CN113045551B - Compound serving as thyroid hormone beta receptor agonist and application thereof - Google Patents

Compound serving as thyroid hormone beta receptor agonist and application thereof

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CN113045551B
CN113045551B CN202011552018.4A CN202011552018A CN113045551B CN 113045551 B CN113045551 B CN 113045551B CN 202011552018 A CN202011552018 A CN 202011552018A CN 113045551 B CN113045551 B CN 113045551B
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alkylene
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CN113045551A (en
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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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Guangdong HEC Pharmaceutical
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Abstract

The present invention relates to a compound as thyroid hormone beta receptor agonist and uses thereof, and further relates to a pharmaceutical composition comprising the compound. The compound or the pharmaceutical composition can be used for preparing medicines for preventing, treating or relieving diseases mediated by thyroid hormone beta receptor activation, and especially for preparing medicines for treating non-alcoholic fatty liver diseases.

Description

Compound serving as thyroid hormone beta receptor agonist and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound serving as a thyroid hormone beta receptor agonist and application thereof, and further relates to a pharmaceutical composition containing the compound. The invention further relates to the use of the compounds and pharmaceutical compositions in the manufacture of a medicament for the prevention, treatment or alleviation of diseases mediated by activation of the thyroid hormone beta receptor, in particular in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.
Background
Thyroid hormone (thyroid hormone, TH) has an extremely important role in growth, differentiation, development and maintenance of metabolic balance. Thyroid hormone is synthesized by the thyroid gland and secreted into the circulatory system in two major forms, triiodothyronine (T3) and tetraiodothyronine (T4). While T4 is the predominant form secreted by the thyroid gland, T3 is the physiologically more active form. T4 is converted to T3 by a tissue-specific deiodinase that is present in all tissues but is primarily present in the liver and kidney.
The physiological effects of TH are mainly through thyroid hormone receptors (thyroid hormone receptor, TR). TR is a member of the nuclear receptor superfamily, a ligand T3-induced transcription factor, and is at the heart in mediating the action of ligand T3.TR is located primarily in the nucleus and forms heterodimers with retinoic acid X receptor (retinoid X receptor, RXR) and other nuclear receptors that bind to thyroid hormone response elements (thyroid hormoneresponse element, TRE) in the target gene promoter region, thereby regulating gene transcription. There are two subtypes of TR: TR alpha and TR beta. TR alpha can be further divided into TR alpha 1 and TR alpha 2, and TR beta can be further divided into TR beta 1 and TR beta 2. Wherein only trα1, trβ1 and trβ2 are capable of binding to ligand T3.Trα mainly regulates heart rate, trβ plays a key role in controlling liver cholesterol metabolism and inhibiting Thyroid Stimulating Hormone (TSH) release, which may be associated with high expression of trβ in the liver and pituitary gland.
If side effects can be minimized or eliminated, thyroid hormone has certain therapeutic benefits (Paul M.Yen et.al.Physiological Reviews,Vol.81(3):pp.1097-1126(2001);Paul Webb et.al.Expert Opin.Investig.Drugs,Vol.13(5):pp.489-500(2004))., e.g., thyroid hormone can increase metabolic rate, oxygen consumption, and caloric production, thereby reducing body weight. Reducing body weight will improve co-morbidity associated with obesity with beneficial effects in obese patients, and may also have beneficial effects on glycemic control in obese patients with type 2 diabetes.
Thyroid hormone also reduces serum Low Density Lipoprotein (LDL) (Eugene Morkin et al journal of Molecular and Cellular Cardiology, vol.37: pp.1137-1146 (2004)). Hyperthyroidism has been found to be 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 thyroid hormone replacement therapy has been reported to reduce total cholesterol (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 hormone has been shown to have the beneficial effect (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)). of increasing HDL cholesterol and increasing the conversion of LDL to HDL by increasing the expression of apo a-1 (one of the main apolipoproteins of HDL) directly correlates with LDL cholesterol levels, thyroid hormone may also reduce the risk of atherosclerosis and other cardiovascular diseases through modulation of LDL and HDL. In addition, there is evidence that 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 the one hand, NAFLD patients have influence on the functions of converting, inactivating and the like of thyroid hormone, and can lead to the reduction of serum thyroid hormone level; on the other hand, the decrease of thyroid hormone level further causes lipid metabolism disorder and glucose metabolism disorder, and participates in NAFLD. Studies have shown that fatty liver formation in rats is induced by choline-methionine deficiency and reversal of fatty liver is observed after T3 re-feeding (Perra A, et al Faseb,2008,22 (8): 2981).
However, endogenous thyroid hormones are non-selective and there are 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 would open new approaches to treating patients with: such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, nonalcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related disorders and diseases.
Disclosure of Invention
The invention provides a compound with better agonistic activity to thyroid hormone beta receptor, and the compound and the composition thereof can be used for preparing medicines for preventing, treating or relieving nonalcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer of patients.
In one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (I),
Wherein,
Y is-O-, -C (=O) -, -CH (OH) -, -CH (CH 3)-、-C(CH3)2 -or-S-;
R 4a、R4b、R4c and R 4d are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl or cyano C 1-6 alkyl;
Cy is a ring
U 1 is CR a or N; u 2 is CR b or N; u 3 is CR c or N;
r 1、R2 and the atoms to which they are each attached together form a heterocyclic ring of 3 to 8 atoms, wherein the heterocyclic ring of 3 to 8 atoms is unsubstituted or substituted with 1,2,3 or 4R d;
R 0 and R 3 are each independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, c 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, Heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, c 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
R a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, c 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, c 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-4 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-4 alkylene group, a, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, wherein the C 1-6 alkyl group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
Or 2R d attached to the same carbon atom and taken together with the carbon atom to which they are attached form a C 3-8 carbocycle or a 3-8 atom heterocycle, wherein the C 3-8 carbocycle and 3-8 atom heterocycle are each independently unsubstituted or substituted with 1,2 or 3R y;
Each R y is independently deuterium, F, cl, br, I, -CN, -OH, -NO 2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6 alkoxy, -C (=o) -C 1-6 alkyl, -C (=o) -C 1-6 alkylamino, -S (=o) 2-C1-6 alkyl, -S (=o) 2-C1-6 alkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, or C 1-6 alkylamino;
W is
Each R 5 is independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (=o) -C 1-6 alkoxy, -C (=o) -C 1-6 alkyl, -C (=o) -C 1-6 alkylamino, -S (=o) 2-C1-6 alkyl, -S (=o) 2-C1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, or cyano C 1-6 alkyl;
n is 0,1, 2, 3 or 4.
In some embodiments, W is
In some embodiments, R 1、R2 and the atoms to which they are each attached together form a heterocyclic ring of 5-6 atoms, wherein the heterocyclic ring of 5-6 atoms is unsubstituted or substituted with 1,2,3, or 4R d.
In some embodiments, R 1、R2 and the atoms to which they are each attached together 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-oxazinan-2-one, 1-dioxo-1, 2-thiazine or 4H-1, 3-oxazin-6- (5H) -one, wherein the 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-thiazine and 4H-1, 3-oxazin-6- (5H) -one are each independently unsubstituted or substituted with 1,2,3 or 4R d.
In some embodiments, each R 5 is independently H, deuterium, F, cl, br, I, -CN, -NO 2、-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-NHCH3、 methylamino, ethylamino, methoxy, ethoxy 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 hydroxymethyl, aminomethyl, carboxymethyl, or cyanomethyl.
In some embodiments, R 0 and R 3 are each independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, c 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-2 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-2 alkylene group, a, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
r a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, Wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-2 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-2 alkylene group, a, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
Each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, wherein the C 1-4 alkyl group, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
Or 2R d attached to the same carbon atom and taken together with the carbon atom to which they are attached form a C 3-6 carbocyclic ring or a heterocyclic ring of 5 to 6 atoms, wherein the C 3-6 carbocyclic ring and the heterocyclic ring of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y.
In some embodiments, R 0 and R 3 are each independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl 、-CH＝CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl 、-CH＝CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、 cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6-membered heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 - pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -and pyrrolyl-CH 2 -are each independently unsubstituted or substituted by 1, 2 or 3R y are substituted;
R a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -ch=ch 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl of 5-6 atoms) -C 1-2 alkylene, Phenyl, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, and, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CH=CH 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino, -CHF 2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -, and pyrrolyl-CH 2 -each independently being unsubstituted or substituted with 1,2, or 3R y;
Each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CH=CH 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, Ethoxy, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl consisting of 5-6 atoms) -C 1-2 alkylene, Phenyl, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, and, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CH=CH 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino, -CHF 2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -, and pyrrolyl-CH 2 -each independently being unsubstituted or substituted with 1,2, or 3R y;
Or 2R d attached to the same carbon atom and the carbon atom to which they are attached together form a cyclopropane, cyclobutane, cyclopentane, cyclohexane or a heterocycle of 5 to 6 atoms, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane and heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y.
In some embodiments, each R y is independently 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-NHCH3、 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 methoxy, ethoxy, methylamino, or ethylamino.
In some embodiments, R 4a、R4b、R4c and R 4d are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 hydroxymethyl, aminomethyl, or cyanomethyl.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound according to the invention, optionally further comprising a pharmaceutically acceptable adjuvant.
In another aspect, the invention relates to the use of a compound of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for agonizing thyroid hormone receptors; or for preventing, treating or alleviating diseases mediated by thyroid hormone receptor activation.
In some embodiments, the thyroid hormone receptor of the present invention is a thyroid hormone β receptor.
In some embodiments, the disease mediated by activation of thyroid hormone receptors of the present invention is a non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolic disorder, a 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 disease, non-alcoholic steatohepatitis-associated cryptogenic cirrhosis, or primary liver cancer.
The foregoing merely outlines certain aspects of the invention and is not limited to these aspects. These and other aspects will be described more fully below.
Detailed Description
The invention provides a compound with better agonistic activity to thyroid hormone beta receptor, a preparation method thereof, a pharmaceutical composition thereof and application thereof. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the scope of the present invention.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application. 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 application. The application is in no way limited to the methods and materials described herein, but rather is intended to be limited to the specific embodiments shown and described herein, in the event that one or more of such incorporated references, patents, and similar materials differ or conflict with the present application, including but not limited to the terms defined, the application of the terms, the techniques described, etc.
It should further be 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 sub-combination.
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, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, the general principles of organic chemistry may be found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 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" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
Unless otherwise indicated, the terms used in the specification and claims of the present invention have the following definitions.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted with … …". The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, an optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6 alkoxy, -C (=o) -C 1-6 alkyl, -C (=o) -C 1-6 alkylamino, -S (=o) 2-C1-6 alkyl, -S (=o) 2-C1-6 alkylamino, alkyl, alkoxy, 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 explicitly indicated otherwise, the description used in this disclosure of the manner in which "each … … is independently" and "… … is independently" and "… … is independently" are to be understood in a broad sense as meaning that the particular choices expressed between the same symbols in different groups do not affect each other, or that the particular choices expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 alkyl" particularly refers to independently disclosed C 1 alkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl; "3-8-atom-composed heterocyclic group" means a 3-atom-composed heterocyclic group, a 4-atom-composed heterocyclic group, a 5-atom-composed heterocyclic group, a 6-atom-composed heterocyclic group, a 7-atom-composed heterocyclic group and an 8-ring-atom-composed heterocyclic group.
In the various parts of the present specification, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited 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 enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Unless otherwise specified, an alkylene group contains 1 to 12 carbon atoms, i.e., a C 1-12 alkylene group. In some embodiments, the alkylene group contains 1 to 8 carbon atoms, i.e., a C 1-8 alkylene group; in other embodiments, the alkylene group contains 1 to 6 carbon atoms, i.e., a C 1-6 alkylene group; In some embodiments, the alkylene group contains 1 to 4 carbon atoms, i.e., a C 1-4 alkylene group; in some embodiments, the alkylene group contains 1 to 3 carbon atoms, i.e., a C 1-3 alkylene group; in some embodiments, the alkylene group contains 1 to 2 carbon atoms, i.e., a C 1-2 alkylene group. Examples include, but are not limited to, methylene (-CH 2 -), ethylene (including-CH 2CH2 -or-CH (CH 3) -), isopropylene (including-CH (CH 3)CH2 -or-C (CH 3)2 -)), n-propylidene (including-CH 2CH2CH2-、-CH(CH2CH3) -or-CH 2CH(CH3) -, and n-butyl (including -CH2(CH2)2CH2-、-CH(CH2CH2CH3)-、-CH2CH(CH2CH3)-、-CH2CH2CH(CH3)- or-CH (CH 3)CH(CH3) -) tert-butyl (including-CH (CH 3)2)-、-CH2CH(CH3)CH2 -or-CH 2C(CH3)2 -); pentylene (e.g., -CH 2(CH2)3CH2 -), hexylene (e.g., -CH 2(CH2)4CH2 -), Etc. wherein the alkylene group may be optionally substituted with one or more substituents described herein.
The term "alkyl" or "alkyl group" refers to a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, i.e., a C 1-10 alkyl group; in some embodiments, the alkyl group contains 1 to 8 carbon atoms, i.e., a C 1-8 alkyl group; in some embodiments, the alkyl group contains 1 to 6 carbon atoms, i.e., a C 1-6 alkyl group; in some embodiments, the alkyl group contains 1 to 4 carbon atoms, i.e., a C 1-4 alkyl group; in some embodiments, the alkyl group contains 1 to 2 carbon atoms, i.e., a C 1-2 alkyl group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (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 there is at least one carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, the alkenyl group comprises 2 to 8 carbon atoms, i.e., a C 2-8 alkenyl group; in some embodiments, the alkenyl group comprises 2 to 6 carbon atoms, i.e., a C 2-6 alkenyl group; in some embodiments, the alkenyl group comprises 2 to 4 carbon atoms, i.e., a C 2-4 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＝CHCH2CH3、-CH2CH＝CHCH3、-CH2CH2CH＝CH2、-CH＝C(CH3)2、-CH＝C(CH3)2、-CH2C(CH3)＝CH2)、 pentenyl (-CH2CH2CH2CH＝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 the like.
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, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, an alkynyl group contains 2 to 8 carbon atoms, i.e., a C 2-8 alkynyl group; in some embodiments, an alkynyl group contains 2 to 6 carbon atoms, i.e., a C 2-6 alkynyl group; in some embodiments, the alkynyl group contains 2 to 4 carbon atoms, i.e., a C 2-4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH 3), propargyl (-CH 2 C.ident.CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.
The term "alkoxy" means that the alkyl group is attached to the remainder 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., a C 1-20 alkoxy group; in some embodiments, the alkoxy group contains 1 to 10 carbon atoms, i.e., a C 1-10 alkoxy group; in some embodiments, the alkoxy group contains 1 to 8 carbon atoms, i.e., a C 1-8 alkoxy group; in some embodiments, the alkoxy group contains 1 to 6 carbon atoms, i.e., a C 1-6 alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., a C 1-4 alkoxy group; in some embodiments, the alkoxy group contains 1 to 3 carbon atoms, i.e., a C 1-3 alkoxy group; in some embodiments, the alkoxy group contains 1 to 2 carbon atoms, i.e., a C 1-2 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-propyloxy, -OCH 2CH2CH3), i-propyloxy (i-PrO, i-propyloxy, -OCH (CH 3)2), 1-butoxy (n-BuO, n-butoxy, -OCH 2CH2CH2CH3), 2-methyl-l-propyloxy (i-BuO, i-butoxy, -OCH 2CH(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 3995), 3-methyl-2-butoxy (-OCH (CH 3)CH(CH3)2), 3-methyl-l-butoxy (-OCH 2-methyl-butoxy), 585, and the like.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" and denotes that the amino groups are each independently substituted with one or two alkyl groups having the definition set forth herein. Wherein the alkylamino group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkylamino group is an alkylamino group wherein one or two C 1-6 alkyl groups are attached to the nitrogen atom, i.e., a C 1-6 alkylamino group; in some embodiments, the alkylamino group is an alkylamino group wherein one or two C 1-4 alkyl groups are attached to the nitrogen atom, i.e., a C 1-4 alkylamino group; in some embodiments, the alkylamino group is an alkylamino group in which one or two C 1-2 alkyl groups are attached to the nitrogen atom, i.e., a C 1-2 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), t-butylamino (N-t-butylamino), and the like.
The term "alkylthio" means that the alkyl group is attached to the remainder of the molecule through a sulfur atom, i.e. -S-alkyl, wherein the alkyl group has the meaning as described herein, wherein the alkylthio group may be optionally substituted with one or more substituents as described herein. In some embodiments, the alkylthio group contains 1 to 20 carbon atoms, i.e., a C 1-20 alkylthio group; in some embodiments, the alkylthio group contains 1 to 10 carbon atoms, i.e., a C 1-10 alkylthio group; in some embodiments, the alkylthio group contains 1 to 8 carbon atoms, i.e., a C 1-8 alkylthio group; in some embodiments, the alkylthio group contains 1 to 6 carbon atoms, i.e., a C 1-6 alkylthio group; in some embodiments, the alkylthio group contains 1 to 4 carbon atoms, i.e., a C 1-4 alkylthio group; in some embodiments, the alkylthio group contains 1 to 3 carbon atoms, i.e., a C 1-3 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., a C 1-10 haloalkyl; in some embodiments, the haloalkyl group contains 1 to 8 carbon atoms, i.e., a C 1-8 haloalkyl; in some embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., a C 1-6 haloalkyl; in some embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., a C 1-4 haloalkyl; in some embodiments, the haloalkyl group contains 1 to 3 carbon atoms, i.e., a C 1-3 haloalkyl; in some embodiments, the haloalkyl group contains 1 to 2 carbon atoms, i.e., a C 1-2 haloalkyl. Examples of haloalkyl include, but are not limited to, fluoromethyl (-CH 2 F), difluoromethyl (-CHF 2), trifluoromethyl (-CF 3), fluoroethyl (-CHFCH 3,-CH2CH2 F), difluoroethyl (-CF 2CH3,-CFHCFH2,-CH2CHF2), perfluoroethyl, fluoropropyl (-CHFCH 2CH3,-CH2CHFCH3,-CH2CH2CH2 F), difluoropropyl (-CF2CH2CH3,-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 halo 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 to 6 carbon atoms, i.e., a C 1-6 haloalkoxy group; in some embodiments, the haloalkoxy group contains 1 to 4 carbon atoms, i.e., a C 1-4 haloalkoxy group; in some embodiments, the haloalkoxy group contains 1 to 3 carbon atoms, i.e., a C 1-3 haloalkoxy group; in some embodiments, the haloalkyl group contains 1 to 2 carbon atoms, i.e., a C 1-2 haloalkoxy group. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy (-OH) groups, 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, the hydroxyalkyl group described herein refers to a C 1-6 alkyl group substituted with one or more hydroxy (-OH), i.e., hydroxy C 1-6 alkyl; in some embodiments, a hydroxyalkyl group refers to a C 1-4 alkyl group substituted with one or more hydroxy (-OH), i.e., hydroxy C 1-4 alkyl; in some embodiments, a hydroxyalkyl group refers to a C 1-2 alkyl group substituted with one or more hydroxy (-OH), i.e., a hydroxyc 1-2 alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH 2 OH), hydroxyethyl (e.g., 2-hydroxyethyl), hydroxy n-propyl (e.g., -CH 2CH2CH2 OH), and the like.
The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups (-NH 2) having the meaning described herein, wherein the aminoalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, an aminoalkyl group as described herein refers to a C 1-6 alkyl group substituted with one or more amino groups (-NH 2), i.e., an amino C 1-6 alkyl group; in some embodiments, an aminoalkyl group refers to a C 1-4 alkyl group substituted with one or more amino groups (-NH 2), i.e., an amino C 1-4 alkyl group; in some embodiments, an aminoalkyl group refers to a C 1-2 alkyl group substituted with one or more amino groups (-NH 2), i.e., an amino C 1-2 alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2NH2), diaminomethyl (-CH (NH 2)2), aminoethyl (e.g., 2-aminoethyl), amino-n-propyl (e.g., -CH 2CH2CH2NH2), and the like.
The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano (—cn) groups, 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, cyanoalkyl groups described herein refer to C 1-6 alkyl substituted with one or more cyano (-CN), i.e., cyano C 1-6 alkyl; in some embodiments, cyanoalkyl groups refer to C 1-4 alkyl substituted with one or more cyano (-CN), i.e., cyanoc 1-4 alkyl; in some embodiments, cyanoalkyl groups refer to C 1-2 alkyl substituted with one or more cyano (-CN), i.e., cyanoc 1-2 alkyl. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH 2 CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxyl groups (-COOH), which have the meaning described herein, wherein the carboxyalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, a carboxyalkyl group as described herein refers to a C 1-6 alkyl group substituted with one or more carboxyl groups (-COOH), i.e., a carboxyl C 1-6 alkyl group; in some embodiments, a carboxyalkyl group refers to a C 1-4 alkyl group substituted with one or more carboxyl groups (-COOH), i.e., a carboxyl C 1-4 alkyl group; in some embodiments, a carboxyalkyl group refers to a C 1-2 alkyl group substituted with one or more carboxyl groups (-COOH), i.e., a carboxyl C 1-2 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, wherein said cycloalkyl group is optionally substituted with substituents described herein, having one or more points of attachment to the remainder of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, i.e., C 3-10 cycloalkyl; in some embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, i.e., C 3-8 cycloalkyl; in some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, i.e., C 3-6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "consisting of m atoms," where m is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is m. For example, piperidinyl is a 6-atom heterocyclyl group, while furyl is a 5-atom heteroaryl group. As another example, "heterocyclyl consisting of 3-8 atoms" refers to heterocyclyl groups consisting of 3, 4, 5, 6, 7, or 8 atoms.
The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 atoms, at least one of which is selected from the group consisting of nitrogen, sulfur, oxygen and phosphorus atoms and the like, wherein said heterocyclyl is non-aromatic and free of any aromatic ring, and wherein said ring system has one or more points of attachment to the remainder of the molecule. Wherein the heterocyclyl group may be optionally substituted with one or more substituents described herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclyl groups include bridged bicyclic heterocyclyl groups, fused bicyclic heterocyclyl groups, and spiro bicyclic heterocyclyl groups. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH 2 -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. In some embodiments, the heterocyclyl is a ring system consisting of 3 to 10 ring atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5 to 10 ring atoms; in some embodiments, heterocyclyl is a ring system consisting of 5 to 8 ring atoms; in some embodiments, the heterocyclyl is a ring system of 6 to 8 ring atoms; in some embodiments, the heterocyclyl is a ring system of 5-6 ring atoms, i.e., a heterocyclyl of 5-6 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 3-6 ring atoms, i.e., a heterocyclyl consisting 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, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, 1, 3-oxazolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, oxaheptanyl, thietanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridinyl (e.g., 1,2,3, 6-tetrahydropyridinyl), 5, 6-dihydro-4H-1, 3-oxazin, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, 1, 3-oxazolidinyl, and the like. Examples of the substitution of the-CH 2 -group in the heterocyclic group 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-oxazin-2-one, 4H-1, 3-oxazin-6- (5H) -one. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholinyl, 1-dioxo-1, 2-thiazine alkyl. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, and the like.
The term "aryl" means a monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring system 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 one or more attachment points are attached to the remainder of the molecule. Wherein the aryl group may be optionally substituted with one or more substituents described herein. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracenyl, among others.
The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic aromatic systems containing 5-10 ring atoms, wherein at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, wherein at least one ring system is aromatic, and wherein the heteroaryl has one or more attachment points to the remainder of the molecule. Wherein the heteroaryl group may be optionally substituted with one or more substituents described herein. Unless otherwise indicated, the heteroaryl group may be attached to the remainder of the molecule (e.g., the host structure in the formula) at any reasonable point (which may be C in CH, or N in NH). When a heteroaryl group is present as a-CH 2 -group, the-CH 2 -group may optionally be replaced by a-C (=o) -. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-7 atoms comprising 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 comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a 5 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in some embodiments, heteroaryl is a 6 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl (2-furyl, 3-furyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl), 5-thiazolyl), tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), thienyl (2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2, 5-thiodiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic or tricyclic groups are also included, but are 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), phenoxathianyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl.
The term "cycloalkyl-alkylene" means that the cycloalkyl group is attached to the remainder of the molecule through an alkylene group, wherein cycloalkyl and alkylene have the meanings described herein. The cycloalkyl-alkylene groups may be optionally substituted with one or more substituents described herein. As used herein, "C 3-6 cycloalkyl-C 1-4 alkylene" means that the C 3-6 cycloalkyl group is attached to the remainder of the molecule via a C 1-4 alkylene group. As used herein, "C 3-6 cycloalkyl-C 1-2 alkylene" means that the C 3-6 cycloalkyl group is attached to the remainder of the molecule via a C 1-2 alkylene group. Examples include, but are not limited to, cyclopropyl-CH 2 -, cyclopropyl-CH 2CH2 -, cyclobutyl-CH 2 -, cyclobutyl-CH 2CH2 -, cyclopentyl-CH 2 -, cyclopentyl-CH 2CH2 -, cyclohexyl-CH 2 -, cyclohexyl-CH 2CH2 -, and the like.
The term "heterocyclyl-alkylene" means that the heterocyclyl group is attached to the remainder of the molecule through an alkylene group, wherein heterocyclyl and alkylene have the meanings described herein. The heterocyclyl-alkylene groups may be optionally substituted with one or more substituents described herein. As used herein "(5-6 atom-containing heterocyclic) -C 1-4 alkylene" means that the 5-6 atom-containing heterocyclic group is attached to the remainder of the molecule through a C 1-4 alkylene group. As used herein "(5-6 atom-containing heterocyclic) -C 1-2 alkylene" means that the 5-6 atom-containing heterocyclic group is attached to the remainder of the molecule through a C 1-2 alkylene group. Examples include, but are not limited to, tetrahydropyranyl-CH 2 -, tetrahydropyranyl-CH 2CH2 -, tetrahydrofuranyl-CH 2 -, tetrahydrofuranyl-CH 2CH2 -, pyrrolidinyl-CH 2 -, piperidinyl-CH 2 -, piperidinyl-CH 2CH2 -, morpholinyl-CH 2 -, morpholinyl-CH 2CH2 -, and the like.
The term "aryl-alkylene" means that the aryl group is attached to the remainder of the molecule through an alkylene group, wherein aryl and alkylene have the meanings described herein. The aryl-alkylene groups may be optionally substituted with one or more substituents described herein. For example, "C 6-10 aryl-C 1-4 alkylene" as used herein means that the C 6-10 aryl group is attached to the remainder of the molecule via a C 1-4 alkylene group. "C 6-10 aryl-C 1-2 alkylene" as used herein means that the C 6-10 aryl group is attached to the remainder of the molecule via a C 1-2 alkylene group. Examples include, but are not limited to, phenyl-CH 2 -, phenyl-CH 2CH2 -, naphthyl-CH 2 -, and the like.
The term "heteroaryl-alkylene" means that the heteroaryl group is attached to the remainder of the molecule through an alkylene group, wherein heteroaryl and alkylene have the meanings described herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents described herein. As used herein "(heteroaryl of 5-6 atoms) -C 1-4 alkylene" means that the heteroaryl of 5-6 atoms is attached to the remainder of the molecule through a C 1-4 alkylene group. As used herein "(heteroaryl of 5-6 atoms) -C 1-2 alkylene" means that the heteroaryl of 5-6 atoms is attached to the remainder of the molecule through a C 1-2 alkylene group. Examples include, but are not limited to, pyridinyl-CH 2 -, pyrrolyl-CH 2 -, pyrrolyl-CH 2CH2 -, quinolinyl-CH 2 -, thienyl-CH 2 -, furanyl-CH 2 -, pyrimidinyl-CH 2 -, pyridinyl-CH 2 -, imidazolyl-CH 2 -, isoxazolyl-CH 2 -, and the like.
The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state forms of S, N, and P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR T (like NR T,RT in N-substituted pyrrolidinyl is a substituent on N).
The term "halogen" refers to F, cl, br or I.
The term "nitro" refers to-NO 2.
The term "mercapto" refers to-SH.
The term "hydroxy" refers to-OH.
The term "amino" refers to-NH 2.
The term "cyano" refers to-CN.
The term "carboxylic acid" or "carboxyl" refers to-C (=o) OH or-COOH.
The term "carbonyl" means- (c=o) -.
The term "deuterium" refers to deuteration, i.e., 2 H.
As described herein, a ring system in which substituent R is attached to the central ring by a bond represents that 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 position on the pyrimidine ring that may be substituted may be optionally substituted with t R; for another example, formula b represents that substituent R may be substituted at any position on the pyrimidine ring that may be substituted, as shown in formulas b-1 through b-3:
As described herein, a ring system formed by a bond attached to the center of a ring represents that the bond may be attached to the remainder of the molecule at any available position on the ring system. For example, formula d represents that the pyrimidine ring may be attached to the remainder of the molecule via any possible attachment position, as shown in formulas d-1 to d-3:
The term "protecting group" or "PG" refers to a substituent group that is used to block or protect a particular functionality when other functional groups in a compound are reacted. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, and silyl, among others. "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-CH 2CH2SO2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature ：T W.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 breaks away from a larger molecule in a chemical reaction, which is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate, and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, hydroxyl groups, and the like.
The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.
The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers, and the like, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, anti-atherosclerosis agents, or lipid lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The term "prodrug" as used herein means 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 enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, 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 documents ：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series;Roche et al.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987;Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345.
The term "metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
The term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: berge et al, describe pharmaceutically 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, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
The term "nitroxide" refers to the oxidation of 1 or more than 1 nitrogen atom to form an N-oxide when the compound contains several amine functions. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, WILEY INTERSCIENCE, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method 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, for example methylene chloride.
Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched form, such as in 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. The substituents on the atoms having unsaturated double bonds may be present in cis- (Z) -or trans- (E) -form, if possible.
Thus, as described herein, the compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers or as a mixture thereof, for example as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or as a mixture thereof.
Any of the resulting isomer mixtures may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, based on the physicochemical differences of the components, for example by chromatography and/or fractional crystallization.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis (e.g Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd 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 invention also includes isotopically-labelled compounds of the invention which are identical to those recited in the invention except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H,3H,13C,14C,15N,16O,17O,31P,32P,36S,18F and 37 Cl.
The compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts of such compounds, are included within the scope of the invention. Isotopically-labeled compounds of the present invention, for example, radioisotopes such as 3 H and 14 C, may be used in drug and/or substrate tissue distribution assays for incorporation into the compounds of the present invention. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for ease of preparation and detection. In addition, substitution with larger mass numbers of isotopes such as deuterium, i.e., 2 H, may afford some therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
Stereochemical definitions and conventions used in the present invention follow substantially the definitions and conventions set forth in S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994. 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 (atropisomer) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. The 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 methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and non-corresponding isomer mixtures, 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 substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
Unless otherwise indicated, structures described herein are also meant to include all isomeric forms of such structures (e.g., enantiomers, diastereomers, atropisomers (atropisomer) and geometric (or conformational)) forms; 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 mixtures, diastereomeric mixtures, and geometric (or conformational) isomer mixtures of the compounds of the invention are all within the scope of the invention.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion 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" is also referred to as "cis-trans isomer" as an isomer resulting from the inability of a double bond (including olefinic double bonds, c=n double bonds, and n=n double bonds) or a single bond of a ring carbon atom to rotate freely.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject is also a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. 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" (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more particularly humans, including non-primates. In one embodiment, the subject is a non-human animal, such as a livestock (e.g., horse, cow, pig, or sheep) or a companion animal (e.g., dog, cat, guinea pig, or rabbit). In other embodiments, "patient" refers to a human.
In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
Description of the Compounds of the invention
The invention provides a compound with better agonistic 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 metabolic disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer. The invention also provides methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds and pharmaceutical compositions to prepare medicaments for treating the aforementioned disorders in mammals, particularly humans. Compared with the existing similar compounds, the compound not only has good pharmacological activity and selectivity, but also has excellent in-vivo metabolic dynamics property and in-vivo pharmacodynamics property. The preparation method of the compound is simple and feasible, and the process method is stable, thereby being suitable for industrial production. Therefore, the compound provided by the invention has better patentability than the existing similar compounds.
Specifically:
in one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (I),
Wherein, ring Cy, Y, W, R 4a、R4b、R4c and R 4d have 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, R 4a、R4b、R4c and R 4d are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyc 1-6 alkyl, aminoc 1-6 alkyl, or cyanoc 1-6 alkyl.
In some embodiments of the present invention, in some embodiments,Wherein R 0、R1、R2、R3、U1、U2 and U 3 have the definitions described herein.
In some embodiments, U 1 is CR a or N, wherein the R a has the definition described herein.
In some embodiments, U 2 is CR b or N, wherein the R b has the definition described herein.
In some embodiments, U 3 is CR c or N, wherein the R c has the definition described herein.
In some embodiments, R 1、R2 and the atoms to which they are each attached together form a heterocyclic ring of 3-8 atoms, wherein the heterocyclic ring of 3-8 atoms is unsubstituted or substituted with 1, 2, 3, or 4R d, wherein each R d has the definition set forth herein.
In some embodiments, R 0 and R 3 are each independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-4 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-4 alkylene group, a, Heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, c 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1,2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, R a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, c 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, Wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, c 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-4 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-4 alkylene group, a, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1,2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterium, or a salt thereof, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-4 alkylene, wherein the C 1-6 alkyl group, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
Or 2R d attached to the same carbon atom and taken together with the carbon atom to which they are attached form a C 3-8 carbocycle or a 3-8 atom heterocycle, wherein the C 3-8 carbocycle and 3-8 atom heterocycle are each independently unsubstituted or substituted with 1, 2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, each R y is independently deuterium, F, cl, br, I, -CN, -OH, -NO 2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-6 alkoxy, -C (=o) -C 1-6 alkyl, -C (=o) -C 1-6 alkylamino, -S (=o) 2-C1-6 alkyl, -S (=o) 2-C1-6 alkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, or C 1-6 alkylamino.
In some embodiments, W is Wherein each R 5 and n has the definition set forth in the present invention.
In some embodiments, each R 5 is independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (=o) -C 1-6 alkoxy, -C (=o) -C 1-6 alkyl, -C (=o) -C 1-6 alkylamino, -S (=o) 2-C1-6 alkyl, -S (=o) 2-C1-6 alkylamino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, or cyano C 1-6 alkyl.
In some embodiments, n is 0, 1,2, 3, or 4.
In some embodiments, W is
In some embodiments, W is
In some embodiments, R 1、R2 and the atoms to which they are each attached together form a heterocyclic ring of 5-6 atoms, wherein the heterocyclic ring of 5-6 atoms is unsubstituted or substituted with 1,2, 3, or 4R d, each R d having the definition set forth herein.
In some embodiments, R 1、R2 and the atoms to which they are each attached together 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-oxazinan-2-one, 1-dioxo-1, 2-thiazine or 4H-1, 3-oxazin-6- (5H) -one, wherein the 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-thiazine and 4H-1, 3-oxazin-6- (5H) -one are each independently unsubstituted or substituted with 1,2,3 or 4R d, each R d having the definition described herein.
In some embodiments, each R 5 is independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C (=o) -C 1-4 alkoxy, -C (=o) -C 1-4 alkyl, -C (=o) -C 1-4 alkylamino, -S (=o) 2-C1-4 alkyl, -S (=o) 2-C1-4 alkylamino, C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, or cyano C 1-4 alkyl.
In some embodiments, each R 5 is independently H, deuterium, F, cl, br, I, -CN, -NO 2、-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-NHCH3、 methylamino, ethylamino, methoxy, ethoxy 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 hydroxymethyl, aminomethyl, carboxymethyl, or cyanomethyl.
In some embodiments, R 0 and R 3 are each independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, c 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-2 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-2 alkylene group, a, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1,2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, R a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, Wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, A heterocyclic group having 5 to 6 atoms, a C 1-2 alkylene group, a C 6-10 aryl group, a C 6-10 aryl-C 1-2 alkylene group, a, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1,2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterium, or a salt thereof, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (heterocyclyl of 5 to 6 atoms) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C 1-2 alkylene, wherein the C 1-4 alkyl group, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, heterocyclyl of 5 to 6 atoms, (5-6 atom composition of heterocyclic) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, Heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 alkylene are each independently unsubstituted or substituted with 1, 2 or 3R y;
or 2R d attached to the same carbon atom and taken together with the carbon atom to which they are attached form a C 3-6 carbocycle or a heterocycle of 5 to 6 atoms wherein the C 3-6 carbocycle and the heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2 or 3R y, each R y having the definition set forth herein.
In some embodiments, R 0 and R 3 are each independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl 、-CH＝CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl 、-CH＝CH2、-CH2CH＝CH2、-CH＝CHCH3、-C≡CH、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、 cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6-membered heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 - pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -and pyrrolyl-CH 2 -are each independently unsubstituted or substituted by 1, 2 or 3R y, wherein each R y has the definition set forth herein.
In some embodiments, R a、Rb and R c are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -ch=ch 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (heterocyclyl of 5-6 atoms) -C 1-2 alkylene, Phenyl, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, and, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CH=CH 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino, -CHF 2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -and pyrrolyl-CH 2 -are each independently unsubstituted or substituted by 1, 2 or 3R y, Wherein each R y has the definition set forth in the present invention.
In some embodiments, each R d is independently deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -ch=ch 2、-CH2CH＝CH2、-CH＝CHCH3, -c≡ch, Methoxy, ethoxy, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 -, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 membered heterocyclyl) -C 1-2 alkylene, Phenyl, phenyl-CH 2 -, phenyl-CH 2CH2 -, furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, and, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -or pyrrolyl-CH 2 -, Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -CH=CH 2、-CH2CH＝CH2、-CH＝CHCH3, -C≡CH, methoxy, ethoxy, methylamino, -CHF 2、-CH2F、-CH2CF3、-CH2CHF2、-OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH 2 - Pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, (5-6 atom heterocyclyl) -C 1-2 -alkylene, phenyl-CH 2 -, phenyl-CH 2CH2 - Furyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, furyl-CH 2 -, thienyl-CH 2 -, imidazolyl-CH 2 -, pyrimidinyl-CH 2 -, isoxazolyl-CH 2 -, pyridinyl-CH 2 -, and pyrrolyl-CH 2 -each independently being unsubstituted or substituted with 1,2, or 3R y;
or 2R d attached to the same carbon atom and the carbon atom to which they are attached together form a cyclopropane, cyclobutane, cyclopentane, cyclohexane or a heterocycle of 5 to 6 atoms, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane and heterocycle of 5 to 6 atoms are each independently unsubstituted or substituted with 1,2 or 3R y, each R y having the definition set forth in the present invention.
In some embodiments, each R y is independently deuterium, F, cl, br, I, -CN, -OH, -NO 2、-COOH、-OH、-NH2、-SH、-C(＝O)-C1-4 alkoxy, -C (=o) -C 1-4 alkyl, -C (=o) -C 1-4 alkylamino, -S (=o) 2-C1-4 alkyl, -S (=o) 2-C1-4 alkylamino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, or C 1-4 alkylamino.
In some embodiments, each R y is independently 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-NHCH3、 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 methoxy, ethoxy, methylamino, or ethylamino.
In some embodiments, R 4a、R4b、R4c and R 4d are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2、-SH、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxyc 1-4 alkyl, aminoc 1-4 alkyl, or cyanoc 1-4 alkyl.
In some embodiments, R 4a、R4b、R4c and R 4d are each independently H, deuterium, F, cl, br, I, -CN, -NO 2、-COOH、-OH、-NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino 、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-OCF3、-OCHF2、 hydroxymethyl, aminomethyl, or cyanomethyl.
In another aspect, the invention relates to a structure of one of the following, or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
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 of the invention or a pharmaceutical composition of the invention for the preparation of a medicament for agonizing thyroid hormone receptors; or for preventing, treating or alleviating diseases mediated by thyroid hormone receptor activation.
In another aspect, the present invention relates to a method of agonizing a thyroid hormone receptor using a compound or pharmaceutical composition of the invention, or for preventing, treating or alleviating a disease mediated by thyroid hormone receptor activation, by administering to an individual in need thereof a therapeutically effective amount of the compound or pharmaceutical composition. Also, the above-mentioned compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for agonizing a thyroid hormone receptor, or for preventing, treating or alleviating a disease mediated by thyroid hormone receptor activation.
In some embodiments, the thyroid hormone receptor of the present invention is a thyroid hormone β receptor.
In some embodiments, the disease mediated by activation of thyroid hormone receptors described herein is a non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, a metabolic disorder, a lipid metabolic disorder, a 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 disease, non-alcoholic steatohepatitis-associated cryptogenic cirrhosis, or primary liver cancer.
The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay action, etc., will generally depend on the particular compound being administered, the patient, the particular disease or disorder and its severity, the route and frequency of administration, etc., and will be determined by the attending physician on a case-by-case basis. For example, in the case of administration of a compound or pharmaceutical composition provided herein by intravenous route, administration may be performed once a week or even at 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 used as intermediates for preparing and/or purifying the compounds of the present invention and/or for separating enantiomers of the compounds of the present invention.
Moreover, 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 inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include both solvated and unsolvated forms.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention relates to a pharmaceutical composition comprising a compound of the structure shown in the compounds or examples of the present invention, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs 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 invention and at least one pharmaceutically acceptable adjuvant. The amount of the compound in the pharmaceutical composition of the invention is effective to detectably agonize the thyroid hormone beta receptor 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 effects or side effects once administered to a patient. Standard pharmaceutical techniques may be employed. The pharmaceutical or pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants as described herein, including any solvents, diluents, liquid vehicles, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like .Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, as applied to the present invention, suitable for the particular intended dosage form, disclose various carriers for use in formulating pharmaceutically acceptable compositions and well known methods of making the same. In addition to conventional adjuvants which are incompatible with the compounds of the invention, for example, which may cause adverse biological effects or deleterious interactions with any of the other components of the pharmaceutically acceptable compositions, any of the other conventional adjuvants and their 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, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), starches cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution (ssolution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants according to the judgment of the formulator, anti-sticking agents, anti-blocking agents, and, coating agents, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
The compounds or compositions of the invention may be administered by any suitable means, and the compounds and pharmaceutically acceptable compositions described above may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), or 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 compound, 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, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable formulations may be formulated, for example, into sterile injectable aqueous or oleaginous suspensions using suitable dispersing or wetting agents and suspending agents according to known techniques. 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 odorless, non-volatile oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used to prepare injectables. For example, injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by the addition of sterilizing agents which are in the form of sterile solid compositions which are soluble or dispersible 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 down the absorption of the compounds by subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials, since the rate of absorption of a compound depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Or delayed absorption of parenterally administered compounds by dissolving or suspending the compounds in an oil vehicle. Or by forming a matrix of microcapsules of the compound in a biodegradable polymer such as polylactide-polyglycolide acid, the release rate of the compound may be controlled depending on the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating adjuvants, such as cocoa butter, polyethylene glycols or suppository waxes, 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 admixed with at least one inert, pharmaceutically acceptable adjuvant, such as sodium citrate or dicalcium phosphate and/or a) fillers or swelling agents, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as, for example, glycerol, d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as, for example, paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as, for example, kaolin and bentonite clay, and i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 similar type can also be used as fillers in soft and hard gel capsules using adjuvants such as lactose or milk sugar, high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
The active compounds may also be in microencapsulated form with one or more of the above-mentioned adjuvants. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances other than inert diluents, such as tabletting lubricants and other tabletting auxiliaries, for example 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.
Topical or transdermal administration forms of the compounds of the invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compounds are combined with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated as falling within the scope of the present invention. In addition, the present invention contemplates the use of skin patches that have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate may 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, bucally, vaginally, or by implantation of a kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the compositions of the invention may be an aqueous or oleaginous 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 odorless, non-volatile oil may be used, including synthetic mono-or diglycerides. In addition, as in particular in polyoxyethylated form, natural pharmaceutically acceptable oils, such as olive oil or castor oil, fatty acids, such as octadecenoic acid and its glyceride derivatives, are used for the preparation of injectables. 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 the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, spans, and other emulsifying agents or bioavailability enhancers 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, common carriers include, but are not limited to, lactose and starch. A lubricant, such as magnesium stearate, is also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavoring agents or coloring agents may also be added.
Or the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing 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, especially when the therapeutic target includes topical instillation in readily accessible areas or organs, including ocular, skin, or lower intestinal disorders. Suitable topical formulations are readily prepared for each of these regions or organs.
Local instillation into the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with 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. Adjuvants suitable for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petroleum jelly, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or creams 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, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH adjusted, sterile saline, or in particular as a solution in isotonic, pH adjusted, sterile saline, with or without a preservative 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 or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical arts 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.
Use of the compounds and pharmaceutical compositions of the invention
The compound or the pharmaceutical composition provided by the invention can be used for preparing medicines for exciting thyroid hormone receptors or preparing medicines for preventing, treating or relieving diseases mediated by thyroid hormone receptor activation.
The compounds or pharmaceutical compositions provided herein 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 thyroid hormone receptor activation, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described above, or a pharmaceutical composition thereof. Also, the above-mentioned compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
The thyroid hormone receptor is a thyroid hormone beta receptor.
The disease is nonalcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolic disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer, wherein the nonalcoholic fatty liver disease is nonalcoholic simple fatty liver disease, nonalcoholic fatty hepatitis, nonalcoholic fatty liver disease-related cryptogenic liver cirrhosis or primary liver cancer.
In addition to being beneficial for human treatment, the compounds of the present invention are also useful in veterinary treatment of pets, introduced species of animals and farm animals, including mammals, rodents and the like. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
An "effective amount", "effective therapeutic amount" or "effective dose" of a compound or pharmaceutically acceptable pharmaceutical composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions referred to herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly broad dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, and may be divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the invention can be any amount and any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
General synthetic and detection methods
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In this specification, a structure is dominant if there is any difference between a chemical name and a chemical structure.
In general, the compounds of the 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 are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known drugs in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The structure of the compound is determined by nuclear magnetic resonance (1H-NMR、13 C-NMR or/and 19 F-NMR). 1H-NMR、13C-NMR、19 The F-NMR chemical shifts (δ) are given in parts per million (ppm). 1H-NMR、13C-NMR、19 The F-NMR was performed using Bruker Ultrashield-400 NMR and Bruker AVANCE III HD 600 NMR, using deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD or MeOH-d 4) or deuterated dimethyl sulfoxide (DMSO-d 6). TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet ), m (multiplet, multiplet), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), brs (broadened singlet, broad singlet). Coupling constant J, in units of hertz (Hz).
Purification or resolution is typically performed using Novasep pump high performance liquid chromatography.
LC-MS was determined using an Agilen-6120 Quadragupole LC/MS mass spectrometer.
Column chromatography generally uses 300-400 mesh silica gel of Qingdao ocean chemical industry as a carrier.
The starting materials for the present invention are known and commercially available from Shanghai remote Company (SHANGHAI ACCELA Company), an Naiji Company (Energy Company), balanwei Company (J & K), tianjin Alfa Elisa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.
The nitrogen atmosphere means that the reaction bottle is connected with a nitrogen balloon or a steel kettle with the volume of about 1L;
The hydrogen atmosphere means that the 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;
Unless otherwise specified, in the examples, the solution means an aqueous solution;
unless otherwise specified in the examples, the reaction temperature was room temperature;
unless otherwise specified, the room temperature is 10℃to 40 ℃.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: the volume ratio of the methylene chloride to the methanol system, the methylene chloride to the ethyl acetate system, the petroleum ether to the ethyl acetate system and 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 systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of ammonia water, acetic acid and the like.
HPLC refers to high performance liquid chromatography;
HPLC was performed using Agilent 1260 high pressure liquid chromatograph (column: agilent ZORBAX Eclipse Plus C, 4.6 mm. Times.150 mm,3.5 μm);
HPLC test conditions: run time: column temperature 25 min: detection wavelength at 35 ℃): 210nm;245nm;
Mobile phase: phase A: 0.05% phosphoric acid solution B phase: acetonitrile; flow rate: 1.0ml/min;
The mobile phase gradient is shown in table a:
Table A
Time of Gradient of mobile phase A Gradient of mobile phase B
0min 90％ 10％
15min 10％ 90％
20min 10％ 90％
25min 90％ 10％
The LC/MS/MS system for analysis in the biological test comprises an Agilent 1200 series vacuum degassing furnace, a binary injection pump, an orifice plate automatic sampler, a column incubator and an Agilent G6430 three-stage four-rod mass spectrometer of an electrified spray ionization source (ESI). Quantitative analysis was performed in MRM mode, and parameters of MRM transitions are shown in table B:
Table B
Full scan 50～1400
Fracture voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 0.28MPa
Dryer flow rate 10L/min
Analysis Using an Agilent XDB-C18, 2.1X130 mm,3.5 μm column, 5. Mu.L of sample was injected. Analysis conditions: the mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4mL/min. The mobile phase gradient is shown in table C:
Table C
Time of Gradient of mobile phase B
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min Termination of
The test conditions for low resolution Mass Spectrometry (MS) data were: agilent 6120 Quadragole HPLC-MS (column model: zorbax SB-C18, 2.1X10 mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase: 5% -95% (CH 3 CN with 0.1% formic acid) in (H 2 O with 0.1% formic acid), UV detection at 210nm/254nm, electrospray ionization mode (ESI).
The following abbreviations are used throughout the present invention:
General synthetic method
Typical synthetic procedures for preparing the disclosed compounds are shown in the synthetic schemes below. Unless otherwise indicated, each U 1、U2、U3、R0, and R 5 have the definitions as described herein.
Synthesis scheme 1:
The compounds having the structure shown in the general formula (I-A) can be prepared by the general synthetic method described in synthetic scheme 1, and reference is made to examples for specific procedures. Firstly, reacting a compound (I-a) with a compound (I-b) under the action of alkali (such as potassium carbonate) to obtain a compound (I-c); nitro reduction 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); the compound (I-e) and the compound (I-f) undergo a coupling reaction to obtain a compound (I-g); demethylation of the compound (I-g) gives the target compound represented by the general formula (I-A).
Synthesis scheme 2:
The compounds having the structure shown in the general formula (I-B) can be prepared by the general synthetic method described in synthetic scheme 2, and reference is made to examples for specific procedures. Firstly, reacting a compound (I-e) with boric acid ester to obtain a compound (I-h); the compound (I-h) and the compound (I-I) undergo a coupling reaction to obtain a compound (I-j); demethylation of the compound (I-j) gives the target compound represented by the general formula (I-B).
Preparation example
Example 15- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1H-pyridazin-3-yl) oxy ] phenyl ] -1H-pyrimidine-2, 4-dione (Compound 1)
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 (0.20 g,0.64 mmol) was dissolved in concentrated sulfuric acid (1 mL), an aqueous solution (2 mL) of sodium nitrite (49 mg,0.70 mmol) was added dropwise thereto under an ice bath, and the mixture was reacted for 10 minutes, and an aqueous solution (2 mL) of potassium iodide (0.21 g,1.30 mmol) was added dropwise thereto, and the reaction was continued at room temperature for 4 hours. The reaction was added dropwise to a saturated sodium carbonate solution (40 mL), extracted with ethyl acetate (10 ml×2), and 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 (50 mg, 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-pyridazin-6-one 1c
3- (2, 6-Dichloro-4-iodo-phenoxy) -5-isopropyl-1H-pyridazin-6-one 1b (0.70 g,1.60 mmol), (2, 4-dimethoxypyrimidin-5-yl) phenylboronic acid (0.30 g,1.60 mmol), potassium carbonate (0.52 g,4.9 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex were dissolved in N, N-dimethylacetamide (5 mL) and reacted at 100℃for 6 hours. The reaction was cooled to room temperature, water (50 mL) was added, stirring was carried out for 15 minutes, filtration was carried out, and the cake was collected and dried in vacuo to give the title compound 1c (0.60 g, yield 83%) 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 ] -1H-pyrimidine-2, 4-dione 1
3- [2, 6-Dichloro-4- (2, 4-dimethoxypyrimidin-5-yl) phenoxy ] -5-isopropyl-1H-pyridazin-6-one 1c (50 mg,0.10 mmol), lithium chloride (40 mg,0.60 mmol) and p-toluenesulfonic acid (0.20 g,0.60 mmol) were dissolved in N, N-dimethylformamide (2 mL) and reacted at 120℃for 3 hours. The reaction solution was cooled to room temperature, a saturated sodium carbonate solution (10 mL) was added, the filtrate was collected, and the cake was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound 1 (23 mg, 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 2 6- [3, 5-dichloro-4- [ (5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy ] phenyl ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 2)
Step 1) 6- [2, 6-dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy ] -4-isopropylpyridazin-3 (2H) -one 2a
3- [2, 6-Dichloro-4-iodo-phenoxy ] -5-isopropyl-1H-pyridazin-6-one 1b (1.15 g,2.71 mmol) was dissolved in tetrahydrofuran (15 mL), a tetrahydrofuran solution of isopropyl magnesium chloride (2.8 mL,5.6mmol,2.0 mol/L) was added dropwise at-15℃followed by addition of 2-isopropoxy-4, 5-tetramethyl-1, 3, 2-dioxaborane (0.83 mL,4.06 mmol), and the reaction was carried out at-15℃for 16 hours. The reaction was quenched by addition of saturated ammonium chloride solution (25 mL) at room temperature, extracted with ethyl acetate (25 ml×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 (0.45 g, 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-isopropylpyridazin-3 (2H) one 2b
6- [2, 6-Dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy ] -4-isopropylpyridazin-3 (2H) -one 2a (0.22 g,0.52 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 4-bromo-2, 6-dimethoxy-pyrimidine (0.11 g,0.52 mmol), tetrakis triphenylphosphine palladium (29 mg,0.025 mmol) and potassium phosphate (0.22 g,1.04 mmol) were sequentially added and reacted at 100℃for 8 hours. The reaction solution was cooled to room temperature, a saturated ammonium chloride solution (20 mL) was added, extraction was performed with ethyl acetate (20 ml×3), and the combined organic phases were washed successively with a saturated sodium chloride solution (20 ml×3), dried over anhydrous sodium sulfate, and concentrated by suction filtration, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) =4/1 ] to give the title compound 2b (86 mg, 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 ] pyrimidine-2, 4 (1H, 3H) -dione 2
6- [2, 6-Dichloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy ] -4-isopropylpyridazin-3 (2H) -one 2b (23 mg,0.053 mmol) was dissolved in acetonitrile (4 mL), sodium iodide (32 mg,0.21 mmol) was added, then replaced with nitrogen protection, and trimethylchlorosilane (0.027 mL,0.21mmol,0.86 g/mL) was slowly added dropwise for reaction at room temperature for 4 hours. To the reaction solution were added a saturated sodium thiosulfate solution (5 mL) and water (5 mL), extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound 2 (19 mg, 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).
Test examples of Activity
1. Detection of TR beta/TR alpha agonistic activity of the inventive compounds in a dual luciferase reporter assay
Test materials:
HEK293 cells purchased from ATCC, cat No. CRL-1573;
fugene HD transfection reaagent, 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 whole medium. pBind-TR beta/TR alpha (100 ng/. Mu.l), pG5Luc (100 ng/. Mu.l), fuGENE HD and Opti-MEM were thoroughly mixed and incubated at room temperature for 15min, HEK293 cells were digested with 0.25% Trypsin-EDTA, resuspended in whole medium, the cell density was calculated, the cell density was adjusted to 500,000cells/ml, the transcription mixture was added to the cell suspension, and plated in 96-well plates (100. Mu.L/well) and incubated at 37℃for 24h. After 24h, test compounds were dissolved in DMSO and 3-fold diluted for a total of 10 concentrations, then diluted with DMEM to a 10% DMSO-containing compound solution, 5 μl of compound was plated in 96-well plates with a final DMSO concentration of 0.5% compound and the compound was co-cultured with cells for 18h. After 18h, the firefly fluorescence signal and the Renilla fluorescence signal were detected with Dual-Luciferase Reporter ASSAY SYSTEM. The firefly fluorescence signal (F) was divided by the Renilla fluorescence signal (R) to calculate the F/R ratio, which was plotted using GRAPH PAD PRISM software and the EC 50 value was calculated.
The test results show that: the compound has obvious agonistic activity and selectivity to TR beta.
2. In vitro binding activity detection of the inventive Compounds on thyroid hormone receptor beta/alpha
Test materials:
LANTHASCREEN TR-FRET Thyroid Receptor beta Coactivator Assay kit were purchased from Invitrogen, cat. No. PV4686;
LANTHASCREEN TR-FRET Thyroid Receptor alfa Coactivator Assay kit were purchased from Invitrogen, cat.No. PV4687.
The test method comprises the following steps:
the method was used for experiments using LANTHASCREEN TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit. Test compounds were dissolved in DMSO and 3-fold diluted, 10 total concentrations, followed by dilution with TR-FRET Coregulator Buffer C in the kit to a compound solution containing 2% DMSO. mu.L of a compound solution containing 2% DMSO was taken into 384-well plates, then 5. Mu.L of 4 XTR beta/alfa-LBD, 5. Mu.L of a mixture containing 0.4. Mu.M fluorescein-SRC2-2 and 8nM Tb anti-GST anti-ibody were added to each well, and after thoroughly mixing, incubated for 1h at room temperature in the dark. After 1h, fluorescence values (RFU) were read at excitation 520nm and emission 495nm using a PHERASTAR FSX microplate reader of BMG LABTECH. The TR-FRET ratio is calculated by dividing the emission signal at 520nm by the emission signal at 495 nm. Curves were plotted using GRAPH PAD PRISM software and EC 50 values were calculated. The test results show that the compound has stronger binding affinity to the TR beta, and particularly, the EC 50 value of the compound to the TR beta is less than 0.5 mu M. Meanwhile, the compound has good selectivity to TR beta, and specifically, the ratio of the EC 50 value of the compound to TR alpha to the EC 50 value of the compound to TR beta is more than 10.
The test results show that: the compound has stronger binding affinity and selectivity to TR beta.
3. Pharmacokinetic assay of the compounds of the invention
The following methods were used to determine the pharmacokinetics of the compounds of the invention.
Test materials:
Experimental reagent and test article used: propranolol (propranolol (internal standard)), methanol, ammonium acetate, K 2 EDTA (potassium ethylenediamine tetraacetate), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), kolliphorHS (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available;
SD rats: male, 180-220g,7-8 week old, purchased from Hunan Style laboratory animal Co.
The test method comprises the following steps:
1. Test sample preparation
The test solutions were prepared in 5% dmso+5% kolliphorhs15+90% physiological saline, specifically adjusted according to the dissolution of each compound, so that the compound was completely dissolved.
2. Design of animal experiment
3. Animal administration dosage scale
Group of Sex (sex) Number of animals Dosage for administration Concentration of drug administration Administration volume
I.v. intravenous. Male male 3 1mg/kg 1mg/mL 1mL/kg
P.O is orally administered. Male male 3 5mg/kg 1mg/mL 5mL/kg
4. Solution preparation
(1) Preparation of sample stock solution: precisely weighing a proper amount of test sample, dissolving with DMSO, diluting with acetonitrile to 1mg/mL, and shaking. And (5) placing the mixture at the temperature of minus 20 ℃ for standby.
(2) Preparing an internal standard substance solution: a quantity of 1mg/mL Propranolol stock solution was pipetted precisely and diluted with water to 100ng/mL.
5. Sample analysis
The method comprises the steps of treating a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis by adopting a multiple reaction ion monitoring (MRM) mode on a triple quadrupole tandem mass spectrometer, and carrying out concentration calculation on the result by using instrument quantitative software.
6. Plasma sample pretreatment
30. Mu.L of plasma sample was precisely aspirated, 250. Mu.L of internal standard was added and vortexed well. Extracting with 1mL MTBE once, centrifuging at 13,000rpm and 4 ℃ for 2min, sucking 800 μl of supernatant, volatilizing in a 96-well nitrogen blower, re-dissolving the residue with 150 μl methanol/water (v/v=50/50), mixing by vortex, and sampling with a sampling amount of 8 μl.
7. Preparation of a Standard sample
Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing plasma samples with the plasma concentrations of 3, 5, 10, 30, 100, 300, 1,000, 3,000, 5,000 and 10,000ng/mL, carrying out double-sample analysis according to the operation of pretreatment of the plasma samples, and establishing a standard curve.
8. Analysis method
The LC/MS method was used to determine the amount of test compound in the plasma of rats after administration of the different compounds.
9. Data processing
And calculating pharmacokinetic parameters by adopting WinNonlin 6.1 software and a non-atrioventricular model method.
The test results show that the compounds of the present invention exhibit excellent pharmacokinetic properties when administered intravenously or orally.
4. Pharmacodynamic evaluation of the Compounds of the invention
Test materials:
WESTERN DIET: purchased from RESEARCH DIET, cat No.: D12079B;
MCD diet: purchased from south Tong Talaofe feed technologies Co., ltd., product number: TP3006R;
ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: purchased from Roche, goods number was: 20764957322, 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 04404483190;
Male OB/OB mice at 8 weeks of age: purchased from Jiangsu Jizhikang biotechnology Co., ltd;
male db/db mice at 8 weeks of age: purchased from Jiangsu Jizhikang biotechnology Co.
A. pharmacodynamic evaluation of Compounds in WESTERN DIET diet-induced OB/OB mice non-alcoholic steatohepatitis (NASH) model
The OB/OB mice are leptin gene deletion mice, and the NASH model of the OB/OB mice induced by WESTERN DIET diet is a commonly used in vivo drug efficacy evaluation model of NASH. The experiment was started after 1 week of acclimatization. The OB/OB mice were fed WESTERN DIET with feed, the feed was changed three times a week (monday, three, five) and the mice were dosed orally once a day for 6 weeks starting at the fifth week after feeding, the whole experimental period being 10 weeks. The animals were monitored daily for baseline conditions during the experiment and mice weights were recorded weekly. After the experiment was completed, the mice were fasted overnight, and after anesthesia, the whole blood was collected by orbital blood collection, and centrifuged at 4℃and 4,000rpm for 10min to obtain serum, which was stored at-80 ℃. Serum was used for ALT, AST, ALP, TG, CHO, HDL, LDL and GLU assays. Mice were dissected, lived and weighed. The middle lobe of the liver was stored in EP tube at-80℃for determination of TG and CHO contents in the liver. After left lobe of liver was fixed in 10% formalin, HE staining was performed and NAS scoring was performed.
B. Pharmacodynamic evaluation of compounds in MCD diet-induced db/db mice non-alcoholic steatohepatitis (NASH) model
The db/db mice are leptin receptor gene deletion mice, and the NASH model of the db/db mice induced by MCD diet is a commonly used in vivo drug effect evaluation model of NASH. The experiment was started after 1 week of acclimatization. db/db mice were fed with MCD feed and the feed was changed three times per week (monday, wednesday, friday) and the mice were tested by mode of administration with molding, once a day for 8 weeks with a total test period of 8 weeks. The animals were monitored daily for baseline conditions during the experiment and mice weights were recorded weekly. After the end of the experiment, the mice were fasted overnight, and after anesthesia, the whole blood was collected by orbital blood collection, and centrifuged at 4℃and 4,000rpm for 10min to obtain serum, which was stored at-80 ℃. Serum was used for ALT, AST, ALP, TG, CHO, HDL, LDL and GLU assays. Mice were dissected, lived and weighed. The middle lobe of the liver was stored in EP tube at-80℃for determination of TG and CHO contents in the liver. After left lobe of liver was fixed in 10% formalin, HE staining was performed and NAS scoring was performed.
The test result shows that the compound can effectively reduce fat accumulation in liver, reduce inflammation and improve liver fibrosis.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (6)

1. A compound having one of the following structures:
Or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable adjuvant.
3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in the manufacture of a medicament for agonizing a thyroid hormone receptor; or for preventing, treating or alleviating diseases mediated by thyroid hormone receptor activation.
4. The use of claim 3, wherein the thyroid hormone receptor is a thyroid hormone beta receptor.
5. The use according to claim 3, wherein the disease mediated by activation of thyroid hormone receptor is non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, obesity, diabetes, metabolic disorders, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
6. The use according to claim 5, wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis-associated cryptogenic cirrhosis or primary liver cancer.
CN202011552018.4A 2019-12-27 2020-12-24 Compound serving as thyroid hormone beta receptor agonist and application thereof Active CN113045551B (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN101228135A (en) * 2005-07-21 2008-07-23 霍夫曼-拉罗奇有限公司 Pyridazinone derivatives as thyroid hormone receptor agonists
CN105408325A (en) * 2013-07-17 2016-03-16 大塚制药株式会社 Cyanotriazole compounds
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Publication number Priority date Publication date Assignee Title
CN101228135A (en) * 2005-07-21 2008-07-23 霍夫曼-拉罗奇有限公司 Pyridazinone derivatives as thyroid hormone receptor agonists
CN105408325A (en) * 2013-07-17 2016-03-16 大塚制药株式会社 Cyanotriazole compounds
WO2019240938A1 (en) * 2018-06-12 2019-12-19 Fronthera U.S. Pharmaceuticals Llc Thyroid hormone receptor agonists and uses thereof

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