阅读说明：本技术 4-苄基氨基苯磺酰胺类衍生物、及其制备和用途 (4-benzyl amino benzene sulfonamide derivative, preparation and application thereof ) 是由 李红良 张晓晶 于 2019-02-03 设计创作，主要内容包括：本发明提供了一种式(I)<Image he="340" wi="700" file="DDA0001967232590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>表示的4-苄基氨基苯磺酰胺类衍生物或其药学上可接受的盐、溶剂化物、或代谢产物,式(I)中的R<Sub>1</Sub>、R<Sub>2</Sub>、R<Sub>3</Sub>、R<Sub>4</Sub>、R<Sub>5</Sub>和R<Sub>6</Sub>各个基团如说明书所定义。还提供用于治疗和/或预防缺血再灌注损伤及相关疾病、病理性心肌肥厚及相关疾病、脂肪性肝病及相关疾病、和/或代谢性疾病。(The invention provides a compound of formula (I) A 4-benzylaminophenylsulfonamide derivative represented by the formula (I) or a pharmaceutically acceptable salt, solvate, or metabolite thereof, R 1 、R 2 、R 3 、R 4 、R 5 And R 6 Each group is as defined in the specification. Also provided are methods for treating and/or preventing ischemia-reperfusion injury and related diseases, pathological myocardial hypertrophy and related diseases, fatty liver disease and related diseases, and/or metabolic diseases.)

1. A4-benzylaminophenylsulfonamide derivative represented by the formula (I) or a pharmaceutically acceptable salt, solvate, or metabolite thereof,

wherein R is₁And R₂Each independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, halogen, amino, aryl, heteroaryl, each optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, hydroxy, C_1-6An alkoxy group;

R₃selected from aryl, heteroaryl, said groups being optionally substituted by one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, amino, hydroxy, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, and thiomorpholinyl; the above-mentioned group C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl may also be substituted by one or more C_1-6Alkyl radical, C_1-6Alkoxy, or C_1-6Alkoxycarbonyl group substituted;

R₄selected from the group consisting of hydroxy, alkyl, alkoxy, alkenyl, alkynyl, halo, amino, mercapto, aryl, heteroaryl, saccharide, uronic acid; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino, mercapto, aryl, heteroaryl, and the like;

R₅and R₆Independently selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, halogen, amino, mercapto, aryl, heteroaryl; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino, mercapto, aryl, heteroaryl, and the like;

and compounds IMA-1 were excluded

2. The 4-benzylaminophenylsulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt, solvate, or metabolite thereof,

wherein R is₁And R₂Each independently selected from H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, amino, each of which is optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, hydroxy, and C_1-6An alkoxy group.

3. The 4-benzylaminophenylsulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₁And R₂Each independently selected from H, C_1-6Alkyl and C_1-6An alkoxy group.

4. The 4-benzylaminophenylsulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₁Is selected from H or C_1-6Alkyl, and R₂Is selected from H or C_1-6An alkoxy group.

5. The 4-benzylaminophenylsulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₃Selected from phenyl, benzothiazolyl, each optionally substituted with one or more groups selected from: c_1-6Alkyl, halogen, amino, hydroxy, and C_1-6An alkoxy group.

6. The 4-benzylaminophenylsulfonamide derivative according to claim 1, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₃Selected from phenyl or benzothiazolyl.

7. According to claimThe 4-benzylaminophenylsulfonamide derivative of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₄Is selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, amino, benzylthio, phenyl, pyridyl, and saccharides; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, halogen, hydroxy and alkoxy.

8. The 4-benzylaminophenylsulfonamide derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₄Substituted with a group selected from hydroxy, glucosyl, fructosyl, galactosyl, lactosyl, glucuronyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, ethynyl, propynyl, halogen, amino, benzylthio, mercapto, phenyl, heteroaryl, heterocyclyl, and pyridyl; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, halogen, hydroxy and alkoxy.

9. The 4-benzylaminophenylsulfonamide derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₅Selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, halogen and amino.

10. The 4-benzylaminophenylsulfonamide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₅Selected from the group consisting of methyl, propoxymethyl, propenyl, and propynyl.

11. The 4-benzylaminophenylsulfonamide derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₆Selected from alkyl and alkoxyAlkyl, alkenyl, alkynyl, halogen, alkylamino, amino, phenyl, and pyridyl.

12. The 4-benzylaminophenylsulfonamide derivative according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein R is₆Selected from the group consisting of methyl, ethoxymethyl, propenyl, propynyl, ethylamino, phenyl, and pyridyl.

13. The following compounds:

14. a pharmaceutical composition comprising a 4-benzylaminophenylsulfonamide derivative or a pharmaceutically acceptable salt, solvate, or metabolite thereof according to any one of claims 1 to 13; and pharmaceutically acceptable auxiliary materials.

15. The pharmaceutical composition of claim 14, which is selected from the following oral or injectable dosage forms: tablet, capsule, pill, powder, granule, suspension, syrup, injection, and powder for injection. Or orally administered, such as orally disintegrating tablets, buccal tablets; it can also be administered topically, such as vaginally, rectally, dermally, intranasally, etc.

16. Use of a 4-benzylaminophenylsulfonamide derivative, or a pharmaceutically acceptable salt, solvate, or metabolite thereof, according to any one of claims 1-13, for the manufacture of a medicament for the treatment, prevention, and/or management of: ischemia reperfusion injury of liver, hepatic cyst, liver transplantation, thrombolytic therapy, hepatic portal block surgery, hepatic coma, hepatic failure, and liver inflammatory disease; ischemia reperfusion injury of heart, myocardial infarction recanalization injury, heart transplantation, coronary thrombolysis, percutaneous coronary angioplasty, coronary artery internal dilatation, coronary artery bypass; kidney transplantation, kidney cyst, renal vascular surgery; cerebral apoplexy, cerebrovascular surgery; cardiac remodeling such as ventricular remodeling, myocardial infarction, heart failure, arrhythmia, hypertension, coronary heart disease, arterial embolism, angina, cardiac conduction block; simple steatosis, non-alcoholic steatohepatitis, alcoholic fatty liver disease, hepatic fibrosis, liver cirrhosis, hepatocarcinoma, obesity, overweight, hyperlipidemia, hyperglycemia, insulin resistance, and diabetes.

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a 4-benzylaminophenylsulfonamide derivative or a pharmaceutically acceptable salt, solvate or metabolite thereof, and a preparation method and application thereof.

Background

Liver plays an important role in fat metabolism, and participates in a plurality of important links in the process of lipid metabolism, including the intake and synthesis of fatty acid, the processing, storage, oxidative decomposition and output of lipid. When the amount of fatty acid obtained by the liver exceeds the processing capacity, lipid is deposited in the liver cells in the form of triglyceride, which causes steatosis of the liver cells, becomes simple steatosis of the liver, and further develops into non-alcoholic steatohepatitis, and some patients can progress into hepatic fibrosis, cirrhosis and even liver cancer (such as liver cancer, the pathogenesis of non-alcoholic fatty liver disease caused by lipid metabolism disorder, the clinical liver and gall disease journal, volume 31, phase 7 in 2015, 1050-. Meanwhile, the non-alcoholic fatty liver disease is closely related to the occurrence of cardiovascular diseases, type II diabetes, obesity and metabolic syndrome, and seriously threatens the health of people. Therefore, the treatment of non-alcoholic fatty liver disease is more and more focused.

Ischemia-Reperfusion Injury (IRI) is the first concept proposed by Jennings in 1960, and refers to Reperfusion of blood after Ischemia of tissue and organ, which can not only restore the function of tissue and organ, but also aggravate dysfunction and structural damage of tissue and organ. Ischemia reperfusion injury can occur in many vital organs including the heart, liver, lung, kidney, gastrointestinal tract, and the like. Studies have shown that inflammatory outbreaks and cell death are the major pathological mechanisms leading to ischemia reperfusion-induced organ damage. How to reduce and eliminate ischemia-reperfusion injury and elucidate the mechanism of the injury has important clinical practical value. Several mechanisms are currently thought to be involved in ischemia reperfusion injury of organs: such as inflammatory cytokines, oxygen radicals, calcium overload, microcirculatory disturbance, energy metabolism disorder, etc., and also by factors such as the time of ischemia, the tissue's demand for oxygen, the establishment of collateral circulation, and electrolyte concentration.

Liver Ischemia Reperfusion Injury (HIRI) is a common pathological process in liver surgery, and is often seen in the pathophysiological processes such as shock, liver surgery requiring blocking of liver blood flow, and liver transplantation. In recent years, with the development of clinical treatment technologies, operations such as liver transplantation, thrombolytic therapy, and hepatic portal block have been increasingly performed, and despite the continuous improvement of liver protection, surgical skills, and intraoperative monitoring, liver injury caused by ischemia reperfusion still causes no function of postoperative organs, transplantation failure, and even death of patients. After the liver undergoes ischemia reperfusion, liver histiocytes generate a series of damages of metabolism, structure and function, and are easy to induce liver failure, which is one of the main reasons influencing disease prognosis, operation success rate and patient survival rate. Therefore, the search for the medicine capable of effectively inhibiting the liver ischemia-reperfusion injury has important clinical significance.

Acute coronary artery obstructive disease is one of the main causes of death of cardiovascular and cerebrovascular diseases at present. Although the treatment of bypass surgery, intervention and thrombolysis has been advanced, the mortality rate of patients with acute myocardial infarction is still high, and one important reason is that no effective method for inhibiting ischemia reperfusion injury caused by the restoration of blood flow of ischemic myocardium is available. After a certain period of myocardial ischemia, the blood supply is restored again, which causes a large amount of inflammatory factors, oxygen free radicals and the like in the organism to be released, the apoptosis rate of myocardial cells is increased, malignant arrhythmia such as ventricular fibrillation, ventricular tachycardia and the like is increased, and myocardial energy metabolism and structural damage occur.

Myocardial hypertrophy is the enlargement of the volume and weight of cardiomyocytes produced by the heart to adapt to various stimuli. The pathological changes include myocardial cell hypertrophy, myocardial interstitial cell proliferation, reconstruction of extracellular matrix of heart and other changes, namely myocardial remodeling. There are many diseases causing myocardial hypertrophy clinically, such as primary or secondary hypertension, myocardial infarction, valvular disease, congenital heart disease, etc. Although early myocardial hypertrophy is beneficial for maintaining normal cardiac function, myocardial hypertrophy itself can increase myocardial oxygen consumption and decrease myocardial compliance, leading to heart failure over time and increasing incidence of sudden death. In recent years, a great deal of research is carried out on the occurrence and development mechanism of myocardial hypertrophy by a plurality of scholars all over the world, a plurality of key genes and important signal conduction paths which are involved in the pathophysiological process of myocardial hypertrophy are discovered, and the interventional factors in the key genes and the important signal conduction paths are deeply researched. However, the mechanism of development of myocardial hypertrophy is still not completely clear, and the existing research and findings have certain limitations in clinical practice, and a truly effective prevention and treatment measure for myocardial hypertrophy cannot be formed.

Disclosure of Invention

The invention provides a 4-benzyl aminobenzene sulfonamide derivative or pharmaceutically acceptable salt, solvate or metabolite thereof, which can be used for treating and/or preventing fatty liver disease and related metabolic diseases, obesity and related metabolic diseases, diabetes and related diseases, ischemia reperfusion injury and related diseases, and/or pathological myocardial hypertrophy and related diseases.

According to one aspect of the present invention, there is provided a 4-benzylaminophenylsulfonamide derivative represented by formula (I) or a pharmaceutically acceptable salt, solvate, or metabolite thereof.

Wherein R is₁And R₂Each independently selected from H, alkyl, alkoxy, alkenyl, alkynyl, halogen, amino, aryl, heteroaryl, each optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, hydroxy, C_1-6An alkoxy group;

R₃selected from aryl, heteroaryl, said groups being optionally substituted by one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, amino, hydroxy, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, and thiomorpholinyl; the above-mentioned group C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, and optionally substituted with one or more C_1-6Alkyl radical, C_1-6Alkoxy, or C_1-6Alkoxycarbonyl group substituted;

R₄selected from the group consisting of hydroxy, alkyl, alkoxy, alkenyl, alkynyl, halo, amino, mercapto, aryl, heteroaryl, saccharide, uronic acid; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino, mercapto, aryl, heteroaryl, and the like;

R₅and R₆Independently selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, halogen, amino, mercapto, aryl, heteroaryl; each of the foregoing groups is optionally substituted with one or more groups selected from: alkane (I) and its preparation methodAlkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino, mercapto, aryl, heteroaryl, and the like;

and compounds IMA-1 were excluded

Brief description of the drawings

FIG. 1: the primary hepatocytes were treated with 20 μ M of different drugs and tested for oil red O18 hours after PA/OA stimulation.

FIG. 2: the mRNA expression levels of the lipid synthesis related genes Acc1, Fasn and Scd1 in primary hepatocytes after 18 hours of PA/OA stimulation (representing P <0.05 compared to control) were administered to the cells after 20 μ M treatment with different drugs.

FIG. 3: the expression level of mRNA of inflammation-related genes in primary hepatocytes after 4 hours of PA/OA stimulation (P <0.05 in comparison with the control group) was determined by administering 20. mu.M of different drugs to the cells.

FIG. 4: after PA/OA and 5 μ M different drug treatment of mouse primary hepatocytes, oil red O staining results and mRNA expression levels of Acc1 and Il6 in cells (× represents P <0.05 compared to control).

FIG. 5: rat primary cardiomyocytes were given 5 μ M treatment with different drugs and mRNA expression levels of the Anp, Bnp and Myh7 genes in the cells were found 48 hours after PE stimulation (P <0.05 compared to control).

FIG. 6: rat primary cardiomyocytes were treated with 5 μ M of different drugs and the cells stained for alpha-actinin 48 hours after PE stimulation (x represents P <0.05 compared to control).

FIG. 7: after 20 μ M treatment with different drugs in rat primary cardiomyocytes and after hypoxia reoxygenation stimulation, the cell viability was measured by cell CCK8 (. beta. represents P <0.05 compared to control).

FIG. 8: rat primary cardiomyocytes were treated with 20 μ M of different drugs and after hypoxic reoxygenation stimulation, the mRNA expression level of the Bax gene in the cells (. beta. represents P <0.05 compared to the control group).

FIG. 9: the mRNA expression level of inflammation-associated genes in the cells after hypoxia-reoxygenation stimulation (P <0.05 in comparison to the control group) was obtained by administering 20 μ M different drug treatments to the primary hepatocytes of mice.

Detailed Description

The present invention relates to novel 4-benzylaminophenylsulfonamide derivatives or pharmaceutically acceptable salts, solvates, or metabolites thereof.

The present invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein. It is to be understood that the invention is not limited to a particular synthetic method, which may, of course, vary.

All patents, patent applications, and references mentioned herein are incorporated by reference in their entirety.

Other features and advantages of the invention will be apparent from the description and the appended claims, which describe the invention. The many features of the invention are not necessarily fully apparent from the claims. It is to be understood, however, that all such novel subject matter is to be considered as part of the present invention.

Definition of

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

The term "pharmaceutically acceptable salts" as used herein refers to derivatives of a pharmaceutically active compound wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), basic or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, salicylic acid, sulfanilic acid, and the like.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon moiety consisting only of carbon and hydrogen atoms, including those having from 1 to 20 atoms. In certain embodiments, alkyl groups will include C₁-C₁₂、C₁-C₁₀、C₁-C₈、C₁-C₆Or C₁-C₄An alkyl group. Non-limiting examples of such substituents include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and isomers thereof. C₁-C₄Alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.

The term "alkenyl" refers to straight and branched carbon chains having at least one carbon-carbon double bond. In certain embodiments, an alkenyl group may include C₂-C₂₀An alkenyl group. In other embodiments, alkenyl includes C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆Or C₂-C₄An alkenyl group. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 2-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1-methyl-2-butenyl, 1, 2-methyl-2-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 1, 3-dimethyl-3-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1, 3-dimethyl-3-butenyl, 2-dimethyl-3-butenyl, 2,3-, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.

"alkynyl" refers to straight and branched carbon chains having at least one carbon-carbon triple bond. In certain embodiments, alkynyl groups include C₂-C₂₀An alkynyl group. In other embodiments, alkynyl groups may include C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆Or C₂-C₄An alkynyl group. For example, the term "C" as used herein₂-C₁₀-alkynyl "meansStraight-chain or branched unsaturated hydrocarbon radicals having from 2 to 10 carbon atoms and comprising at least one triple bond, such as, for example, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-butyn-1-yl, N-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-pent-2-yn-5-yl, n-methylbut-1-yn-4-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, N-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term "haloalkyl" or "halogen-substituted alkyl" refers to an alkyl group, as defined herein, which is substituted with one or more halogen atoms. E.g. C₁-C₄Haloalkyl includes, but is not limited to, chloromethyl, bromoethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromomethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2,2, 2-trichloroethyl, pentafluoroethyl, and the like.

The term "haloalkenyl" or "halogen-substituted alkenyl" refers to an alkenyl group, as defined herein, which is substituted with one or more halogen atoms.

The term "haloalkynyl" or "halogen-substituted alkynyl" refers to an alkynyl group, as defined herein, which is substituted with one or more halogen atoms.

The term "alkoxy" refers to a moiety of the formula-OR, wherein R is a straight chain saturated alkyl OR branched chain saturated alkyl group as defined herein bonded through an oxygen atom. The alkoxy group may be optionally substituted as defined herein. Non-limiting examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and the like.

Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy", "haloalkycloalkoxy", and "halocycloalkenyloxy" refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl and halocycloalkenyl are as defined above. C₁-C₆Examples of-alkoxy include, but are not limited to, methoxy, ethoxy, C₂H₅-CH₂O-、(CH₃)₂CHO-, n-butyloxy, C₂H₅-CH(CH₃)O-、(CH₃)₂CH-CH₂O-、(CH₃)₃CO-, n-pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, n-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1, 2-trimethylpropyloxy, 2-methylpropyloxy, 1-methylpropyloxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like.

The term "aryl" refers to a carbocyclic aromatic system containing 1 or 2 rings, wherein such rings may be fused. If the rings are fused, one of the rings must be fully unsaturated, and the fused ring may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, benzo [ b][1,4]Oxazin-3 (4H) -keto, 2, 3-dihydro-1H-indenyl and 1,2,3, 4-tetrahydronaphthyl. Aryl groups may optionally be substituted as desired with 1 to 5 suitable substituents as defined herein, such as C₁-C₄Alkyl, oxo, OH, CH₂OH, halogen, C₁-C₄Alkoxy, cyano, or C (O) NH₂Wherein said alkyl and alkoxy groups are optionally substituted with: OH, halogen, C (O) NH₂、C(O)NHCH₃、C(O)N(CH₃)₂、 -S(C₁-C₄Alkyl) or C₃-C₅Cycloalkyl groups, and the like.

The term "heteroaryl" refers to a monovalent aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, having one or more oxygen, nitrogen and sulfur heteroatoms, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms, in the ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple condensed rings, provided that the point of attachment is through a heteroaryl ring atom. Preferred heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazinyl, quinolinyl,Azolyl radical, isoOxazolyl, isothiazolyl, pyrazolyl, benzothiazolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, and benzothienyl. The heteroaryl ring may be unsubstituted or substituted with one or more moieties as described for aryl above.

Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; and 5-membered ring substituents, e.g. triazolyl, imidazolyl, furyl, thiaThienyl, pyrazolyl,Azolyl radical, isoAzolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2, 5-or 1,3,4-Oxadiazolyl and isothiazolyl groups. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent bonded to the group may be one of the heteroatoms, or it may be a ring carbon atom. Similarly, if the heteroaryl substituent is instead substituted with a group or substituent, that group or substituent may be bonded to one of the heteroatoms, or it may be bonded to a ring carbon atom.

The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring. Further examples include furyl, thienyl,Azolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isooxazolylAzolyl, isothiazolyl, thiazolyl,Oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2 (1H) -onyl, pyridazin-2 (1H) -onyl, pyrimidin-2 (1H) -onyl, pyrazin-2 (1H) -onyl, imidazo [1,2-a ] o]A pyridyl group. The heteroaryl group may be optionally substituted, as desired, with 1 to 5 suitable substituents, such as C, as defined herein₁-C₄Alkyl, oxo, OH, CH₂OH, halogen, C₁-C₄Alkoxy, cyano, or C (O) NH₂Wherein said alkyl and alkoxy groups are optionally substituted with: OH, halogen,C(O)NH₂、C(O)NHCH₃、C(O)N(CH₃)₂、-S(C₁-C₄Alkyl) or C₃-C₅Cycloalkyl groups, and the like.

The term "halogen atom" as used herein refers to F, Cl, Br and I. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

The term "hydroxy" as used herein refers to an-OH group.

The compounds of the present invention also include isomers of the compounds of the present invention, such as optical isomers, geometric isomers and tautomers, hydrates, solvates, complexes, polymorphs, isotopically labeled derivatives, metabolites and prodrugs.

A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. Metabolism refers to the sum of processes (including hydrolysis and enzymatic reactions, such as oxidation) by which an organism alters a particular substance. Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyl transferase catalyzes the transfer of an activated glucuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free thiols. Additional information on metabolism can be obtained from The pharmacological basis of Therapeutics, 9 th edition, McGraw-Hill (1996), which is incorporated herein by reference. In certain embodiments, the compound metabolism is a pharmacologically active metabolite.

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" as used herein refers to a physical association of a compound with one or more solvent molecules (organic or inorganic molecules, including water ("hydrate")).

Compounds of the invention

The invention relates to 4-benzylaminophenylsulfonamide derivatives represented by the compound of formula I or pharmaceutically acceptable salts, solvates, or metabolites thereof,

wherein R is₁And R₂Each independently selected from H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, amino, aryl, heteroaryl, each of which is optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, hydroxy, C_1-6An alkoxy group;

R₃selected from aryl, heteroaryl, said groups being optionally substituted by one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, amino, hydroxy, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, and thiomorpholinyl; the above-mentioned group C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, cycloalkyl, aryl, piperazinyl, piperidinyl, pyridyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, and optionally substituted with one or more C_1-6Alkyl radical, C_1-6Alkoxy, or C_1-6Alkoxycarbonyl group substituted;

R₄selected from the group consisting of hydroxy, alkyl, alkoxy, alkenyl, alkynyl, halo, amino, mercapto, aryl, heteroaryl, saccharide, uronic acid; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino, mercapto, aryl, heteroaryl, and the like;

R₅and R₆Independently selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, halogen, amino, mercapto, aryl, heteroaryl; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, amino,Mercapto, aryl, heteroaryl, and the like;

and compounds IMA-1 were excluded

In one embodiment of the invention, R₁And R₂Each independently selected from H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo (including F, Cl, Br, I), amino, each of which is optionally substituted with one or more groups selected from: c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, hydroxy, and C_1-6An alkoxy group.

In another embodiment of the invention, R₁And R₂Each independently selected from H, C_1-6Alkyl and C_1-6An alkoxy group.

In other embodiments of the invention, R₁Is selected from H or C_1-6An alkyl group.

In other embodiments of the invention, R₂Is selected from H or C_1-6Alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

In other embodiments of the invention, R₂Selected from methoxy.

In one embodiment of the invention, R₃Selected from aryl, heteroaryl, e.g. phenyl, benzothiazolyl, said groups being optionally substituted by one or more groups selected from: c_1-6Alkyl, halogen, amino, hydroxy, and C_1-6An alkoxy group.

In another embodiment of the invention, R₃Selected from phenyl or benzothiazolyl.

In another embodiment of the invention, R₃Is selected from benzothiazolyl.

In one embodiment of the invention R₄Selected from hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, halogen, amino, sulfydryl and arylHeteroaryl, saccharides, uronic acids; each of the above groups is optionally substituted with one or more groups selected from: alkyl, halogen, hydroxy, alkoxy, and aryl.

In one embodiment of the invention R₄Selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen, amino, benzylthio, phenyl, pyridyl, and saccharide; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, halogen, hydroxy and alkoxy.

In one embodiment of the invention, R₄Substituted with a group selected from the group consisting of glucosyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, ethynyl, propynyl, halogen, amino, benzylthio, phenyl, and pyridyl; each of the foregoing groups is optionally substituted with one or more groups selected from: alkyl, halogen, hydroxy and alkoxy.

In a preferred embodiment of the invention, R₄Selected from the group consisting of hydroxy, glucosyl, fructosyl, galactosyl, lactosyl, glucuronyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, ethenyl, propenyl, ethynyl, propynyl, fluoro, chloro, bromo, iodo, amino, benzylthio, phenyl, and pyridyl.

In another preferred embodiment of the invention, R₄Selected from the group consisting of hydroxy, glucosyl, fructosyl, galactosyl, lactosyl, glucuronyl, methyl, methoxy, vinyl, ethynyl, chloro, amino, benzylthio, phenyl, and pyridyl.

In one embodiment of the invention, R₅Selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, halogen and amino.

In a preferred embodiment of the invention, R₅Selected from the group consisting of methyl, propoxymethyl, propenyl, and propynyl.

In one embodiment of the invention, R₆Selected from alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynylHalogen, alkylamino, amino, phenyl, and pyridyl.

In a preferred embodiment of the invention, R₆Selected from the group consisting of methyl, ethoxymethyl, propenyl, propynyl, ethylamino, phenyl, and pyridyl.

More specifically, the invention relates to compounds of the following series:

series 1 Compound (IMA-2 ~ IMA-11)

Series 2 compounds (IMA-12 ~ IMA-15)

Series 3 compounds (IMA-16 ~ IMA-23)

According to another aspect of the present invention, there is provided a pharmaceutical composition characterized in that it comprises a 4-benzylaminophenylsulfonamide derivative or a pharmaceutically acceptable salt, solvate, or metabolite thereof.

According to the present invention, it is preferred that the pharmaceutical composition further comprises pharmaceutically acceptable adjuvants.

The pharmaceutically acceptable excipients are various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH adjusters, preservatives, lubricants, disintegrants, and the like.

Such diluents are for example: lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, and the like. The binder is, for example: starch, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like. The antioxidant is, for example: vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole, etc. The pH adjusting agent is, for example: hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like. Such preservatives are, for example: methyl paraben, ethyl paraben, m-cresol, benzalkonium chloride, and the like. The lubricant is, for example: magnesium stearate, aerosil, talc powder and the like. The disintegrant is, for example: starch, methyl cellulose, xanthan gum, croscarmellose sodium, and the like.

The dosage form of the medicament of the invention can be in the form of oral preparations, such as tablets, capsules, pills, powders, granules, suspensions, syrups and the like; it can also be made into injection, such as injection solution, powder for injection, etc., by intravenous, intraperitoneal, subcutaneous or intramuscular route; or orally administered, such as orally disintegrating tablets, buccal tablets; it can also be administered topically, such as vaginally, rectally, dermally, intranasally, etc. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.

According to another aspect of the present invention, the present invention provides a use of a 4-benzylaminophenylsulfonamide derivative or a pharmaceutically acceptable salt, solvate, or metabolite thereof for the manufacture of a medicament for the treatment and/or prevention of fatty liver disease and related metabolic diseases, obesity and related metabolic diseases, diabetes and related diseases, ischemia-reperfusion injury and related diseases, and/or pathological cardiac hypertrophy and related diseases.

According to the present invention, the fatty liver disease and related diseases include, but are not limited to: simple steatosis, nonalcoholic steatohepatitis, alcoholic fatty liver disease, hepatic fibrosis, liver cirrhosis, liver cancer, etc.

According to the present invention, the obesity and related diseases include, but are not limited to: obesity, excessive body weight, hyperlipidemia, fatty liver, coronary heart disease, hypertension, sleep apnea syndrome, cardiovascular and cerebrovascular diseases, cancer, etc.

According to the present invention, the diabetes and related diseases include, but are not limited to: hyperglycemia, insulin resistance, type I diabetes, type II diabetes, abnormal carbohydrate metabolism, diabetic nephropathy, diabetic foot, acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma, glucagon tumor, and the like.

According to the invention, the ischemia-reperfusion injury and related diseases are preferably liver ischemia-reperfusion injury and related diseases, heart ischemia-reperfusion injury and related diseases, kidney ischemia-reperfusion injury and related diseases, and/or brain ischemia-reperfusion injury and related diseases; more preferably, the ischemia-reperfusion injury of the liver and related diseases and the ischemia-reperfusion injury of the heart and related diseases are selected. The ischemia reperfusion injury can be caused by organ transplantation, partial or complete tissue excision, tissue recanalization after ischemia caused by vascular embolism and other reasons.

Liver ischemia reperfusion injury and related diseases include but are not limited to: liver cyst, liver transplantation, thrombolytic therapy, hepatic portal block surgery, hepatic coma, liver failure, liver inflammatory diseases, etc.

Cardiac ischemia reperfusion injury and related diseases include, but are not limited to: myocardial infarction, myocardial infarction recanalization injury, heart transplantation, coronary thrombolysis, percutaneous coronary angioplasty, intracoronary dilatation, coronary artery bypass.

Renal ischemia reperfusion injury and related diseases include but are not limited to: kidney transplantation, kidney cyst, renal vascular surgery.

Cerebral ischemia reperfusion injury and related diseases include but are not limited to: stroke, cerebral vascular surgery, etc.

According to the present invention, said pathological myocardial hypertrophy and related disorders include, but are not limited to: cardiac remodeling such as ventricular remodeling, myocardial infarction, heart failure, arrhythmia, hypertension, coronary heart disease, arterial embolism, angina, cardiac conduction block, and the like.

The medicament of the present invention may be administered to any animal that may or may not have the above-mentioned disease. These animals include both human and non-human animals, such as pets or livestock, and the like.

The agents of the invention may be administered to a subject by any route known in the art, including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraperitoneal, intrahepatic, intramyocardial, intrarenal, vaginal, rectal, buccal, sublingual, intranasal, transdermal, and the like.

The dosage administered will depend on the age, health and weight of the recipient, the type of combination, the frequency of treatment, the route of administration, etc. The drug may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. The medicament can be administered before, during or after surgery. The dose may be administered one or more times, and the administration time may be from a single day to several months or longer. The single dose of the drug may vary over a wide range of about 0.0001 to about 10000mg per patient per day. This range may more particularly be about 0.001mg/kg to 100mg/kg body weight per day for an adult (about 60 kg).

According to the invention, the medicament can also be administered in combination with other medicaments for the treatment of the above-mentioned diseases.

General synthetic schemes

The compounds of the present invention can be prepared by following reaction schemes from commercially available starting materials, compounds known in the literature, or readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art. It is to be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar proportions of reactants, solvent, pressure, etc.) are given; other preparation conditions may also be used unless otherwise specified. The reaction conditions may vary with the particular reactants or solvents used. Those skilled in the art will recognize that the nature and order of the synthetic steps provided may be varied to optimize the formation of the compounds described herein.

The compounds prepared are identified according to any suitable method known in the art. For example, nuclear magnetic resonance spectroscopy (e.g., nuclear magnetic resonance spectroscopy)¹H or¹³C) Infrared spectroscopy, spectrophotometry, mass spectrometry, or monitoring product formation by chromatography such as High Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), gel-permeation chromatography (GPC), or Thin Layer Chromatography (TLC).

The following routes, including those mentioned in the examples and preparations, illustrate the synthesis of compounds of formula (I). It will be appreciated by those skilled in the art that the compounds of the invention and intermediates thereof may be prepared by methods other than those specifically described herein. Accordingly, the methods described herein can be varied by those skilled in the art by synthetic methods known in the art.

When solvent ratios are given, the ratios are by volume.

It will be appreciated by those skilled in the art that the experimental conditions set forth in the schemes that follow illustrate suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for preparing the compounds of formula (I).

Synthesis scheme of series 1 compounds

Synthesis scheme of series 3 compounds

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.