharmaceutically acceptable adjuvants, as used herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonicity agent, thickener, 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 adjuvants which are incompatible with the compounds of the present invention, e.g., which may produce undesirable biological effects or which may deleteriously interact with any other component of a pharmaceutically acceptable composition, any other conventional adjuvant and its use are also contemplated by the present invention.
Some examples of substances that may be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride 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, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), Powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as 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 (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifiers, coating agents, sweetening and flavoring agents, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.
The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions 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. In addition to inert diluents, 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 adjuvants 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, since the rate of absorption of the compound 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. Alternatively, injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid, the rate of release of the compounds being controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable 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 adjuvants, 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 auxiliary, 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 carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, 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) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, sodium, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such adjuvants as lactose or milk sugar as well as high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. 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 compounds may also be present in microencapsulated form with one or more of the abovementioned adjuvants. 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 additional substances in addition to the inert diluents, for example tableting lubricants and other tableting auxiliaries, such as magnesium stearate and microcrystalline cellulose. 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.
Formulations for topical or transdermal administration of the compounds of the present 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. 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, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. 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 can be prepared by mixing the agent and the non-irritating excipient. Such materials include, but are 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.
Local instillation to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or 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 adjuvants. Suitable adjuvants 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 as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable adjuvants. Suitable adjuvants 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 a medicament for stimulating thyroid hormone receptors or preparing a medicament for preventing, treating or alleviating diseases mediated by thyroid hormone receptor activation.
The compounds or pharmaceutical compositions provided by the present invention are useful for agonizing thyroid hormone receptors or for preventing, treating or alleviating diseases mediated by thyroid hormone receptor activation.
The present invention provides a method for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disease mediated by activation of 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. Examples of other 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 of the invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or reduce the severity of one or more of the conditions referred to herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. 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, 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 embodiments, but is provided as a means of practicing 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 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 resonance1H-NMR、13C-NMR or/and19F-NMR).1H-NMR、13C-NMR、19F-NMR chemical shifts (δ) are given in parts per million (ppm).1H-NMR、13C-NMR、19F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer in deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD or MeOH-d4) 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.
The LC-MS was determined 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, are available from Shanghai Accela Company, Annage Company, Bailingwei Company (J & K), Tianjin Afaha Angsa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.
The nitrogen atmosphere refers to 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 means an aqueous solution;
in the examples, the reaction temperature is room temperature unless otherwise specified;
in the examples, the room temperature is 10 ℃ 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 adjusted according to the polarity of the compound.
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: 25min column temperature: 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 includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice plate automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with electric spray ionization source (ESI). 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. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic 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
The test conditions for low resolution Mass Spectrometry (MS) 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 with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) at 210nm/254nm with UV detection, using electrospray ionization mode (ESI).
The following acronyms are used throughout the invention:
Figure BDA0002858004110000281
general synthetic methods
Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. Unless otherwise stated, each U1、U2、U3、R0And R5Having the definitions as described in the present invention.
Synthesis scheme 1:
Figure BDA0002858004110000282
the compounds having the structure shown in general formula (I-A) can be prepared by general synthetic methods described in scheme 1, and specific procedures can be referred to examples. Firstly, reacting a compound (I-a) with a compound (I-b) under the action of a base (such as potassium carbonate) to obtain a compound (I-c); reducing the nitro group of the compound (I-c) to obtain a compound (I-d); the amino group of the compound (I-d) is substituted by iodine to obtain a compound (I-e); carrying out coupling reaction on the compound (I-e) and the compound (I-f) to obtain a compound (I-g); the methyl group of the compound (I-g) is removed to obtain the target compound represented by the general formula (I-A).
Synthesis scheme 2:
Figure BDA0002858004110000291
compounds having the structure shown in general formula (I-B) can be prepared by general synthetic methods described in scheme 2, with reference to the examples for specific procedures. Firstly, reacting a compound (I-e) with boric acid ester to obtain a compound (I-h); carrying out coupling reaction on the compound (I-h) and the compound (I-I) to obtain a compound (I-j); the methyl group of the compound (I-j) is removed to obtain the target compound shown in the general formula (I-B).
Preparation examples
Example 15- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1H-pyridazin-3-yl) oxy ] phenyl ] -1H-pyrimidine-2, 4-dione (Compound 1)
Figure BDA0002858004110000292
Step 1)3- (2, 6-dichloro-4-iodo-phenoxy) -5-isopropyl-1H-pyridazin-6-one 1b
3- (4-amino-2, 6-dichloro-phenoxy) -5-isopropyl-1H-pyridazin-6-one 1a (0.20g,0.64mmol) was dissolved in concentrated sulfuric acid (1mL), an aqueous solution (2mL) of sodium nitrite (49mg,0.70mmol) was added dropwise under ice-cooling, the reaction was carried out for 10 minutes, an aqueous solution (2mL) of potassium iodide (0.21g,1.30mmol) was added dropwise, and the reaction was carried out at room temperature for 4 hours. The reaction was added dropwise to a saturated sodium carbonate solution (40mL), extracted with ethyl acetate (10mL × 2), the combined organic layers 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) ═ 2/1] to give the title compound 1b (50mg, yield 18%) as a white solid.
MS(ESI,pos.ion)m/z:425.0[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm)12.21(s,1H),8.00(s,2H),7.38(s,1H),3.10-2.97(m,1H),1.18(d,J＝6.9Hz,6H)。
Step 2)3- [2, 6-dichloro-4- (2, 4-dimethoxypyrimidin-5-yl) phenoxy]-5-isopropyl-1H-pyridazine- 6-keto 1c
3- (2, 6-dichloro-4-iodo-phenoxy) -5-isopropyl-1H-pyridazin-6-one 1b (0.70g,1.60mmol), (2, 4-dimethoxypyrimidin-5-yl) phenylboronic acid (0.30g,1.60mmol), potassium carbonate (0.52g,4.9mmol) and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane complex were dissolved in N, N-dimethylacetamide (5mL) and reacted at 100 ℃ for 6 hours. The reaction was cooled to room temperature, water (50mL) was added, stirred for 15 minutes, filtered, and the filter cake was collected and dried under vacuum to give the title compound 1c (0.60g, 83% yield) as a gray solid.
MS(ESI,pos.ion)m/z:437.0[M+H]+。
Step 3)5- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1H-pyridazin-3-yl) oxy]Phenyl radical]-1H-pyrimidine Pyridine-2, 4-dione 1
3- [2, 6-dichloro-4- (2, 4-dimethoxypyrimidin-5-yl) phenoxy ] -5-isopropyl-1H-pyridazin-6-one 1c (50mg,0.10mmol), lithium chloride (40mg,0.60mmol) and p-toluenesulfonic acid (0.20g,0.60mmol) were dissolved in N, N-dimethylformamide (2mL) and reacted at 120 ℃ for 3 hours. The reaction solution was cooled to room temperature, and a saturated sodium carbonate solution (10mL) was added, followed by filtration, and the filter cake was collected and purified by silica gel column chromatography (100% ethyl acetate) to give the title compound 1(23mg, yield 49%, HPLC purity: 97.77%) as a white solid.
MS(ESI,neg.ion)m/z:407.0[M-H]-；
1H NMR(400MHz,DMSO-d6)δ(ppm)12.19(s,1H),11.40(s,2H),7.90(d,J＝5.9Hz,1H),7.82(s,2H),7.40(s,1H),3.04(dt,J＝13.7,6.9Hz,1H),1.19(d,J＝6.8Hz,6H)。
Example 26- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy ] phenyl ] pyrimidine-2, 4(1H,3H) -dione (Compound 2)
Figure BDA0002858004110000301
Step 1)6- [2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] benzene]-4- Isopropylpyridazin-3 (2H) -one 2a
3- [2, 6-dichloro-4-iodo-phenoxy ] -5-isopropyl-1H-pyridazin-6-one 1b (1.15g,2.71mmol) was dissolved in tetrahydrofuran (15mL), a solution of isopropyl magnesium chloride in tetrahydrofuran (2.8mL,5.6mmol,2.0mol/L) was added dropwise at-15 deg.C followed by 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborane (0.83mL,4.06mmol), and reaction at-15 deg.C for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (25mL) at room temperature, extracted with ethyl acetate (25mL × 3), 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) ═ 3/1] to give the title compound 2a (0.45g, yield 39%) as a pale yellow solid.
1H NMR(400MHz,DMSO-d6)δ(ppm)11.01(s,1H),7.37(s,1H),7.35(s,1H),7.12(d,J＝0.7Hz,1H),3.27-3.15(m,1H),1.27(d,J＝6.9Hz,6H),1.24(s,12H)。
Step 2)6- [2, 6-dichloro-4- (2, 6-dimethoxypyrimidin-4-yl) phenoxy]-4-isopropylpyridazine-3 (2H) Ketones 2b
6- [2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] -4-isopropylpyridazin-3 (2H) -one 2a (0.22g,0.52mmol) was dissolved in N, N-dimethylformamide (10mL), and 4-bromo-2, 6-dimethoxy-pyrimidine (0.11g,0.52mmol), tetratriphenylphosphine palladium (29mg,0.025mmol) and potassium phosphate (0.22g,1.04mmol) were added in this order, and reacted at 100 ℃ for 8 hours. The reaction solution was cooled to room temperature, a saturated ammonium chloride solution (20mL) was added, extraction was performed with ethyl acetate (20mL × 3), the combined organic phases were washed successively with a saturated sodium chloride solution (20mL × 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) ═ 4/1] to give the title compound 2b (86mg, yield 36%) as a pale yellow oil.
MS(ESI,pos.ion)m/z:437.0[M+H]+。
Step 3)6- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy]Phenyl radical]Pyrimidine as one kind of food Pyridine-2, 4(1H,3H) -dione 2
6- [2, 6-dichloro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] -4-isopropylpyridazin-3 (2H) -one 2b (23mg,0.053mmol) was dissolved in acetonitrile (4mL), sodium iodide (32mg,0.21mmol) was added, then the nitrogen blanket was replaced, and trimethylchlorosilane (0.027mL,0.21mmol,0.86g/mL) was slowly added dropwise and reacted at room temperature for 4 hours. To the reaction solution were added saturated sodium thiosulfate solution (5mL) and water (5mL), extracted with ethyl acetate (10 mL. times.3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL. times.3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 2(19mg, yield 90%, HPLC purity: 92.69%) as a white solid.
MS(ESI,neg.ion)m/z:407.0[M-H]-；
1H NMR(400MHz,DMSO-d6)δ(ppm)11.45(s,1H),11.32(s,1H),7.66(s,1H),7.64(s,1H),7.60(s,1H),7.41-7.36(m,1H),5.40(s,1H),3.14-3.06(m,1H),1.24(d,J＝6.8Hz,6H)。
Activity test examples
First, the compound of the invention detects the activation activity of TR beta/TR alpha in a dual-luciferase reporter gene experiment
Test materials:
HEK293 cells, purchased from ATCC, Cat No. CRL-1573;
fugene HD transfection 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. After mixing pBind-TR beta/TR alpha (100 ng/. mu.l), pG5Luc (100 ng/. mu.l), FuGENE HD and Opti-MEM well and incubating at room temperature for 15min, HEK293 cells were digested with 0.25% Trypsin-EDTA,resuspend with whole culture medium, calculate cell density, adjust cell density to 500,000cells/ml, add transcription mixture and mix with cell suspension, plate in 96-well plate (100. mu.L/well), incubate 24h at 37 ℃. After 24h, test compounds were dissolved in DMSO and diluted 3-fold for 10 concentrations, then diluted with DMEM to 10% DMSO in compound solution, 5 μ L of compound was taken in a 96-well plate with a final DMSO concentration of 0.5% compound and the compound was co-cultured with the cells for 18 h. After 18h, firefly fluorescence signal and renilla fluorescence signal were detected using the Dual-Luciferase Reporter Assay System. The F/R ratio was calculated by dividing the firefly fluorescence signal (F) by the Renilla fluorescence signal (R), and EC was calculated by plotting using Graph Pad Prism software50The 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 of the compound of the invention to thyroid hormone receptor beta/alpha is detected
Test materials:
LanthaScreen TR-FRET thyoid Receptor beta activator Assay kit purchased 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, followed by dilution 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 384 well plates, 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 at room temperature for 1h in the dark. After 1h, fluorescence values (RFU) were read at excitation 520nm and emission 495nm using a 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. Rendering Using Graph Pad Prism 5 softwareCurve and calculate EC50The value is obtained. Test results show that the compound has stronger binding affinity to TR beta, particularly, the EC of the compound on the TR beta50The value was less than 0.5. mu.M. Meanwhile, the compound has good selectivity to TR beta, in particular to EC of the compound on TR alpha50Value and EC for TR β50The ratio of the values is greater than 10.
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 used experimental reagents and test articles are as follows: propranolol (internal standard)), methanol, ammonium acetate, K2EDTA (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 the solubility of each compound so that the compound was completely dissolved.
2. Design of animal experiments
Figure BDA0002858004110000311
Figure BDA0002858004110000321
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 sex 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 for use.
(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL Propranol stock solution was precisely aspirated and 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 μ L of plasma sample, adding 250 μ L of internal standard, and 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 of the invention
Test materials:
western diet: purchased from Research die, cat #: 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 8 weeks old: purchased from Jiangsu Jiejiaokang Biotech limited;
8 week old male db/db mice: purchased from Jiangsu Jiejiaokang Biotech limited.
A. Compound on OB/OB mouse nonalcoholic steatohepatitis (NASH) model induced by Western diet 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 performance during the experiment and mouse body weights were recorded weekly. 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 scored for NAS.
B. Efficacy of Compounds 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, 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 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 is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, 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 (14)

1. A compound which 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,
Figure FDA0002858004100000011
wherein the content of the first and second substances,
y is-O-, -C (═ O) -, -CH (OH) -, -CH (CH)3)-、-C(CH3)2-or-S-;
R4a、R4b、R4cand R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylthio radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl or cyano C1-6An alkyl group;
ring Cy is
Figure FDA0002858004100000012
U1Is CRaOr N; u shape2Is CRbOr N; u shape3Is CRcOr N;
R1、R2and together with the atoms to which they are attached form a 3-8 atom heterocycle, wherein said 3-8 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdSubstituted;
R0and R3Each independently is H, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene radicalWherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-4Alkylene, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-4Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-4Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-8A carbocyclic ring or a heterocyclic ring of 3 to 8 atoms in which said C3-8The carbocycle and the heterocycle of 3 to 8 atoms are each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Haloalkoxy, C1-6Alkoxy or C1-6An alkylamino group;
w is
Figure FDA0002858004100000021
Figure FDA0002858004100000022
Each R5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -C (═ O) -C1-6Alkoxy, -C (═ O) -C1-6Alkyl, -C (═ O) -C1-6Alkylamino, -S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkylamino radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl or cyano C1-6An alkyl group;
n is 0, 1,2,3 or 4.
2. The compound of claim 1, wherein W is
Figure FDA0002858004100000023
Figure FDA0002858004100000024
3. The compound of claim 1 or 2, wherein R is1、R2And together with the atoms to which they are attached form a 5-6 atom heterocycle, wherein the 5-6 atom heterocycle is unsubstituted or substituted with 1,2,3, or 4RdAnd (4) substituting.
4. The compound of claim 1, wherein R is1、R2And together with the atoms to which they are attached form pyrrolidine, pyrazolidine, 1, 3-oxazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperazinePyridin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazinan-2-one, 1-dioxo-1, 2-thiazine, or 4H-1, 3-oxazin-6- (5H) -one, wherein said pyrrolidine, pyrazolidine, 1, 3-oxazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1,2,3, 6-tetrahydropyridine, 5, 6-dihydro-4H-1, 3-oxazine, morpholin-3-one, piperidin-2-one, thiomorpholin-3-one, 5, 6-dihydropyridin-2 (1H) -one, Oxazolidin-2-one, pyrrolidin-2-one, 1, 3-oxazinan-2-one, 1-dioxo-1, 2-thiazinan and 4H-1, 3-oxazin-6- (5H) -one are each independently unsubstituted or substituted with 1,2,3 or 4RdAnd (4) substituting.
5. The compound of claim 1, wherein each R is5Independently H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3Methylamino, ethylamino, methoxy, ethoxy, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.
6. The compound of claim 1, wherein R is0And R3Each independently is H, deuterium, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2、-SH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C1-2Alkylene, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-2Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C1-2Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-2Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C1-2Alkylene is each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdTogether with the carbon atom to which they are attached form C3-6A carbocyclic ring or a heterocyclic ring of 5 to 6 atoms in which said C3-6The carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted by 1,2 or 3RyAnd (4) substituting.
7. The compound of claim 1, wherein R is0And R3Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH＝CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CHF2、-CH2F、-CH2CF3、-CH2CHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
Ra、Rband RcEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, AAlkyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RyGet itGeneration;
each RdIndependently deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-or pyrrolyl-CH2-, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH ═ CH2、-CH2CH＝CH2、-CH＝CHCH3-C.ident.CH, methoxy, ethoxy, methylamino, -CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5 to 6 atoms) -C1-2Alkylene, phenyl-CH2-, phenyl-CH2CH2-, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, isoxazolyl-CH2-, pyridinyl-CH2-and pyrrolyl-CH2Each independently unsubstituted or substituted by 1,2 or 3RySubstituted;
or 2R bound to the same carbon atomdAnd together with the carbon atom to which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane or heterocycle of 5-6 atoms, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane and heterocycle of 5-6 atoms are each independently unsubstituted or substituted with 1,2 or 3RyAnd (4) substituting.
8. The compound of claim 1, each RyIndependently deuterium, F, Cl, Br, I, -CN, -OH, -NO2、-COOH、-OH、-NH2、-SH、-C(＝O)-OCH3、-C(＝O)-OCH2CH3、-C(＝O)-OCH(CH3)2、-C(＝O)-OCH2CH2CH3、-C(＝O)-O(CH2)3CH3、-C(＝O)-OCH2CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-NHCH3、-C(＝O)-N(CH3)2、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-NHCH3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Methoxy, ethoxy, methylamino or ethylamino.
9. The compound of claim 1, wherein R is4a、R4b、R4cAnd R4dEach independently is H, deuterium, F, Cl, Br, I, -CN, -NO2、-COOH、-OH、-NH2-SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2Hydroxymethyl, aminomethyl or cyanomethyl.
10. The compound of claim 1, having one of the following structures:
Figure FDA0002858004100000051
Figure FDA0002858004100000061
Figure FDA0002858004100000062
or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, optionally further comprising pharmaceutically acceptable adjuvants.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for agonising a thyroid hormone receptor; or for preventing, treating or ameliorating a disease mediated by thyroid hormone receptor activation.
13. The use of claim 12, wherein the thyroid hormone receptor is thyroid hormone beta receptor.
14. The use of claim 12, wherein the disease mediated by thyroid hormone receptor activation is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity, diabetes, a metabolic disorder, a lipid metabolism disorder, 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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