WO2016107603A1 - Dérivés hétérocycliques contenant de l'azote substitué et leurs applications - Google Patents

Dérivés hétérocycliques contenant de l'azote substitué et leurs applications Download PDF

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WO2016107603A1
WO2016107603A1 PCT/CN2015/100201 CN2015100201W WO2016107603A1 WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1 CN 2015100201 W CN2015100201 W CN 2015100201W WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1
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mmol
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李德群
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成都贝斯凯瑞生物科技有限公司
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07F9/6509—Six-membered rings

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 inhibit the synthesis of glycerol by the liver mainly by inhibiting the decomposition of fat and the formation of free fatty acids. Triester (TG) and very low density lipoprotein (VLD-L) to lower blood lipids.
  • TG Triester
  • 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
  • Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NR 5 -, -SO 2 O-, -SO 2 NR 5 - , -P(O)R 5 R 6 or Z is not an atom (ie, the chemical group attached to Z is 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 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 , Z, M, 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, oxy, sulphur , sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
  • R 5 , R 6 , R 7 , R 8 , R', R", Z, ring X, M, m, n, q, t 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, silyl, -COOH, carboxylate, substituted or unsubstituted amino, 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),
  • 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, silyl, -COOH, carboxylate, substituted or unsubstituted amino, 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 , M, q, t are as described above.
  • the present invention relates to the compound of the formula (IX), wherein R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halogen, -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, An aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl 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, 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, silyl, -COOH, carboxylate, substituted or unsubstituted amino, 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 represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein a preparation method comprises the steps of:
  • X1 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. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • 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 general formula (V) disclosed in the present invention has a novel structure and a novel structural feature, and is expected to have a novel effect on PCSK9, compared with a compound disclosed in the prior patent document which is a target of PCSK9.
  • the candidate drug of the mechanism and eventually become a new generation of lipid-lowering drugs with a novel mechanism 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.
  • a commercially available starting material having a functional group such as "amine”, “aldehyde” or “halogenated hydrocarbon” can be used to prepare a target compound by one-step chemical reaction. 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 for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • X4 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. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
  • Another preparation method includes the following steps:
  • X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
  • a compound represented by the formula (VII) of the present invention, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein one of the preparations includes the following steps:
  • X5 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. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
  • Another preparation method includes the following steps:
  • X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
  • X1 and X6 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 X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
  • Another preparation method includes the following steps:
  • X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
  • X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
  • Another preparation method includes the following steps:
  • X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
  • 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, imidazole-4- Base-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 oxy 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 lipid package 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.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene
  • a glycol or oil vehicle such as peanut oil, liquid paraffin or olive oil mixed soft gelatin capsules provides an oral formulation.
  • 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 for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
  • Another preparation method includes the following steps:
  • X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
  • V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
  • X4 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. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
  • Another preparation method includes the following steps:
  • X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
  • X5 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. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
  • Another preparation method includes the following steps:
  • X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
  • X1 and X6 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 X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
  • Another preparation method includes the following steps:
  • X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
  • X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
  • Another preparation method includes the following steps:
  • X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
  • 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.
  • the compound 3C (1.5 g, 5 mmol) was weighed in a round bottom flask, THF was added, dissolved, and then the material was added 3D (0.81 g, 5 mmol), stirred for 10 min, then STAB (1.27 g, 6 mmol) was added and reacted at room temperature for 3 h. After the reaction of the thin layer is completed, the reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture is extracted three times with ethyl acetate. The organic phase is combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate Product 3 (1.6 g, 72%) was obtained.
  • 16D (330 mg, 0.92 mmol) was added to a 50 ml round bottom flask, and ethanol (20 ml) was dissolved. Then, Pd/C (10 mg, 0.09 mmol) was added thereto, and the mixture was purged with H 2 for 5 times (atmospheric pressure), and allowed to react at room temperature overnight. Filtration, washing the filter cake with ethanol, collecting the filtrate, and evaporating the solvent to give a crude product 16E.
  • 46C (126.6 mg, 0.718 mmol) and 46D (200 mg, 0.653 mmol) were dissolved in 1,2-dichloroethane, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was slowly added in an ice bath.
  • 57A (225mg, 1.5mmol) was added to a 50ml round bottom flask, dissolved in dichloromethane (10ml), then oxalyl chloride (213 ⁇ l, 2.5mmol) and N,N-dimethylformamide (1 drop) were added and reacted at room temperature. overnight. The solvent and an excess of oxalyl chloride were evaporated to give a crude material.
  • the compound 70A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, which was dissolved in dichloromethane (10 mL), and the mixture was stirred and stirred for 5 min, pyridine (0.5 mL) was added and the mixture was stirred for 10 min. After stirring at room temperature for 30 min, compound acetic anhydride (2 mL) was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate 5:1).
  • 74A (2g, 24.1mmol) and 74B (400mg, 2.41mmol) were dissolved in 10ml of methanol, stirred at room temperature for 12h, then sodium borohydride (109.4, 2.892mmol) was added slowly, after 15min reaction, filtered by diatomite After the solvent was removed by pressure, the mixture was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) ).
  • 74C (188.5 mg, 0.798 mmol) and 74D (222 mg, 0.725 mg) were dissolved in 5 ml of 1,2-dichloroethane, and sodium triacetoxyborohydride (230 mg, 1.09 mmol) was slowly added at room temperature under ice bath.
  • 75A (90mg, 0.731mmol), thionyl chloride (1mL) was added to a 50mL round bottom flask, refluxed in an oil bath of 80 ° C for 2h, spin dry to give 75B, then add 75C (200mg, 0.609mmol), THF (20 mL), DMAP (10 mg), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The residue was purified by column chromatography (dichloromethane: methanol: 100:1) to afford white solid compound 75 (28 mg, yield: 10.6%).
  • the compound 91A (2000 mg, 10.34 mmol), the compound 91B (2118 mg, 11.37 mmol), potassium carbonate (2140 mg, 15.51 mmol), DMF (5 ml) was added to a 100 ml round bottom flask, and the reaction was cooled after stirring at 70 ° C overnight. The mixture was diluted with EtOAc (3 mL).
  • the compound 16E was obtained according to the preparation of Example 16 and the compound 16E was dissolved in 15 mL of dichloromethane, then 140 ⁇ L (1.01 mmol) of triethylamine was added thereto, and stirred at room temperature, and then compound 148B 223 mg (1.01 mmol) was added portionwise. After the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid.
  • Compound 16E was prepared according to Example 16 and Compound 16E 300 mg (0.916 mmol) was dissolved in 15 mL of dichloromethane, then, then, triethylamine, 140 ⁇ L (1.01 mmol), and stirred at room temperature, and then added 149B 223 mg (1.01 mmol) ), after the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid. The methyl chloride was washed, and the cake was collected.
  • 5-formylsalicylic acid 151A (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 151E was obtained as in Example 151.
  • Compound 151E 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 155B 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.
  • Example 151E was obtained as in Example 151.
  • Compound 151E 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 156B 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 157A (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 evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 157B.
  • 1-(4-Nitrophenyl)piperazine 158A (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 evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 158B.
  • 160F (10 mmol, 1.41 g), 160 g (15 mmol, 1.5 g) and triethylamine (15 mmol, 2.08 ml) were added to a 50 ml round bottom flask, dissolved in DMSO (15 ml), and reacted at 100 ° C for 10 h. After cooling to room temperature, 100 ml of water was added, and a solid was precipitated. Then, 50 ml of ethyl acetate was further added and the mixture was stirred for 10 min, filtered, and washed three times with water to give compound 160H, a yellow solid, 1.67 g, yield 75.6%.
  • 3,4-Dimethoxybenzaldehyde 160A (499 mg, 3.0 mM) was dissolved in methanol (10 mL), sodium borohydride (170 mg, 4.5 mM) was added in portions and stirred at room temperature for 15 min. The mixture was diluted with a saturated aqueous solution of ammonium chloride, and the mixture was evaporated, evaporated, evaporated, evaporated.
  • the above product 160E was dissolved in dichloromethane (15 mL), triethylamine (58 ⁇ L, 0.42 mM) and 4-diphenylsulfonyl chloride (71 mg, 0.28 mM) were added and reacted for 2.5 h, and the reaction was completely monitored by TLC.
  • the aqueous solution of citric acid was extracted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate %).

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Abstract

L'invention concerne un composé représenté par la formule (V), son procédé de préparation et ses applications pharmaceutiques. Spécifiquement, l'invention concerne des dérivés représentés par la formule (V), leur procédé de préparation et leurs utilisations en tant qu'agents thérapeutiques pour prévenir et traiter l'hyperlipidémie, l'hypercholestérolémie, l'hypertriglycéridémie, la dégénérescence graisseuse du foie, le diabète de type 2, l'hyperglycémie, l'obésité ou la résistance à l'insuline, le syndrome métabolique et les cancers. Les composés de l'invention peuvent également réduire les niveaux de cholestérol total, de cholestérol LDL et de triglycérides, et réguler positivement l'expression du récepteur LDL du foie et négativement l'expression de PCSK9.
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US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
WO2018165718A1 (fr) 2017-03-17 2018-09-20 Cardio Therapeutics Pty Ltd Inhibiteurs hétérocycliques de pcsk9
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10556013B2 (en) 2017-06-20 2020-02-11 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
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
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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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US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
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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
US10568882B2 (en) 2015-08-21 2020-02-25 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
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US11844840B2 (en) 2017-06-20 2023-12-19 Imbria Pharmaceuticals, Inc. Compositions and methods for increasing efficiency of cardiac metabolism
US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
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