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WO2016107602A1 - Dérivés hétérocycliques d'azote substitués et leur utilisation - Google Patents

Dérivés hétérocycliques d'azote substitués et leur utilisation Download PDF

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WO2016107602A1
WO2016107602A1 PCT/CN2015/100189 CN2015100189W WO2016107602A1 WO 2016107602 A1 WO2016107602 A1 WO 2016107602A1 CN 2015100189 W CN2015100189 W CN 2015100189W WO 2016107602 A1 WO2016107602 A1 WO 2016107602A1
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compound
alkyl
substituted
heteroaryl
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Chinese (zh)
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李德群
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Chengdu Bestchiralbio Limited-Liability Co
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Chengdu Bestchiralbio Limited-Liability Co
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present technology relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity, metabolic syndrome and Uses, compounds and compositions in anti-tumor.
  • hyperlipidemia including hypertriglyceridemia and hypercholesterolemia
  • hepatic steatosis hepatic steatosis
  • type II diabetes hepatic steatosis
  • hyperglycemia hepatic steatosis
  • insulin resistance obesity
  • metabolic syndrome Uses, compounds and compositions in anti-tumor.
  • Metabolic Syndrome is a pathological state in which a variety of metabolic components are abnormally aggregated. It is a complex metabolic disorder syndrome and is a risk factor for diabetes and cardiovascular and cerebrovascular diseases.
  • Cardio-cerebral vascular disease is the number one killer of human health. Its cause is very complicated. Hyperlipidemia is regarded as a very important risk factor by most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The incidence and mortality of the disease increased significantly, and there are reports in the literature that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, and myocardial infarction.
  • Hyperlipidemia is often explained by the fact that fat metabolism or abnormal function causes one or more lipids in plasma to be above normal. Hyperlipidemia is a systemic disease, usually referred to as serum total cholesterol (TC), triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is too low, modern medicine called dyslipidemia . Lipids are insoluble or sparingly soluble in water, so they must bind to proteins to form lipoproteins. Therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
  • TC serum total cholesterol
  • TG triglyceride
  • HDL-C high density lipoprotein cholesterol
  • Hyperlipidemia and cerebral infarction The increase of cholesterol in the blood is easy to form atherosclerotic plaque. When these plaques accumulate in the arterial wall, the arterial cavity will be narrowed, and the blood will flow into the corresponding part, which will cause kinetic energy defect. When it occurs in the cerebral blood vessels, it can cause cerebral infarction. Medical evidence: long-term lipid-lowering treatment can not only treat cerebral infarction, but also prevent cerebral infarction.
  • Coronary heart disease is also known as coronary atherosclerotic heart disease. Coronary artery is the main artery that supplies blood to the heart. If too much fat is deposited, it will cause arteriosclerosis, which will hinder blood flow, cause heart ischemia, and a series of symptoms, namely coronary heart disease. There are many risk factors for coronary heart disease, such as: high blood lipids, smoking, obesity, high blood pressure, lack of physical activity, diabetes, family history of coronary heart disease, etc. Among them, high blood lipids are one of the important risk factors for coronary heart disease. Therefore, the most basic treatment for coronary heart disease is to regulate blood lipids.
  • Fatty liver refers to the accumulation of fat in the liver, often accompanied by increased blood lipids.
  • the incidence of fatty liver is as high as 5-10%, and about 35% of adult patients with transaminase are fatty liver. Some severe patients can develop cirrhosis. Therefore, fatty liver treatment should also be treated with lipid-lowering.
  • Hyperlipidemia and diabetes Hypertension, hyperlipidemia and hyperglycemia are often referred to as “three highs” and are a major factor threatening the health of people with diabetes. The three are closely related, high blood lipids can aggravate the symptoms of diabetes, most diabetic patients with high blood lipids, more likely to cause stroke, coronary heart disease, limb necrosis, fundus lesions, kidney disease, neuropathy, etc., therefore, in addition to treatment of hyperglycemia in diabetic patients In addition, attention should be paid to regulating blood lipids, which is very important to reduce mortality and disability in diabetic patients.
  • Hyperlipidemia is defined as a dyslipidemia or dyslipidemia. Usually refers to the body's blood lipid concentration is beyond the normal range. Includes triglyceride (TG), serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) Level reduction With the in-depth study of hyperlipidemia and cardiovascular disease, people began to realize that hypolipidemicemia is very important for reducing the risk of cardiovascular disease.
  • TG triglyceride
  • TC serum total cholesterol
  • VLDL-C very low-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • the blood lipid-lowering drugs commonly used in the market mainly include statins, fibrates, niacins, and bile acid sequestrants.
  • Statins represent drugs: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and the like. These drugs are the fastest-developing lipid-lowering drugs in recent years, mainly to inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the serum total cholesterol (TC) synthesis pathway. The activity reduces TC synthesis; increases the number of low-density lipoprotein receptors, accelerates LDL degradation, and increases HDL content, which is beneficial to the clearance and transport of TC.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • statins the side effects are inevitable, such as: rhabdomyolysis, myositis and various enzyme activities in the liver, and some patients are not well adapted to the treatment of statins, more important The single statin treatment often does not achieve the desired results.
  • the fibrates represent drugs: clofibrate, gemfibrozil, fenofibrate, etc. After long-term clinical application, these drugs have been proven to be a class of drugs that are well tolerated and have good lipid-lowering effects.
  • its lipid-lowering pathway increases the activity of lipoprotein lipase, which increases the clearance of triglyceride (TG); lowers blood sugar, which makes the synthesis of glucose and free fatty acids tend to glucose. Lipid synthesis is reduced.
  • Niacin represents a drug: niacin, inositol niacin, acyclovir and the like. These drugs mainly inhibit the synthesis of triglyceride (TG) and very low density lipoprotein (VLD-L) by inhibiting the decomposition of fat and the formation of free fatty acids to reduce blood lipids.
  • TG triglyceride
  • VLD-L very low density lipoprotein
  • Inadequacies The effect of lowering blood lipids in diabetic patients is not obvious. Side effects such as: liver poisoning, high blood sugar is more obvious, and skin reactions such as skin plague and itching often occur.
  • the bile acid sequestrants represent drugs: Ezetimibe, polyunsaturated fatty acids, and the like. Such lipid-lowering drugs can be classified into two types: cholesterol absorption inhibitors and polyunsaturated fatty acids.
  • Cholesterol absorption inhibitor (Yibei Maibu): combined with bile acid, hinders the reabsorption of bile acid, thereby promoting the conversion of cholesterol into bile acid, which is excreted in the intestine and the drug.
  • LDL low-density lipoprotein
  • LDLR low-density lipoprotein receptor
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • PCSK9 is a serine protease that is mainly synthesized in the liver, which can reduce the amount of LDLR in hepatocytes. After binding to LDLR located on the cell surface, PCSK9 internalizes into cells and promotes LDLR degradation in lysosomes. Inhibition of PCSK9 activity increases the number of LDLRs and decreases plasma LDL levels.
  • PCSK9 inhibitors are an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
  • the current research work focuses on the development of biologic drugs (including protein drugs and long-chain nucleic acid drugs) (see table below), biologic drugs and small molecules. When the drug is used to treat the same disease, the biopharmaceutical is costly, and only a limited preparation method such as an injection preparation can be used. At present, no small molecule PCSK9 inhibitor has become a clinical drug candidate.
  • a series of patent applications for small molecule compounds of PCSK9 inhibitors are disclosed, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, WO2014150326, WO2014150395, WO2014139008, and the like.
  • the object of the present invention is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
  • Compound of formula V is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
  • Y is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • M is a nitrogen atom, or a carbon atom
  • W is a nitrogen atom, or a carbon atom
  • K is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)-, -C(O)O-, -C(O)NH-, -SO 2 O-, -SO 2 -, -SO 2 NH-, -P(O)R 5 R 6 ;
  • Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NH-, -SO 2 O-, -SO 2 NH-, or Z is not any atom (that is, the two groups associated with Z are directly linked by a chemical bond);
  • Ring X is a 3- to 10-membered ring, and the 3- to 10-membered ring X is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl Alkyl, heterocyclic or heterocyclylalkyl,
  • n 1, 2, 3;
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, including the compound (VI) of the formula
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halo, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkyne , cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • R 5 , R 6 , R 7 , R 8 , Z, M, K, q, t, ring X and ring Y are as described above.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VII),
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • R 5 , R 6 , R 7 , R 8 , R', R′′, K, Z, ring X, M, m, n, q, r are as described above.
  • the present invention relates to the compound of the formula (VII) wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halo, substituted or unsubstituted Substituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkyl base;
  • R 17 , R 18 , R 19 , R 20 , R 21 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R' , -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkane Oxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, also selected from :
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, -COOH, carboxylate, substituted or unsubstituted amino, silyl, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VIII),
  • Ring Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R', R′′, M, W, K, Z, m, n, p, q, s , t is as described above.
  • the present invention relates to the compound of the formula (VIII), wherein R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", Substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hetero A cycloalkyl or heterocyclylalkyl group, also selected from the group consisting of:
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, -COOH, carboxylate, substituted or unsubstituted amino, silyl, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including the compound (IX) of the formula
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are as described above;
  • R 22 , R 23 , R 24 , R 25 , R 26 are as described above;
  • R 5 , R 6 , R 7 , R 8 , K, Z, M, q are as described above.
  • the present invention relates to the compound (IX) of the formula: wherein:
  • K is -C(O)-, -SO 2 -, -SO 2 NH-, -P(O)R 5 R 6 ;
  • R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R ", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl , a heterocyclic or heterocyclylalkyl group, further selected from the group consisting of:
  • R 27 is selected from phenyl, C 1-6 alkyl, cyclo C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, Tolyl,
  • C 1-6 alkyl is optionally substituted by 0 to 13 substituents
  • thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
  • the pyridyl group is optionally substituted with from 0 to 4 substituents.
  • pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
  • the phenyl group is optionally substituted with from 0 to 5 substituents.
  • quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
  • the naphthyl group is optionally substituted with from 0 to 7 substituents.
  • substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, -COOH, carboxylate, substituted or unsubstituted amino, silyl, alkyl, alkoxy, alkenyl, alkynyl, ring
  • R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
  • the present invention relates to a compound selected from the following compounds, but is not limited to the following compound ranges:
  • the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, comprising the steps of:
  • X1 and X2 are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature, and X1 and X2 are in a certain alkaline state under a certain reaction temperature condition.
  • Compound V is obtained by coupling in the presence of a reagent.
  • the present invention relates to a compound of the formula (V), which comprises a pharmaceutical composition comprising a compound of any one and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition consisting of a compound of the formula (V), which comprises a compound which is administered to any one of a therapeutically effective amount of a patient in need of treatment.
  • the present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for lowering the lipid level of a patient's plasma and/or liver.
  • the present invention relates to a compound of any one of the compounds represented by the general formula (V) for use in the treatment of hyperlipemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, metabolic syndrome, antitumor drugs. the use of.
  • the present invention relates to the use of any one of the compounds of the general formula (V) for the preparation of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
  • the present invention relates to a compound of the formula (V), and the compounds disclosed herein have the following beneficial effects:
  • the small molecule compound of the general formula (V) disclosed in the present invention is expected to be a new generation of lipid-lowering drug in inhibiting the expression of PCSK9 gene, increasing the expression of LDLR and enhancing the uptake of hepatocytes to LDL.
  • PCSK9 inhibitors as lipid-lowering drugs is an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
  • biologic drugs including protein drugs and long-chain nucleic acid drugs.
  • PCSK9 inhibitors have been developed. Clinical drug candidates. The following table:
  • the biopharmaceutical is expensive, and only a limited preparation method such as an injection preparation can be used, and the small molecule drug has the advantages of low manufacturing cost, various preparation methods, and the like, and the present invention discloses
  • the small molecule compound of the general formula (V) exhibits significant inhibition of PCSK9 gene expression at the cellular level and enhances the significant function of hepatocytes to uptake of LDL, and is expected to have a new generation of lipid-lowering drugs.
  • the formulation of small molecule drugs is more extensive than that of biomacromolecules, which is conducive to the development of a variety of drug formulations for later drug development. Compared to biomacromolecular drugs, it can be provided for a wide range of formulation types. satisfy people's demands.
  • the compound of the formula (V) disclosed in the present invention has a novel structure and a novel knot as compared with a compound disclosed in the prior patent document which targets a target of PCSK9.
  • the structure is expected to become a candidate drug with a novel mechanism of action for PCSK9, and eventually become a new generation of lipid-lowering drugs with novel mechanisms of action.
  • Patent Application WO2014139008 reports a class of small molecule compounds, some of which are mainly characterized by the inclusion of "borate and boric acid” structural fragments, although multiple bone marrows are currently available.
  • Tumor treatment drug - bortezomib containing “boric acid” structural fragments
  • the application of "boric acid” drugs in non-tumor treatment areas is still limited, mainly because Potential neurotoxic side effects of boron drugs, as well as their potential for "irreversible binding" to biological organisms (Chem. Res. Toxicol., 2013, 26(4), pp 608-615), the chemical properties of the drug
  • the potential “carcinogenicity” that may be caused by molecular design, “reproductive toxicity” has been widely recognized by pharmaceutical chemists.
  • the compound of the formula (V) disclosed in the present invention has novel structure and novel unique structural features, and indicates that the compound disclosed in the present invention
  • the novel molecular structure features may bring unexpected "drug-like characteristics", and it is expected to become a candidate drug with a novel mechanism of action for PCSK9, and eventually become a new generation of lipid-lowering drugs with novel mechanism of action.
  • the compound of the formula (V) disclosed in the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the cost is low.
  • the small molecule compound of the formula (V) disclosed in the present invention is mainly prepared by using a commercially available intermediate, and then subjected to a fragment coupling reaction by a simple chemical reaction.
  • the target compound can be prepared, for example, by using a commercially available starting material having a functional group such as "amine” or "acid halide” and then performing a "amide bond” chemical reaction or other chemical reaction in one step. Therefore, the compound of the formula (V) disclosed in the present invention has the advantages that the raw materials are easily available, the preparation process is simple, and the cost is low.
  • the compound of the general formula (V) disclosed in the present invention has the activity of activating AMPK kinase, suggesting that the compound of the present invention can not only be developed into a new generation of lipid-lowering drugs, but also can play a role in controlling blood sugar, and is a comprehensive metabolic synthesis.
  • the comprehensive benefits of patients with lipid-lowering and hypoglycemic agents are more advantageous than the existing single-acting drugs.
  • X1 and X2 are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • X1 and X2 is obtained by coupling under certain reaction temperature conditions in the presence of a certain alkaline reagent.
  • the preparation scheme of the general compound (V) is introduced by taking a representative synthetic preparation procedure in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes:
  • X1, X3, X3', X3" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in a certain alkaline reagent. Under the conditions, V-1, V-1', V-1" were prepared by a coupling reaction.
  • X1, X4, X4', X4" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in a certain alkaline reagent. Under the conditions, V-2, V-2', V-2" were prepared by a coupling reaction.
  • X1 and X5 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • the starting material is prepared by a coupling reaction under the conditions of a certain alkaline reagent under certain reaction conditions to obtain V-3.
  • W1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. W1 and X2 are compounded to give compound VI by coupling at a certain reaction temperature in the presence of a certain basic reagent.
  • Y1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. Y1 and X2 are compounded to give compound VII by coupling in the presence of a certain basic reagent under a certain reaction temperature.
  • X1 and Z1 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and Z1 are compounded by coupling at a certain reaction temperature in the presence of a certain basic reagent.
  • the preparation scheme of the general compound (VIII) is introduced by taking a representative synthetic preparation procedure in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes:
  • Y1 and Z2, Z2', Z2" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in certain alkaline reagents. Under the conditions, IX-1, IX-1', IX-1" were obtained by a coupling reaction.
  • Y1 and Z3, Z3', Z3" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in certain alkaline reagents. Under the conditions, IX-2, IX-2', IX-2" were obtained by a coupling reaction.
  • Y1 and Z4 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • IX-3 is prepared by a coupling reaction under the conditions of a certain alkaline reagent under certain reaction conditions of Y1 and Z4.
  • Figure 1 shows the effect of the fluorescence intensity observed under the microscope on the ability of the sample to take up LDL by hepatocytes after compound treatment.
  • Fig. 2 is a graph showing the comparison of serum low-density lipoprotein cholesterol (LDL-C) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • LDL-C serum low-density lipoprotein cholesterol
  • Fig. 3 shows a comparison of the results of determination of total cholesterol (TC) in serum of a high-fat SD rat after oral administration of a part of the compound of the present invention for four weeks.
  • Figure 4 is a graph showing the comparison of serum alanine aminotransferase (ALT) levels in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • Fig. 5 is a graph showing the comparison of the results of serum aspartate aminotransferase (AST) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
  • AST serum aspartate aminotransferase
  • the present technology provides novel compounds, and the use of the compounds in reducing plasma and/or liver lipid levels, as well as in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Uses in hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • the compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the methods disclosed herein.
  • the invention also provides the use of the compound for the preparation of a pharmaceutical formulation and a medicament, the use of the compound for lowering lipid levels in plasma and/or liver, and the compound in the treatment of hyperlipidemia, hypercholesterolemia Use in disease, hypertriglyceridemia, hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
  • an element such as hydrogen or H
  • R group is defined to include hydrogen or H, it also includes ruthenium and osmium.
  • Compound comprises a radioisotope (e.g., tritium, C 14, P 32 and S 35) is therefore also within the scope of the present invention. Means for inserting such markers into the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein.
  • substituted means an organic group (e.g., an alkyl group) as defined below wherein one or more hydrogen-bonded bonds are replaced by a bond to a non-hydrogen atom or a non-carbon atom.
  • Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds (including double or triple bonds) linking the heteroatoms.
  • a substituted group is substituted with one or more substituents. In some embodiments, the substituent is substituted with 1, 2, 3, 4, 5 or 6 substituents.
  • substituents examples include halogen (i.e., F, Cl, Br, and I), a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • halogen i.e., F, Cl, Br, and I
  • a hydroxyl group an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl, also include ring and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom.
  • the substituted cycloalkyl, aryl, heterocyclic and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.
  • the alkyl group includes a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R', -C(O)OR', -S(O) m R', - NR'R", -C(O)NR'R", -NR'C(O)R", -NR'S(O) m R" or -S(O) m NR'R".
  • a cycloalkylalkyl group means an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 Up to 10 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • Alkenyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
  • Cycloalkenyl refers to an unsaturated cycloalkyl group as defined above having at least one double bond between two carbon atoms.
  • a cycloalkenyl group can have one, two or three double bonds but does not include an aromatic compound.
  • the cycloalkenyl group contains 4 to 14 carbon atoms or, in some embodiments, 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5, 6, 7 or 8 carbon atoms.
  • Examples of the cycloalkenyl group include a cyclohexenyl group, a cyclopentenyl group, a cyclohexadienyl group, a butadienyl group, a pentadienyl group, and a hexadienyl group.
  • alkynyl group means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
  • the aryl group is a cyclic aromatic hydrocarbon containing no hetero atoms.
  • Aryl groups include monocyclic, bicyclic, and tricyclic systems herein.
  • aryl groups include, but are not limited to, phenyl, methoxyheptyl, diphenyl, indenyl, phenanthryl, anthracenyl, fluorenyl, indanyl, cyclopentadienyl, and naphthyl.
  • the aryl group contains 6-14 carbons, preferably 6 to 12, more preferably 6-10 carbon atoms in the ring portion of the group.
  • the aryl group is phenyl or naphthyl.
  • aryl includes groups containing a fused ring (eg, a fused aromatic-aliphatic ring system) (eg, indanyl, tetrahydronaphthyl, and the like), it does not include having members with rings
  • An aryl group of one of the other groups bonded for example, an alkyl group or a halogenated group.
  • a group such as a tolyl group is referred to as a substituted aryl group.
  • Representative substituted aryl groups can be monosubstituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or naphthyl groups, which may be substituted, for example, with the substituents listed above.
  • Aralkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above.
  • the aralkyl group contains from 7 to 16 carbon atoms, preferably from 7 to 14 carbon atoms, more preferably from 7 to 10 carbon atoms.
  • the substituted aralkyl group may be substituted at the alkyl group, the aryl group, or both the alkyl group and the aryl moiety.
  • Representative aralkyl groups include, but are not limited to, benzyl and phenethyl and fused (cycloalkylaryl)alkyl (eg, 4-indolylethyl).
  • Representative substituted aralkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms such as, but not limited to, N. , O and S.
  • a heterocyclic group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl includes mono, di, and tricyclic rings having from 3 to 16 ring members.
  • Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems such as imidazolyl, imidazolinyl and imidazolidinyl.
  • heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]. Dioxoalkyl and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic systems containing heteroatoms such as, but not limited to, quinuclidinyl. However, the phrase does not include heterocyclic groups having other groups (eg, alkyl, oxo or halo groups) bonded to one of the ring members.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiazolinyl, isothiazolyl, thiadiazo, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetra
  • substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted or substituted by various substituents such as those listed above A disubstituted pyridyl or morpholinyl group.
  • a heteroaryl group is an aromatic ring compound containing five or more ring member atoms, wherein one or more ring members are heteroatoms such as, but not limited to, N, O and S.
  • Heteroaryl groups include, but are not limited to, the following groups, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, fluorenyl, azaindolyl (pyrrolopyridinyl), oxazolyl, benzimidazolyl, Imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzox
  • Heteroaryl groups include fused ring compounds in which all of the rings are aromatic, such as fluorenyl groups, which also include fused ring compounds in which only one ring is aromatic, such as 2,3-dihydroindenyl.
  • heteroaryl includes fused ring compounds, the phrase does not include heteroaryl groups having other groups (eg, alkyl groups) bonded to one of the ring members.
  • a heteroaryl group having such a substitution is referred to as a "substituted heteroaryl group.”
  • Representative substituted heteroaryl groups can be substituted one or several times with, for example, the various substituents listed above.
  • Heterocyclylalkyl is an alkyl group as defined above, but wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above.
  • the substituted heterocyclic alkyl group may be substituted at the alkyl group or the heterocyclic group or at both the alkyl group and the heterocyclic group.
  • Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran 2-yl-ethyl and ind-2-yl-propyl.
  • Representative substituted heterocyclylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • Heteroarylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above.
  • the substituted heteroarylalkyl group may be substituted at the alkyl or heteroaryl portion or at both the alkyl and heteroaryl portions.
  • Representative substituted heteroarylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
  • the groups described herein having two or more points of attachment are designated by the prefix "sub".
  • the divalent alkyl group is an alkylene group
  • the divalent aryl group is an arylene group
  • the divalent heteroaryl group is a heteroarylene group, and the like.
  • Substituted groups having a single point of attachment to a compound of the invention do not use a "sub" designation.
  • chloroethyl is not referred to herein as chloroethylene.
  • An oxo group means a substituent group formed by linking with an oxygen atom, wherein the group bonded to the oxygen atom is a substituted or unsubstituted alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, an alkyl group. , aryl acyl, heteroaryl acyl.
  • the above group may be bonded to an oxygen atom to form an alkoxy group, an aryloxy group, a heteroaryloxy group, a cycloalkyloxy group, an alkyl acyloxy group, an aryl acyloxy group, a heteroaryl acyloxy group, and a ring.
  • Alkyl acyloxy Alkyl acyloxy.
  • the alkoxy group is a substituent in which a bond to a hydrogen atom in a hydroxyl group (-OH) is replaced by a bond to a carbon atom of the substituted or unsubstituted alkyl group defined above.
  • linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
  • branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
  • cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Representative substituted alkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • alkanoyl and “alkanoyloxy” as used herein mean -C(O)-alkyl and -O-C(O)-alkyl, respectively, each of which contains from 2 to 5 carbon atoms.
  • aryloxy and arylalkoxy mean, respectively, a substituent formed by bonding a substituted or unsubstituted aryl group to an oxygen atom, a substituted or unsubstituted aralkyl group and an oxygen atom.
  • a substituent formed by bonding examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy.
  • Representative substituted aryloxy and arylalkoxy groups can be substituted one or several times with, for example, the substituents listed above.
  • carboxylic acid refers to a -COOH group.
  • Carboxylate refers to a -COOR' group.
  • R' is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic group as defined herein.
  • amide includes both C-amide and N-amide groups, i.e., -C(O)NR'R” and -NR'C(O)R” groups, respectively.
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
  • the amide group thus includes, but is not limited to, a carbamoyl group (-C(O)NH 2 ) and a carboxamide group (-NHC(O)H).
  • the amide is -NR'C(O) -(C 1-5 alkyl), this group is referred to as "carbonylamino", in other embodiments, the amide is -NHC(O)-alkyl, the group is referred to as "alkanoylamino" .
  • nitrile or "cyano” as used herein refers to a -CN group.
  • Carbamates include N-carbamate groups and O-carbamate groups, i.e., -NR'C(O)OR” and -OC(O)NR'R” groups, respectively.
  • R' and R" are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein.
  • R' can also be H.
  • amine refers to a radical -NR'R", wherein R' and R" are, independently, hydrogen or substituted or unsubstituted alkyl, as defined herein, Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic.
  • the amine is an alkylamino, dialkylamino, arylamino or alkylarylamino group.
  • the amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.
  • sulfonamide includes both S-sulfonamide groups and N-sulfonamide groups, i.e., -SO 2 NR'R" and -NR'SO 2 R” groups, respectively.
  • R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
  • the sulfonamide group thus includes, but is not limited to, a sulfonyl group (-SO 2 NH 2 ).
  • the sulfonamide is -NHSO 2 -alkyl, which is referred to as "alkylsulfonylamino" .
  • thiol refers to the -SH group, while the sulfide includes the -SR' group, the sulfoxide includes the -S(O)R' group, the sulfone includes the -SO 2 R' group, and the sulfonyloxy group includes -OSO 2 R', the sulfonic acid oxygen group includes -OSO 2 OR'.
  • R' is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein.
  • the sulfide is an alkyl thiol group, -S-alkyl.
  • urea refers to a -NR'-C(O)-NR'R” group.
  • the R' and R" groups are independently hydrogen or substituted or unsubstituted alkyl, alkenyl as defined herein. , alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl.
  • ⁇ refers to -C(NR')NR'R" and -NR'C(NR')R", wherein R' and R" are each independently hydrogen as defined herein or substituted or not Substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • ⁇ refers to -NR'C(NR')NR'R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, cycloalkyl, as defined herein, Alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl.
  • halo refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • hydroxy refers to -OH, or may be an ionized form as used herein -O -.
  • imide refers to -C(O)NR'C(O)R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, ring, as defined herein. Alkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
  • nitrogen-containing heterocyclic group refers to a ring system containing a nitrogen atom which may "couple” aromatic and non-aromatic ring systems, or link other ring systems through “spirocarbon atoms", such as the following structure:
  • the term "imine” refers to a -CR' (NR") and -N (CR'R”) group, wherein R' and R" are each independently hydrogen or substituted or unsubstituted as defined herein.
  • An alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an arylarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, and satisfies: R' and R" are not hydrogen at the same time.
  • nitro means -NO 2 when used herein.
  • trifluoromethyl refers to a -CF 3.
  • salts of the compounds described herein are within the scope of the invention and include such acid addition or base addition salts which retain the desired pharmacological activity and are not biologically potential Poor effects (eg, salts are not excessively toxic, sensitizing or irritating, and are bioavailable).
  • the compound of the present invention has a basic group (for example, an amino group), it can be combined with a mineral acid (for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid), an organic acid (for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (eg aspartame)
  • a mineral acid for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid
  • an organic acid for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric
  • the compound of the present invention When the compound of the present invention has an acidic group such as a carboxylic acid group, it can be combined with a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ) ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine) ) form a salt.
  • a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ )
  • ammonia or organic amines such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine,
  • the compounds of the invention may exhibit tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
  • formulae in the specification and claims represent only one of the possible tautomeric, conformational, stereoisomeric or geometric isomeric forms, it is to be understood that the invention includes a compound having one of the ones described herein or Any tautomeric, conformational, stereoisomeric, and/or geometric isomeric form for a variety of uses, as well as mixtures of these various forms.
  • Stereoisomers of the compounds including all chiral, diastereomeric and racemic forms of the structure, unless explicitly indicated for stereochemistry.
  • compounds useful in the present invention include optical isomers that are enriched or resolved at any or all of the asymmetric atoms. Racemic and diastereomeric mixtures, as well as optical isomers, may be isolated or synthesized to be substantially free of their corresponding isomers or diastereomers, and these stereoisomers are also Within the scope of the invention.
  • the compounds of the invention may exist as solvates, especially as hydrates.
  • the hydrate can be formed during the manufacture of the compound or composition comprising the compound, or the hydrate can be formed over time due to the hygroscopic nature of the compound.
  • the compounds of the invention may also exist as organic solvates, including ethers and alcohol solvates, and the like. Identification and preparation of any particular solvate is known to those of ordinary skill in the art of synthetic organic or pharmaceutical chemistry.
  • Lipids include both synthetic and naturally occurring fat-soluble compounds, including both neutral and amphiphilic molecules.
  • Amphoteric lipids typically comprise a hydrophilic component and a hydrophobic component.
  • Exemplary lipids include fatty acids, triglycerides, neutral fats, phospholipids, glycolipids, fatty alcohols, waxes, hydrazines, steroids such as cholesterol, and surfactants.
  • Lipid-lowering agent refers to a compound that has one or more of the following effects when administered to a patient: increased liver expression of LDLR; increased half-life of LDLR mRNA in hepatocytes; increased liver to plasma LDL, cholesterol Or uptake of triglycerides; enhance fatty acid oxidation in the liver, reduce triglyceride synthesis and secretion in the liver, and lower total cholesterol, LDL-cholesterol, VLDL-cholesterol or triglyceride levels in plasma and/or liver.
  • the lipid reducing agents disclosed herein include the compounds of the invention.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver, comprising administering to said patient a reduced effective amount of a compound as described herein or combination.
  • the reduced lipid level may be one or more of total cholesterol, LDL-cholesterol (LDL-C), triglyceride (TG), and unesterified long-chain fatty acids.
  • the compounds and compositions described herein are useful for the prevention or treatment of diseases including, for example, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (hepatic steatosis), type 2 diabetes, hyperglycemia Disease, obesity or insulin resistance and metabolic syndrome.
  • a method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or composition described herein.
  • the compounds of the invention are also useful in the treatment or prevention of disease states or conditions characterized by elevated plasma or hepatic cholesterol or triglycerides or associated with elevated plasma or hepatic cholesterol or triglycerides.
  • the present technology also provides for the treatment or prevention of diseases using the compounds of the invention (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin)
  • diseases eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin
  • the use of an effective amount of a drug for resistance or metabolic syndrome eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin.
  • the compounds and compositions disclosed herein increase the stability of LDLR mRNA by increasing the LDLR mRNA stability by increasing the transcription of the LDLR gene by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9). ) mediated degradation of LDLR proteins or all of the above possible cellular mechanisms to reduce lipid levels.
  • Increased levels of LDLR in the liver increase uptake and processing of plasma LDL-C, resulting in decreased plasma levels of cholesterol, LDL-C, and triglycerides.
  • compounds can increase phosphorylation of acetyl CoA carboxylase (ACC) by activating AMP-activated protein kinase (AMPK), a key molecule of bioenergy metabolism regulation.
  • ACC acetyl CoA carboxylase
  • AMPK AMP-activated protein kinase
  • Increased phosphorylation of ACC enhances fatty acid oxidation in the liver, resulting in reduced TG accumulation in the liver and TG secretion in VLDL, which also helps reduce TG, LDL-C, total cholesterol, and unesterified long chains. Plasma levels of fatty acids, thereby preventing or treating diseases associated with hyperlipidemia.
  • AMPK is essential for the body to maintain glucose balance, and that compounds can ultimately treat type 2 diabetes, hyperglycemia, obesity or insulin resistance or metabolism by activating AMPK. Syndrome.
  • the compounds provided herein have the use of increasing LDLR expression comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby increasing LDLR in said subject expression.
  • the invention provides a use of a compound of the invention to reduce plasma LDL-cholesterol and/or plasma triglycerides, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The composition thereby reducing plasma LDL-cholesterol in the patient.
  • the invention provides a lipid lowering agent comprising a compound and a composition thereof.
  • the compounds and compositions are useful in the methods and treatments of reducing lipids described herein.
  • the invention provides a compound of formula V, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and/or a pharmaceutically acceptable salt thereof.
  • the present technology provides pharmaceutical compositions and medicaments comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • a pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome is provided.
  • Such compositions include a lipid reducing effective amount of any of the compounds described herein.
  • the pharmaceutical composition is packaged in unit dosage form.
  • the unit dosage form is effective in reducing blood lipids and/or lipid levels in the liver (eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids) when administered to a subject in need thereof. At least one).
  • blood lipids and/or lipid levels in the liver eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids
  • compositions By diluting one or more compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, dilutions Agents and the like are mixed to prepare a pharmaceutical composition to prevent or treat a condition associated with increased plasma and/or liver lipid levels.
  • pharmaceutically acceptable carriers eg, hyperlipidemia, hypercholesterolemia, hepatic steatosis, and metabolic syndrome
  • compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the compositions of the present invention may be formulated in a variety of forms for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration or by implantation of a reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injection.
  • the dosage forms described below are given as examples and should not be construed as limiting the techniques of the present invention.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared by any of the methods known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Gelatin capsules provide oral preparations.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol , or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or a partial ester of ethylene oxide with a fatty acid and a hexitol anhydride Condensation products such as polyethylene oxide sorbitan
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives such as ethylparaben or n-propylparaben
  • coloring agents such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be prepared as an injection.
  • Dosage forms for topical (including buccal and sublingual) or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
  • the active component can be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient and with any preservative or buffers which may be required.
  • Powders and sprays can be prepared, for example, with excipients such as sugars, mica, silicic acid, sodium hydroxide, calcium silicates and polyamine powders or mixtures of these materials.
  • Ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. , bentonite, silicic acid, mica and zinc oxide or a mixture thereof.
  • Absorption enhancers can also be used to increase the flow of the compounds of the invention through the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the compounds of the invention may also be administered with other conventional therapeutic agents useful in the treatment or prevention of hyperlipemia.
  • exemplary therapeutic agents for combination therapy with one or more compounds of the invention include, but are not limited to, anti-inflammatory drugs, therapeutic antibodies, and cholesterol lowering drugs, for example, statins.
  • Useful additional therapeutic agents useful in combination formulations and co-therapy include, for example, anti-hyperlipidemic agents; anti-dyslipidemic agents; anti-diabetic agents including, but not limited to, cholesterol biosynthesis inhibitors, such as HMG-CoA reductase Inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduction synthase inhibitors; Squalene epoxidase inhibitor or squalene synthetase inhibitor (also known as squalene synthase inhibitor); microsomal triglyceride transfer protein (MTP) inhibitor; bile acid sequestrant anion exchange resin, These include, but are not limited to, cholestyramine, cholestyramine, colesevelam or dialkylaminoalkyl derivatives of cross-linked dextran; LDL
  • Additional therapies may also include increased exercise, surgery, and changing diets (eg, becoming a low-cholesterol diet).
  • Some botanicals are also effective for combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, gum ketone , garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimeric pantothenic acid, red yeast rice and royal jelly.
  • Berberine and related compounds can also be used as a second therapeutic agent in combination with the lipid lowering agent of the present invention.
  • berberine sulfate, berberine hydrochloride, berberine chloride, berberine, dihydroberberine, 8-cyanodihydroberberine, tetrahydroberberine N-oxide can be used.
  • Compounds of the invention may also be modified, for example by covalently linking organic structural fragments or conjugates, to improve pharmacokinetic properties, toxicity or bioavailability (e.g., increased in vivo half-life).
  • the conjugate can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
  • the polymeric group can comprise a molecular weight that can be adjusted by one skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability.
  • Exemplary conjugates can include polyalkanols (eg, polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone, and fatty acid or fatty acid ester groups, which Each may independently comprise from about 8 to about 70 carbon atoms.
  • Conjugates for use with the compounds of the invention may also be used as linkers, for example, for any suitable substituent or group, radiolabel (marker or tag), halogen, protein, enzyme, polypeptide, other therapeutic agent (eg drugs or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids and/or liposomes.
  • the conjugate can include polyvinylamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG).
  • PI polyvinylamine
  • PEG polyethylene glycol
  • mPEG methoxypolyethylene glycol
  • Conjugates The compounds of the invention may also be linked to, for example, labeled (fluorescing or luminescent) or a label (radioactive, radioisotope and/or isotope) to comprise a probe of the invention. Conjugates for use with the compounds of the invention may improve in vivo half-life in one aspect.
  • linking and/or “binding” may refer to a chemical or physical interaction, such as between a compound of the invention and a target of interest. Examples of linkages or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophobic interactions, hydrophobic-hydrophobic interactions, and complexes. "Links” may also generally be referred to as “binding” or “affinity,” each of which may be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also a routine technique for those skilled in the art.
  • X1 and X2 are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • X1 and X2 are obtained by coupling to a compound V under a certain reaction temperature in the presence of a certain alkaline reagent.
  • the preparation scheme of the general compound (V) is introduced by taking a representative synthetic preparation procedure in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes:
  • X1, X3, X3', X3" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in a certain alkaline reagent. Under the conditions, V-1, V-1', V-1" were prepared by a coupling reaction.
  • X1, X4, X4', X4" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in a certain alkaline reagent. Under the conditions, V-2, V-2', V-2" were prepared by a coupling reaction.
  • X1 and X5 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • the starting material is prepared by a coupling reaction under the conditions of a certain alkaline reagent under certain reaction conditions to obtain V-3.
  • W1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. W1 and X2 are compounded to give compound VI by coupling at a certain reaction temperature in the presence of a certain basic reagent.
  • Y1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. Y1 and X2 are compounded to give compound VII by coupling in the presence of a certain basic reagent under a certain reaction temperature.
  • X1 and Z1 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and Z1 are compounded by coupling at a certain reaction temperature in the presence of a certain basic reagent.
  • the preparation scheme of the general compound (VIII) is introduced by taking a representative synthetic preparation procedure in the patent of the present invention as an example.
  • the preparation scheme of the compound of the present invention is not limited to the following representative processes:
  • Y1 and Z2, Z2', Z2" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in certain alkaline reagents. Under the conditions, IX-1, IX-1', IX-1" were obtained by a coupling reaction.
  • Y1 and Z3, Z3', Z3" are the starting materials of the scheme, which can be obtained by commercially available products or prepared according to the methods reported in the literature.
  • the starting materials are present under certain reaction conditions in certain alkaline reagents. Under the conditions, IX-2, IX-2', IX-2" were obtained by a coupling reaction.
  • Y1 and Z4 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • IX-3 is prepared by a coupling reaction under the conditions of a certain alkaline reagent under certain reaction conditions of Y1 and Z4.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS silane
  • chemical shift is given in units of 10 -6 (ppm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or with reference to methods known in the art, or may be purchased from companies such as GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, TCI Chemicals, Angie Chemicals, and the like.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction was usually evacuated, charged with hydrogen, and operated three times.
  • reaction temperature is room temperature, and the temperature range is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane And the acetone system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
  • Compound 4 is a by-product of the synthesis of zzj-8-20B, probably because the starting material A10 is a trifluoroacetate salt.
  • 6A (107mg, 0.547mmol), oxalyl chloride (116 ⁇ L, 1.37mmol), dichloromethane (10mL), 1 drop of DMF, reacted at room temperature for 2h, spin dry to obtain 6B, then add 6C (in order) 200 mg, 0.602 mmol), methylene chloride (20 mL), EtOAc (EtOAc (EtOAc)EtOAc. The residue was dried over anhydrous sodium sulfate (MgSO4).
  • MgSO4 anhydrous sodium sulfate
  • 8A (132mg, 0.602mmol), thionyl chloride (3mL), dichloromethane (1mL) was added to a 50mL round bottom flask, reacted in an oil bath at 60 ° C for 4h, spin dry to obtain 8B, then add 8C (200mg) , 0.602 mmol), methylene chloride (12 mL), EtOAc (EtOAc, EtOAc (EtOAc). The residue was dried over anhydrous sodium sulfate (MgSO4).
  • the compound 19 was obtained by referring to the experimental scheme of Example 3 and related literature, MS (ESI) m/z [M+H] + : 511.15.
  • the compound 31 was obtained by referring to the experimental scheme of Example 3 and related literature, MS (ESI) m/z [M+H] + : 481.58.
  • the compound 33 was obtained by referring to the experimental scheme of Example 3 and related literature to obtain MS (ESI) m/z [M+H] + : 439.50.
  • 3,5-Dimethoxyphenylacetic acid 73B (883 mg, 4.5 mM) was dissolved in dichloromethane (25 mL), EDCI (949 mg, 4.95 mM) and triethylamine (752 ⁇ L, 5.4 mM) were added and stirred for half an hour. .
  • 1-(4-Nitrophenyl)piperazine 73A (933 mg, 4.5 mM) was added, the reaction was continued, and the reaction was completed by EtOAc.
  • EtOAc EtOAc (EtOAc) The organic acid solution, water and saturated brine were washed, dried over anhydrous sodium sulfate and concentrated to dryness to afford product 73C.
  • 1-(4-Nitrophenyl)piperazine 79A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, and the solvent was evaporated, evaporated, evaporated, evaporated.
  • 1-(4-Nitrophenyl)piperazine 80A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC. The solvent was concentrated and evaporated, then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 80B.
  • the above product 80D was dissolved in methanol (10 mL), and 4M HCl/methanol (10 mL) was added dropwise, and the reaction was allowed to stand for half an hour, and the reaction was completely monitored by TLC.
  • 5-formylsalicylic acid 83A (1.66 g, 10.0 mM) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (4.14 g, 30 mM) and methyl iodide (2.18 mL, 35 mM) , overnight at room temperature. The reaction was completed by TLC. EtOAc was evaporated.
  • Example 83E was obtained as in Example 83.
  • Compound 84E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added and stirred at room temperature, then danyl chloride 84B 283 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature.
  • the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
  • 83E was obtained as in Example 83.
  • Compound 83E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then 2-naphthalenesulfonyl chloride 85B 239 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature. .
  • the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
  • 1-(4-Nitrophenyl)piperazine 86A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, and the solvent was evaporated, evaporated, evaporated,
  • the product 86G (150 mg, 0.35 mM) was dissolved in dichloromethane (8 mL), triethylamine (146 uL, 1.05 mM) and 2-bromo-4'-methoxyacetophenone (80 mg, 0.35 mM). Stir overnight.
  • 1-(4-Nitrophenyl)piperazine 87A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, and the solvent was evaporated, evaporated, evaporated, evaporated.
  • the purpose of this experiment is to reflect the inhibitory effect of the compound on the expression of PCSK9 gene.
  • a validated PCSK9 quantitative PCR primer, ⁇ -Actin quantitative PCR primer was used as a primer for PCSK9 and the internal reference gene ⁇ -Actin.
  • the quantitative PCR reaction system of each sample was prepared by using template, primer, Power SYBR Green PCR Master Mix (Invitrogen), and real-time PCR was performed on the quantitative PCR instrument CFX96 Real-Time PCR Detection System (Bio-Rad) according to the requirements of the PCR instrument. , obtain expression data.
  • the expression level data were processed by ⁇ CT method, and ⁇ -Actin was used as the internal reference.
  • the expression level of PCSK9 in the blank control was set to 1, and the relative expression level of PCSK9 relative to the control in the remaining samples (multiples relative to the control) was obtained.
  • This experiment was to reflect the effect of compounds on lowering LDL at the cellular level. Excessive LDL levels can cause atherosclerosis. This experiment directly detects the ability of hepatocytes to take up LDL at the cellular level, which directly reflects the lipid-lowering effect of the compound.
  • the surface of hepatocytes expresses LDL receptors and has the ability to take up LDL.
  • the fluorescent substance Dil-labeled LDL (Dil-LDL) was added to the medium, and HepG2 liver cancer cells were observed to take Dil-LDL into the cells under a fluorescence microscope.
  • the drug can increase the amount of LDL receptors on the surface of hepatocytes to enhance the ability of hepatocytes to take up LDL. Therefore, the fluorescence intensity observed under a microscope can be used to evaluate the effect of the sample on the ability of hepatocytes to take up LDL.
  • HepG2 cells were routinely cultured, seeded into 96-well plates at a density of 2.5 x 104 cells per well, and cultured overnight at 37 ° C, 5% CO 2 . The next day, the supernatant was discarded, and samples and positive drugs were added for treatment for 20 hours. The supernatant was discarded, and fresh medium containing 2 ⁇ g/ml of fluorescent Dil-LDL (Invitrogen) was added to each well, and incubation was continued for 4 hours at 37 ° C under 5% CO 2 .
  • fluorescent Dil-LDL Invitrogen
  • the supernatant was discarded, and the cells were washed twice with PBS, replaced with fresh medium, and the fluorescence intensity of each well was observed under a fluorescence microscope (Leica DM IL LED Microsystems). Normal cells treated with no sample and Dil-LDL were used as negative controls. The effect of the sample on the ability of hepatocytes to take up LDL was evaluated by fluorescence intensity observed under a microscope and graded for comparison.
  • the classification method is as follows:
  • +++ indicates a strongly increased fluorescence intensity compared to normal cell controls
  • the experimental results show that the compound of the present invention can significantly enhance the uptake ability of hepatocytes to LDL.
  • hepatocytes treated with the lower concentration of the compound of the present invention exhibit significant energy uptake of LDL.
  • HepG2 cells were treated with the compounds of the invention and the activation of ERK and AMPK was detected.
  • the insulin-resistant obese mouse model induced by high-fat feeding has the effects of reducing blood sugar and reducing body weight, and has the characteristics of significantly improving glucose tolerance, insulin resistance, and insulin sensitivity.
  • Model establishment SD rats were fed with high-fat diet, and the normal group was fed with normal large mouse growth feed. After 4 weeks, animal serum was collected and the index was changed. Compared with the normal group, the levels of LDL-C and TC in serum induced by high-fat diet were significantly increased and statistically significant, which proved that the hyperlipidemia model was successfully established.
  • Acute toxicity test continuous administration of a single dose for 7 days, the test compound showed no significant side effects at a dose of 500 mg/kg.
  • Test group and dose design normal control group, high fat model control group, simvastatin group (8 mg/kg), compound group 73 (20 mg/kg), compound group 80 (20 mg/kg), compound group 83 (20 mg) /kg), compound 86 group (20 mg/kg).
  • Dosing frequency once a day.
  • Figure 2 The results of Figure 2, Figure 3, Figure 4, and Figure 5 show that Compound 73, Compound 80, Compound 83, and Compound 86 of the present invention significantly reduced LDL-C and TC in model animals.
  • Figures 4 and 5 show that the levels of alanine aminotransferase and aspartate aminotransferase in the high-fat model group and the simvastatin group are significantly elevated, indicating abnormal liver function, but the compound of the present invention exhibits significant lipid-lowering activity in vivo.
  • Study animals The experimental animals used in this experiment used the animals in the above-mentioned "SD rat model lipid-lowering experiment". After the animal serum index study was completed, the animals were sacrificed and dissected, and the liver tissue of the animals was taken, and some formalin was fixed. Partially stored at -80 ° C for cryopreservation, after more than 48 hrs, pathological section staining (H&E staining, oil red-O staining) was performed. Focus on liver structural integrity, inflammatory cell infiltration and fatty liver severity, and score (score: 0; normal; level 1: ⁇ 20%; level 2: 20-40%; level 3: 40-60 %; Level 4: 60-80%; Level 5: >80%). See the table below for the results.
  • Test animal group Empty packet denaturation Inflammation fat Capsular congestion Normal animal 0 0 0 0 High fat control group 4 3 4 3 Simvastatin group 4 3 4 2
  • Compound 73 group 1 0 1 1
  • Compound 80 group 1 0 1 1
  • Compound 83 group 1 1 1 1
  • Compound 86 group 1 0 0 1
  • the compound 73, compound 80, compound 83 and compound 86 all have a certain protective effect on the liver structure from the vacuolar degeneration score, and the liver damage caused by the fat cells is repaired.
  • Compound 73, Compound 80, Compound 83, Compound 86 can also significantly reduce inflammatory cell infiltration, reduce liver inflammation, reduce fat accumulation and increase fat cell volume, reduce liver fat .
  • liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated.
  • the compound 73, the compound 80, the compound 83 and the compound 86 of the present invention all have a certain protective effect on liver tissues, and the compound of the present invention has medicinal value for treating fatty liver.
  • the compound of the present invention exhibits a lipid-lowering activity and does not affect the normal function of the liver. Within the safe dose range, the compounds of the present invention exhibited lipid-lowering activity in vivo and did not cause an increase in the level of transaminase in the rat, suggesting that no damage was caused to the liver. However, simvastatin lipid-lowering drugs, while exhibiting lipid-lowering activity, further increased the level of animal transaminase, indicating that normal liver function was damaged and showed significant liver toxicity. The compound of the present invention has the characteristics of lowering lipid but not affecting liver function, and clinical application indicates that the compound of the present invention has a more significant safety advantage than the statin.
  • the compound of the present invention has a potential therapeutic effect on fatty liver symptoms in a high-fat model animal, and the lipid-lowering drugs such as statins do not have the above effects. It can be seen from the "SD rat model non-alcoholic steatohepatitis experiment" that the compound of the present invention reduces the degree of liver inflammation, can reduce fat accumulation and increase the volume of fat cells, reduce the degree of liver fat, and obtain liver damage caused by fat cells. It has been repaired to reduce the degree of vacuolar denaturation. However, in the liver anatomy of the simvastatin group, liver structural integrity, inflammatory cell infiltration, and fatty liver severity were consistent with the high-fat model group, and fatty liver symptoms were not alleviated.
  • the lipid-lowering mechanism of the compound of the present invention is different from the existing listed lipid-lowering drugs (for example, statins, fibrates, etc.), and its excellent lipid-lowering activity and its Good safety characteristics and potential therapeutic value in the treatment of fatty liver are expected to become a new generation of lipid-lowering drugs for patients with cardiovascular diseases to obtain good therapeutic benefits.
  • lipid-lowering drugs for example, statins, fibrates, etc.

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Abstract

La présente invention concerne des composés de formule (V), leur procédé de préparation et leur utilisation médicale. En particulier, la présente invention concerne des dérivés des composés de la formule générale (V), et un procédé de préparation et une utilisation de ceux-ci en tant qu'agent thérapeutique dans la prévention et le traitement de l'hyperlipidémie, l'hypercholestérolémie, l'hypertriglycéridémie, la stéatose hépatique, le diabète de type II, l'hyperglycémie, l'obésité ou le syndrome d'insulinorésistance et le syndrome métabolique, ainsi que dans la préparation d'un médicament antitumoral. Les composés selon la présente invention permettent également de réduire le cholestérol total, le cholestérol LDL et les triglycérides, d'augmenter l'expression du récepteur hépatique des LDL, et de réduire l'expression de PCSK9.
PCT/CN2015/100189 2015-01-01 2015-12-31 Dérivés hétérocycliques d'azote substitués et leur utilisation Ceased WO2016107602A1 (fr)

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US10821106B2 (en) 2015-08-21 2020-11-03 Srx Cardio, Llc Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US10947242B2 (en) 2016-11-02 2021-03-16 Janssen Pharmaceutica, Nv [1,2,4]triazolo[1,5and#8208;A]pyrimidine compounds as PDE2 inhibitors
US10947239B2 (en) 2015-11-02 2021-03-16 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compound
US11053248B2 (en) 2016-11-02 2021-07-06 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11214625B2 (en) 2015-10-29 2022-01-04 Min Chen Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases
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US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9
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US12115154B2 (en) 2020-12-16 2024-10-15 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9)
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US11945782B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity
US10980801B2 (en) 2015-08-21 2021-04-20 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US10568882B2 (en) 2015-08-21 2020-02-25 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US10821106B2 (en) 2015-08-21 2020-11-03 Srx Cardio, Llc Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US11925637B2 (en) 2015-08-21 2024-03-12 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11214625B2 (en) 2015-10-29 2022-01-04 Min Chen Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases
US10947239B2 (en) 2015-11-02 2021-03-16 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compound
US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9
US11319321B2 (en) 2016-11-02 2022-05-03 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11053248B2 (en) 2016-11-02 2021-07-06 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US10947242B2 (en) 2016-11-02 2021-03-16 Janssen Pharmaceutica, Nv [1,2,4]triazolo[1,5and#8208;A]pyrimidine compounds as PDE2 inhibitors
US12390462B2 (en) 2019-12-02 2025-08-19 Contineum Therapeutics, Inc. Muscarinic acetylcholine M1 receptor antagonists
US12115154B2 (en) 2020-12-16 2024-10-15 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9)
CN116120261A (zh) * 2022-11-30 2023-05-16 浙大宁波理工学院 一种3-[（4-磺胺哌嗪-1-基）甲基]苯甲酸类化合物的制备方法
CN116120261B (zh) * 2022-11-30 2024-01-23 浙大宁波理工学院 一种3-[（4-磺胺哌嗪-1-基）甲基]苯甲酸类化合物的制备方法

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