CN117500791A - Compounds useful for treating liver diseases - Google Patents

Compounds useful for treating liver diseases Download PDF

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CN117500791A
CN117500791A CN202280033302.1A CN202280033302A CN117500791A CN 117500791 A CN117500791 A CN 117500791A CN 202280033302 A CN202280033302 A CN 202280033302A CN 117500791 A CN117500791 A CN 117500791A
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alkyl
group
independently
haloalkyl
hydrogen
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J-L·H·达瑟
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Abionix Pharmaceuticals
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Abionix Pharmaceuticals
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Priority claimed from US17/219,058 external-priority patent/US11634387B2/en
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Priority claimed from PCT/IB2022/000106 external-priority patent/WO2022189856A1/en
Publication of CN117500791A publication Critical patent/CN117500791A/en
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Abstract

The present invention provides, for example, compounds of formulas (a) - (H) and (J) - (AA) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof. The invention further provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or vehicle. The compounds and compositions disclosed herein are useful for treating or preventing various diseases and conditions, for example liver diseases such as liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH), and kidney diseases such as Acute Kidney Injury (AKI).

Description

Compounds useful for treating liver diseases
1. Cross-reference to related applications
The present application claims priority from U.S. patent No. 17/195,334 to 2021, 3, 8 and U.S. patent No. 17/219,058 to 2021, 3, 31, each of which is incorporated herein by reference in its entirety.
2. Field of the invention
The present invention provides novel compounds, such as compounds of formulae (a) - (H) and (J) - (AA), and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, such as 2- (4- (3-hydroxy-3- (4- (methylsulfanyl) phenyl) prop-1-en-1-yl) -2, 6-dimethylphenoxy) -2-methylpropanoic acid ("compound I"), 3- (4- ((1-hydroxy-2-methylpropan-2-yl) oxy) -3, 5-dimethylphenyl) -1- (4- (methylsulfanyl) phenyl) prop-2-en-1-one ("compound II") and 3- (4- ((1-hydroxy-2-methylpropan-2-yl) oxy) -3, 5-dimethylphenyl) -1- (4- (methylsulfanyl) phenyl) prop-2-en-1-ol ("compound III"), and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof. The invention further provides pharmaceutical compositions comprising novel compounds described herein, e.g., compounds of formulas (a) - (H) and (J) - (AA), or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof (e.g., compound I, compound II, or compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof), and a pharmaceutically acceptable carrier or vehicle. The compounds and compositions disclosed herein are useful for treating or preventing disorders, for example liver diseases such as liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
3. Background art
Elevated low density lipoprotein cholesterol (LDL-C) and triglyceride levels are associated with mixed dyslipidemia. Type IIb hyperlipidemia is a mixed dyslipidemia characterized by elevated levels of apolipoprotein B, very low density lipoprotein cholesterol (VLDL-C), intermediate density lipoprotein cholesterol (IDL) and small density Low Density Lipoprotein (LDL) in addition to elevated levels of LDL-C and triglycerides.
Liver diseases, such as nonalcoholic fatty liver disease (NAFLD), include a range of conditions ranging from relatively benign steatosis to more severe nonalcoholic steatohepatitis (NASH), which, if untreated, may lead to fibrosis, cirrhosis, liver failure, or hepatocellular carcinoma. NAFLD and NASH may develop due to overproduction and accumulation of triglycerides in the liver. NAFLD is closely related to the characteristics of obesity, diabetes, dyslipidemia, hyperlipidemia and metabolic syndrome, including obesity, insulin resistance, type 2 diabetes and dyslipidemia. NASH can lead to liver swelling, inflammation, fibrosis, damage and eventual loss of function. NASH tends to develop in overweight or obese, or people with diabetes, mixed dyslipidemia, high cholesterol or high triglycerides or inflammatory conditions. NASH is characterized by a bulge of hepatocytes and inflammation of the liver, which can lead to liver injury and progress to scarring and irreversible changes, similar to those caused by high volume drinking.
Liver steatosis and fibrosis may also be caused by drugs such as amiodarone, valproic acid, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents (Amacher, d.e., et al, semin. Lever dis.,2014,34,205). Drug-induced liver steatosis is reversible and may involve drug accumulation in the liver.
NAFLD, NASH, fatty liver or drug induced liver steatosis can lead to metabolic complications including elevated liver enzymes, fibrosis, cirrhosis, hepatocellular carcinoma and liver failure. Liver failure is life threatening, and there is a need to develop therapeutic methods to delay the progression of fatty liver, prevent the formation of fatty liver, or reverse the condition of fatty liver.
Peroxisome Proliferator Activated Receptors (PPARs) have been identified as targets for the treatment of cardiovascular metabolic diseases, including diabetes, insulin resistance, dyslipidemia, and liver diseases (e.g., NAFLD and NASH). PPARs are of three types: pparα, pparγ, and pparδ. Several PPAR agonists have been marketed, including fenofibrate (pparα agonist), bezafibrate (pparpan agonist), pioglitazone (pparγ agonist) and rosiglitazone (pparγ agonist). Recently, PPAR agonists such as seladelpar (pparδ agonist), lanilano (lanibrator) (pan agonist) and elafilbar (pparα/δ dual agonist) have been studied for the treatment of NASH and primary cholangitis (PBC). However, some clinical trials involving such PPAR agonists fail due to toxicity or failure to reach the primary endpoint. For example, in phase 3 trials in adults with NASH and fibrosis, the primary endpoint of elafibor to NASH regression did not show statistically significant effect without fibrosis exacerbation (ir. Genfit. Com/news-release-details/genes-processes-results-inter-analysis-resolution-it-phase-3).
Pparδ agonists have also been proposed for the treatment of Acute Kidney Injury (AKI). See, e.g., WO 2018/067857.AKI is common in ICU patients, with an estimated incidence of >50% (Hoste et al, 2015,Intensive Care Med;41:1411-1423). Furthermore, an increase in AKI severity is associated with an increase in mortality. Sepsis is the leading cause of AKI, accounting for 45% to 70% of cases of AKI, and about 25% of sepsis originates intraperitoneally (Seymour et al, 2016, jama,315:762-774;Bagshaw et al, 2007,Clin J Am Soc Nephrol,2:431-439). Ischemia/reperfusion injury (IRI) can lead to AKI and is a common complication in subjects receiving organ transplants with a incidence of 50-75% after lung and heart transplants (Gueler et al 2014,Transplantation 98:337-338). PPARdelta agonist ASP1128 (also known as MA-0217) (Astella) is being investigated as a possible treatment for AKI after coronary bypass surgery and/or valve surgery (ClinicalTrials gov identifier NCT 03941483). However, no pparδ agonists have been approved and marketed for the treatment of AKI to date.
There remains a need for new prophylaxis and treatment of liver disorders, kidney disorders and other conditions associated with PPARs.
4. Summary of the invention
The present invention provides novel compounds and their use in the treatment of various disorders, such as liver disorders (e.g., NASH), kidney disorders (e.g., AKI), and other conditions associated with PPAR. Without being bound by theory, the inventors believe that the clinical utility of PPAR agonists, such as elafibor, is limited by their toxicity, such that the dose is often not sufficiently increased to achieve an effective dose. The present invention provides novel compounds, including elafibor derivatives and related compounds described in WO 2011/020001, WO 2017/06246, WO 2017/180818 and WO 2018/067857, and derivatives of PPAR modulators. Without being bound by theory, the inventors believe that the compounds described herein may act as PPAR agonists and/or PPAR agonist prodrugs, which have advantageous properties resulting in improved bioavailability and/or half-life and/or safety and/or efficacy and/or improved therapeutic index after administration. In particular, the compounds may thus have improved therapeutic index. The Therapeutic Index (TI) is the ratio of the dose at which a compound is toxic to its effective dose. One common measurement of TI is TD 50 /ED 50 Wherein TD 50 And ED 50 Respectively a toxic dose and an effective dose for 50% of the population. The larger the TI, the safer the compound. Compounds with low TI may be difficult to use in clinical practice and it is often necessary to monitor plasma concentrations to prevent toxicity. One or more advantageous properties of the compounds of the present disclosure (e.g., elafibor or one or more PPAR agonists described in WO 2011/020001, WO 2017/06246, WO 2017/180818, and/or WO 2018/067857) may include, for example, better solubility, better kinetics, better absorption, better PPAR receptor selectivity at pharmaceutically effective doses, reduced drug metabolism of cytochrome P450 or other enzymes such as reductase, reduced glucuronidation, reduced toxicity, or a combination thereof, as compared to known PPAR agonists.
In various aspects, the invention provides compounds of formulas (a) - (H) and (J) - (AA), and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
In one aspect, the invention provides a compound of formula (a):
and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C 3 -C 7 Cycloalkyl groups;
x is-CH 2 OH、-COOH、-COH、-COOR 3 、-COOCH 2 CONR 4 R 5 、-SO 3 H、
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
In another aspect, the present invention also provides a compound of formula (B):
and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C 3 -C 7 Cycloalkyl groups;
x is-CH 2 OH、-COH、-COOCH 2 CONR 4 R 5 、-SO 3 H、
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
The present invention provides 2- (4- (3-hydroxy-3- (4- (methylsulfanyl) phenyl) prop-1-en-1-yl) -2, 6-dimethylphenoxy) -2-methylpropanoic acid ("compound I") and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein compound I has the structure:
The present invention also provides 3- (4- ((1-hydroxy-2-methylpropan-2-yl) oxy) -3, 5-dimethylphenyl) -1- (4- (methylsulfanyl) phenyl) prop-2-en-1-one ("compound II") and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein compound II has the structure:
the invention further provides 3- (4- ((1-hydroxy-2-methylpropan-2-yl) oxy) -3, 5-dimethylphenyl) -1- (4- (methylsulfanyl) phenyl) prop-2-en-1-ol ("compound III") and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein compound III has the structure
In another aspect, the present invention provides a compound of formula (C)
And pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, wherein:
R 1 is phenyl, naphthyl, pyridinyl, thienyl, furyl, quinolinyl or benzothienyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
R 2 is C 2-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl or C substituted by phenyl, naphthyl or pyridyl 1-6 Alkyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
a is oxygen, sulfur or NR 9 Wherein R is 9 Is hydrogen or C 1-8 An alkyl group;
x is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy or hydroxy substituted and having 0 or 1 double bond;
y is C (=O), C (=N-OR 10 )、CH(OR 11 ) Ch=ch, c≡c or C (=ch 2 ) Wherein R is 10 And R is 11 Each hydrogen or C 1-8 An alkyl group;
R 3 、R 4 and R is 5 Each independently is hydrogen,C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl; optionally, wherein R 3 、R 4 And R is 5 At least one of which is not hydrogen;
b is CH or nitrogen;
z is oxygen or sulfur;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
Each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In other aspects, the invention provides compounds of formulas (D) - (H) and (J) - (AA) and pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
The invention further provides a device with the following structureCompounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
The invention further provides a device with the following structureCompounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
The invention further provides a device with the following structure
Pharmaceutically acceptable salts, solvates, esters, amides and prodrugs.
The invention further provides a device with the following structureCompounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
In a further aspect, the invention provides compounds of formulae (D) - (H) and (J) - (AA) (e.g., as described in section 5.2 (including sub-portions)) as well as pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
The invention further provides a device with the following structure
Compounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
The invention further provides a device with the following structure
Compounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
The invention further provides a device with the following structure
Compounds of (c) and pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof.
Each of the compounds of formulae (a) - (H) and (J) - (AA), each of the compounds I, II, III, IV, V, va, vb, VI, VII and VIII, and each of the compounds described in paragraphs 5-7 (including sub-portions thereof), or pharmaceutically acceptable salts, solvates, esters, amides and prodrugs thereof, are "compounds of the invention". Exemplary characteristics of the compounds of the present invention are described below in section 5.2 and in embodiments 1 to 50 in section 7.1 and in embodiments 1 to 209 in section 7.2.
The invention also provides compositions comprising i) an effective amount of a compound of the invention and ii) a pharmaceutically acceptable carrier or vehicle (each composition is a "composition of the invention"). Exemplary features of the pharmaceutical compositions of the present disclosure are described below in section 5.3 and in section 7.1 embodiments 51-54 and in section 7.2 embodiments 210-213.
The invention further provides methods for treating or preventing liver disorders, dyslipidemia, kidney disease, a glucose metabolism disorder, a lipid metabolism disorder, a carbohydrate metabolism disorder (a disorder of glucid metabolism), cardiovascular disease, vascular disease, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorders, sepsis, thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders associated with neovascularization, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, tumor diseases, muscle atrophy, cholestasis, mitochondrial dysfunction, ocular diseases, lysosomal storage diseases, kidney disease (e.g., acute kidney injury), or impotence, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for treating or preventing hyperlipidemia (hyperlipemia), hyperlipidemia (hyperlipidemia), hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia or dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.
The invention further provides a method for treating a subject having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, or preventing a subject from having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, comprising administering to the subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for treating a subject having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject or preventing a subject from having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for treating a subject having or preventing a subject having or having a abnormally reduced or deficient concentration or activity of a lipoprotein lipase in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a composition of the invention or a composition of the invention.
The present invention provides a method for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with alzheimer's disease, or familial mixed hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for reducing abnormally high concentrations of triglycerides, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) (Lp (a)), the ratio of apolipoprotein B, HDL/(vldl+ldl), apolipoprotein C-II or apolipoprotein C-III in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for increasing abnormally low concentrations of High Density Lipoprotein (HDL) -associated protein, HDL-cholesterol, apolipoprotein a-I, or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for increasing abnormally low glucose metabolism or abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for treating or preventing one or more symptoms of inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for reducing the fat content of livestock meat comprising administering to livestock an effective amount of a compound of the invention or a composition of the invention.
The invention further provides a method for reducing the cholesterol content of an avian egg comprising administering to an avian an effective amount of a compound of the present invention or a composition of the present invention.
Exemplary uses of the compounds and compositions of the present disclosure are described in embodiments 55-163 in section 7.1 and embodiments 214-322 in section 7.2 below.
5. Detailed description of the invention
5.1. Definition of the definition
The term "about" when immediately preceding a numerical value refers to ± up to 20% of the numerical value. For example, an "about" value refers to a value of ± up to 20%, in some embodiments, ±up to 19%, ±up to 18%, ±up to 17%, ±up to 16%, ±up to 15%, ±up to 14%, ±up to 13%, ±up to 12%, ±up to 11%, ±up to 10%, ±up to 9%, ±up to 8%, ±up to 7%, ±up to 6%, ±up to 5%, ±up to 4%, ±up to 3%, ±up to 2%, ±up to 1%, ±up to less than 1%, or any other value or range of values therein.
Throughout this specification, certain amounts of numerical ranges are provided. These ranges include all subranges therein. Thus, a range of "from 50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Moreover, all values within a given range may be endpoints of the range encompassed thereby (e.g., ranges 50 to 80 include ranges having endpoints such as 55 to 80, 50 to 75, etc.).
The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts. Pharmaceutically acceptable salts can be obtained by reacting a compound of the invention as a base with an inorganic or organic acid to form a salt (e.g., a salt of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, and the like). Pharmaceutically acceptable salts can also be obtained by reacting the present invention as an acid with an inorganic or organic base to form a salt (e.g., a salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonia, isopropylamine, trimethylamine, choline, betaine, and the like). Inorganic bases may include, but are not limited to, calcium hydroxide, potassium hydroxide, sodium hydroxide, and sodium carbonate. Organic bases may include, but are not limited to, primary, secondary, tertiary, substituted amines (including naturally occurring substituted amines) and cyclic amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, glucosamine, N-alkyl glucamines, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and the like. Those skilled in the art will further recognize that pharmaceutically acceptable salts may be prepared by reacting the compounds of the present invention with a suitable inorganic or organic acid or base via any of a variety of known methods.
The term "solvate" refers to a solvated complex. Solvates may be formed by solvation (combination of solvent molecules with molecules or ions of the compounds of the invention), or solvates may be aggregates comprising solute ions or molecules or solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and the like. Solvates may be formed by hydration, including by absorption of moisture. Pharmaceutically acceptable salts may also be solvates. When the solvate is obtained by crystallization from a solvent, the solvent may be an alcohol, such as methanol or ethanol; an aldehyde; ketones, such as acetone; or esters, such as ethyl acetate.
The compounds of the present invention may have one or more asymmetric centers and thus may be enantiomers, racemates, diastereomers, other stereoisomers, and mixtures thereof. The compounds of the present invention include all such possible isomers (including geometric isomers), as well as their racemic and optically pure forms, whether or not they are specifically described herein. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing or separating the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate using, for example, chiral High Pressure Liquid Chromatography (HPLC). Likewise, the compounds of the present invention include all tautomeric forms.
The phrase "substantially free of its corresponding opposite enantiomer" refers to having no more than about 10 mole%, in another embodiment no more than about 5 mole%, in another embodiment no more than about 2 mole%, in another embodiment no more than about 1 mole%, in another embodiment no more than about 0.5 mole%, and in another embodiment no more than about 0.1 mole% of its corresponding opposite enantiomer.
The phrase "substantially free of its corresponding opposite stereoisomer" means having no more than about 10 mole%, in another embodiment no more than about 5 mole%, in another embodiment no more than about 2 mole%, in another embodiment no more than about 1 mole%, in another embodiment no more than about 0.5 mole%, and in another embodiment no more than about 0.1 mole% of its corresponding opposite stereoisomer.
The phrase "substantially free of its corresponding other olefin configuration" refers to having no more than about 10 mole%, in another embodiment no more than about 5 mole%, in another embodiment no more than about 2 mole%, in another embodiment no more than about 1 mole%, in another embodiment no more than about 0.5 mole%, and in another embodiment no more than about 0.1 mole% of its corresponding other olefin configuration.
When used in connection with a compound of the present invention, an "effective amount" refers to an amount of a compound of the present invention that is effective to treat or prevent a disease or disorder disclosed herein when administered to a subject alone or in combination with another pharmaceutically active agent.
When used in connection with another pharmaceutically active agent, an "effective amount" refers to an amount of the other pharmaceutically active agent that is effective, alone or in combination with a compound of the present invention, to treat or prevent the diseases or conditions disclosed herein.
A "subject" is a human or non-human mammal, such as a cow, horse, cat, dog, rodent or non-human primate. The person may be male or female, a child, a teenager or an adult. The female may be a beginner before or after the beginning of the tide.
"mammal" includes humans, domestic animals such as laboratory animals (e.g., mice, rats, rabbits, monkeys, dogs, etc.), and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic wild animals.
All weight percentages referred to herein (i.e., "wt%" and "wt.%" and w/w) are relative to the total weight of the mixture or composition (as the case may be), unless otherwise indicated.
"alkyl" refers to a fully saturated straight or branched hydrocarbon chain having from 1 to 12 carbon atoms, and which is attached to an atom by a single bond. Including alkyl groups having carbon numbers ranging from 1 to 12. An alkyl group having 1 to 12 carbon atoms is C 1 -C 12 Alkyl (alternatively denoted C 1-12 Alkyl) having 1 to 10 carbon atoms is C 1 -C 10 Alkyl (alternatively denoted C 1-10 Alkyl) having 1 to 6 carbon atoms is C 1 -C 6 Alkyl (alternatively denoted C 1-6 Alkyl) having 1 to 5 carbon atoms is C 1 -C 5 Alkyl (alternatively denoted C 1-5 Alkyl), and the like. C (C) 1 -C 5 Alkyl includes C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl and C 1 Alkyl (i.e., methyl). C (C) 1 -C 6 Alkyl groups include C as described above 1 -C 5 All parts of alkyl groups, and also C 6 An alkyl group. C (C) 1 -C 10 Alkyl groups include C as described above 1 -C 5 Alkyl and C 1 -C 6 All parts of alkyl groups, and also C 7 、C 8 、C 9 And C 10 An alkyl group. Similarly, C 1 -C 12 Alkyl includes all of the foregoing moieties, but also includes C 11 And C 12 An alkyl group. C (C) 1 -C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless otherwise indicated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, the alkyl group is unsubstituted.
"alkoxy" refers to RO, wherein R is alkyl.
"alkenyl" refers to a straight or branched hydrocarbon chain having from 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to an atom by a single bond. Comprising alkenyl groups having a number of carbon atoms ranging from 2 to 12. Having 2 toThe alkenyl radical having 12 carbon atoms being C 2 -C 12 Alkenyl (or C) 2-12 Alkenyl) having 2 to 10 carbon atoms is C 2 -C 10 Alkenyl (or C) 2-10 Alkenyl) having 2 to 6 carbon atoms is C 2 -C 6 Alkenyl (or C) 2-6 Alkenyl) and an alkenyl group having 2 to 5 carbon atoms is C 2 -C 5 Alkenyl (or C) 2-5 Alkenyl), and the like. C (C) 2 -C 5 Alkenyl groups include C 5 Alkenyl, C 4 Alkenyl, C 3 Alkenyl and C 2 Alkenyl groups. C (C) 2 -C 6 Alkenyl groups include C as described above 2 -C 5 All parts of alkenyl groups, and also C 6 Alkenyl groups. C (C) 2 -C 10 Alkenyl groups include C as described above 2 -C 5 Alkenyl and C 2 -C 6 All parts of alkenyl groups, and also C 7 、C 8 、C 9 And C 10 Alkenyl groups. Similarly, C 2 -C 12 Alkenyl includes all of the foregoing moieties, and also includes C 11 And C 12 Alkenyl groups. C (C) 2 -C 12 Non-limiting examples of alkenyl groups include vinyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecacarbon Alkenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl and 11-dodecenyl. Unless otherwise indicated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, the alkenyl group is unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to an atom by a single bond. Including alkynyl groups having carbon numbers ranging from 2 to 12. Alkynyl groups having 2 to 12 carbon atoms are C 2 -C 12 Alkynyl (alternatively denoted C 2-12 Alkynyl), alkynyl groups having 2 to 10 carbon atoms being C 2 -C 10 Alkynyl (alternatively denoted C 2-10 Alkynyl), alkynyl groups having 2 to 6 carbon atoms being C 2 -C 6 Alkynyl (alternatively denoted C 2-6 Alkynyl) and alkynyl groups having 2 to 5 carbon atoms are C 2 -C 5 Alkynyl (alternatively denoted C 2-5 Alkynyl). C (C) 2 -C 5 Alkynyl includes C 5 Alkynyl, C 4 Alkynyl, C 3 Alkynyl and C 2 Alkynyl groups. C (C) 2 -C 6 Alkynyl groups include C as described above 2 -C 5 All parts of alkynyl groups, and also C 6 Alkynyl groups. C (C) 2 -C 10 Alkynyl groups include C as described above 2 -C 5 Alkynyl and C 2 -C 6 All parts of alkynyl groups, and also C 7 、C 8 、C 9 And C 10 Alkynyl groups. Similarly, C 2 -C 12 Alkynyl includes all of the foregoing moieties, and also includes C 11 And C 12 Alkynyl groups. C (C) 2 -C 12 Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise indicated, alkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, the alkynyl group is unsubstituted.
"aryl" means a radical comprising hydrogen, 6 to 18 carbon atoms andat least one aromatic hydrocarbon ring system group. The aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, acetenyl (acetenyl), acenaphthenyl (acenaphthenyl), anthracyl, azulenyl (azulenyl), chicoryRadicals (chrysenyl), phenylfluorenyl (fluorohedyl), fluorenyl, as-dicyclopentadienyl (as-indacenyl), s-dicyclopentadienyl, indanyl, indenyl, naphthyl, radicals (phenalenyl), phenanthryl, phenyl, biphenyl (pleiadienyl), pyrenyl and triphenylenyl (triphenylenyl). Unless otherwise indicated, aryl groups may be unsubstituted or substituted with substituents as disclosed herein. In some embodiments, the aryl group is unsubstituted.
"cycloalkyl" refers to a non-aromatic monocyclic or polycyclic, fully saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include a fused or bridged ring system having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and which is attached to an atom by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7 dimethyl-bicyclo [2.2.1] heptyl, and the like. Unless otherwise indicated, cycloalkyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, the cycloalkyl group is unsubstituted.
"halo" or "halogen" means chloro, fluoro, bromo or iodo.
"haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen. Examples of haloalkyl groups include trifluoromethyl (CF 3 ) Difluoromethyl (CF) 2 H) Fluoromethyl (CH) 2 F) Pentafluoroethyl (CF) 2 CF 3 ) Tetrafluoroethyl (CHFCF) 3 ) Fluoroethyl (CH) 2 CH 2 F) Trifluoroethyl (CH) 2 CF 3 ) Tetrafluorotrifluoromethyl ethyl (CF) 3 ) 2 )。
"haloalkoxy" refers to RO, wherein R is a haloalkyl group.
"heteroaryl" refers to a 5-to 20-membered ring system group comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 nitrogen, oxygen or sulfur heteroatoms, and at least one aromatic ring. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples of heteroaryl groups include, but are not limited to, azepinyl (azepinyl), acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl (benzodioxanyl), benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxacycloheptyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyranonyl (benzofuranyl), benzofuranyl, benzofuranonyl (benzofuranonyl), benzothiophenyl (benzothiophene), benzotriazolyl, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, zeng Qinji (cinnolyl), dibenzofuranyl, dibenzothiophene, furanyl, isoxazolyl, indazolyl, indolinyl, isoindolinyl, 2-Oxoazepinyl (2-oxazepinyl), oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl). Unless otherwise indicated, heteroaryl groups may be unsubstituted or substituted. In some embodiments, the heteroaryl group is unsubstituted.
"heterocyclyl" refers to a 3 to 20 membered non-aromatic, partially unsaturated or aromatic ring group containing 2 to 12 carbon atoms and from 1 to 6 nitrogen, oxygen or sulfur heteroatoms. Heterocycles include heteroaryl groups as defined herein. Unless otherwise indicated, heterocyclyl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused, bridged and spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl groups may be partially or fully saturated. Examples of heterocyclyl groups include, but are not limited to, dioxanyl, thienyl [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiohexanyl (trithianyl), tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxothiomorpholinyl. Unless otherwise indicated, heterocyclyl groups may be unsubstituted or substituted with substituents disclosed herein. In some embodiments, the heterocyclyl group is unsubstituted.
As used herein, a symbolThe term "attachment point bond" refers to a bond at an attachment point between two chemical entities, one of which is described as attached to the attachment point bond and the other of which is not described as attached to the attachment point bond. For example, a->Meaning that chemical entity "XY" is bonded to another chemical entity through a point of attachment.
5.2. Compounds of the invention
5.2.1. A compound of formula (A)
In some embodiments, the compounds of the present invention are compounds of formula (a):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C 3 -C 7 Cycloalkyl;
x is-CH 2 OH、-COOH、-COH、-COOR 3 、-COOCH 2 CONR 4 R 5 、-SO 3 H、
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
In some embodiments, the compound of formula (a) is a racemate or a mixture of enantiomers or diastereomers. In some embodiments, the compound of formula (a) has the olefin isomer configuration of (Z) or (E). In some embodiments, the hydroxyl-bearing allylic carbon atom of the compound of formula (a) has (R) -or (S) -stereochemistry.
In some embodiments, the compound of formula (a) is the (Z) -isomer (or cis) and has the structure:in some embodiments, the compound of formula ((Z) -a) is substantially free of its corresponding other olefin configuration (i.e., (E) -isomer).
In some embodiments, the compound of formula (a) is the (E) -isomer (or trans) and has the structure:in some embodiments, the compound of formula ((E) -a) is substantially free of its corresponding other olefin configuration (i.e., (Z) -isomer).
In some embodiments, the compound of formula (a) has an allylic carbon atom with a hydroxyl group, the carbon atom has (R) -stereochemistry, and the compound has the structure:
in some embodiments, the compound of formula ((R) -a) is substantially free of its corresponding opposite stereoisomer (i.e., a compound of formula (a) having an (S) -stereochemically pure allylic carbon atom with a hydroxyl group).
In some embodiments, the compound of formula (a) has an allylic carbon atom with a hydroxyl group, the carbon atom has (S) -stereochemistry, and the compound has the structure:
in some embodiments, the compound of formula ((S) -a) is substantially free of its corresponding opposite stereoisomer (i.e., a compound of formula (a) having an (R) -stereochemically pure allylic carbon atom with a hydroxyl group).
In some embodimentsIn (a), the compound of formula (a) is the (Z) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, the carbon atom having (R) -stereochemistry, and the compound has the structure:in some embodiments, the compound of formula ((Z) - (R) -a) is substantially free of the compound of formula ((Z) - (S) -a), ((E) - (R) -a) or ((E) - (S) -a).
In some embodiments, the compound of formula (a) is the (Z) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, the carbon atom having the (S) -stereochemistry, and the compound has the structure:in some embodiments, the compound of formula ((Z) - (S) -a) is substantially free of the compound of formula ((Z) - (R) -a), ((Z) - (R) -a) or ((Z) - (S) -a).
In some embodiments, the compound of formula (a) is an (E) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, the carbon atom having (R) -stereochemistry, and the compound has the structure:in some embodiments, the compound of formula ((E) - (R) -a) is substantially free of the compound of formula ((E) - (S) -a), ((Z) - (R) -a) or ((Z) - (S) -a).
In some embodiments, the compound of formula (a) is an (E) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, the carbon atom having (S) -stereochemistry, and the compound has the structure: In some embodiments, the compound of formula ((E) - (S) -a) is substantially free of the compound of formula ((E) - (R) -a), ((Z) - (R) -a) or ((Z) - (S) -a).
In the formula (A), ((Z) -A), ((E) -A), ((R) -A), ((S) -A), ((E) - (R) -A), ((E) - (S) -A), ((Z) - (R) -A) orIn some embodiments of the compounds of (Z) - (S) -A), each R 1 And R is 2 Independently is-C 1 -C 6 An alkyl group. In some embodiments, each R 1 And R is 2 independently-C 1 -C 3 An alkyl group. In some embodiments, each R 1 And R is 2 Independently methyl.
In some embodiments of the compounds of formula (a), ((Z) -a), ((E) -a), ((R) -a), ((S) -a), ((E) - (R) -a), ((E) - (S) -a), ((Z) - (R) -a) or ((Z) - (S) -a), X is-CH 2 OH, -COOH, -COH, or-COOR 3 or-COOCH 2 CONR 4 R 5 . In some embodiments, X is-CH 2 OH、-COOH、-COOR 3 、-COOCH 2 CONR 4 R 5 . In some embodiments, X is-CH 2 OH or-COOH.
In some embodiments of the compounds of formula (a), ((Z) -a), ((E) -a), ((R) -a), ((S) -a), ((E) - (R) -a), ((E) - (S) -a), ((Z) - (R) -a) or ((Z) - (S) -a), R 3 is-C 1- C 6 An alkyl group. In some embodiments, R 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
In some embodiments of the compounds of formula (a), ((Z) -a), ((E) -a), ((R) -a), ((S) -a), ((E) - (R) -a), ((E) - (S) -a), ((Z) - (R) -a) or ((Z) - (S) -a), n is 0, 1, 2 or 3, in some embodiments n is 0, 1 or 2. In some embodiments, n is 0 or 1.
5.2.1.1. Compound I
In some embodiments, the compounds of the present invention are compound I having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
In some embodiments, compound I is a racemate or a mixture of enantiomers. In some embodiments, compound I has the olefin isomer configuration of (Z) or (E). In some embodiments, compound I has an allylic carbon atom with a hydroxyl group, the carbon atom having (R) -or (S) -stereochemistry.
In some embodiments, compound I is the (Z) -isomer (or cis) and has the following structure:in some embodiments, compound I is the (Z) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (E) -isomer).
In some embodiments, compound I is the (E) -isomer (or trans) and has the following structure:in some embodiments, compound I is the (E) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z) -isomer).
In some embodiments, compound I has an allylic carbon atom with a hydroxyl group, has an (R) -enantiomer, and the compound has the structure:
In some embodiments, compound I has an allylic carbon atom with a hydroxyl group, has the (R) -enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (S) -enantiomer).
In some embodiments, compound I has an allylic carbon atom with a hydroxyl group, has an (S) -enantiomer, and the compound has the structure:
in some embodiments, compound I has an allylic carbon atom with a hydroxyl group, has the (S) -enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (R) -enantiomer). In some embodiments, compound I is a non-racemate of its (R) -enantiomer and (S) -enantiomerAnd (3) a mixture. In some embodiments, the non-racemic mixture has an excess of the (R) -enantiomer relative to the (S) -enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S) -enantiomer relative to the (R) -enantiomer. />
In some embodiments, compound I is a (Z) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, having an (R) -enantiomer, and the compound has the structure:in some embodiments, the compound ((Z) - (R) -I) is substantially free of the compound ((Z) - (S) -I), ((E) - (R) -I) or ((E) - (S) -I).
In some embodiments, compound I is a (Z) -isomer having an allylic carbon atom with a hydroxyl group, having an (S) -enantiomer, and the compound has the structure:in some embodiments, the compound ((Z) - (S) -I) is substantially free of the compound ((Z) - (R) -I), ((E) - (R) -I) or ((E) - (S) -I).
In some embodiments, compound I is an (E) -isomer (or trans) having an allylic carbon atom with a hydroxyl group, having an (R) -enantiomer, and the compound has the structure:in some embodiments, the compound ((E) - (R) -I) is substantially free of the compound (E) - (S) -I), ((Z) - (R) -I) or ((Z) - (S) -I).
In some embodiments, compound I is an (E) -isomer having an allylic carbon atom with a hydroxyl group, having an (S) -enantiomer, and the compound has the structure:in some embodiments, the compound ((E) - (S) -I) is substantially free of the compound ((E) - (R) -I), ((Z) - (R) -I) or ((Z) - (S) -I).
5.2.1.2. Compound III
In some embodiments, the compounds of the present invention are compound III having the structure:
or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
In some embodiments, compound III is a racemate or a mixture of enantiomers. In some embodiments, compound III has the olefin isomer configuration of (Z) or (E). In some embodiments, compound III has an allylic carbon atom with a hydroxyl group, the carbon atom having (R) -or (S) -stereochemistry.
In some embodiments, compound III is the (Z) -isomer (or cis) and has the following structure:in some embodiments, compound III is the (Z) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (E) -isomer).
In some embodiments, compound III is the (E) -isomer (or trans) and has the following structure:in some embodiments, compound III is the (E) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z) -isomer).
In some embodiments, compound III has an allylic carbon atom with a hydroxyl group, has an (R) -enantiomer, and the compound has the structure:
in some embodiments, compound III has an allylic carbon atom with a hydroxyl group, has the (R) -enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (S) -enantiomer).
In some embodiments, compound III has an allylic carbon atom with a hydroxyl group, has the (S) -enantiomer and has the structure:in some embodiments, compound III has an allylic carbon atom with a hydroxyl group, has the (S) -enantiomer and is substantially free of its corresponding opposite enantiomer (i.e., (R) -enantiomer). In some embodiments, compound III is a non-racemic mixture of its (R) -enantiomer and (S) -enantiomer. In some embodiments, the non-racemic mixture has an excess of the (R) -enantiomer relative to the (S) -enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S) -enantiomer relative to the (R) -enantiomer.
In some embodiments, compound III is a (Z) -isomer (or cis) having an allylic carbon atom with a hydroxyl group, having an (R) -enantiomer, and the compound has the structure:in some embodiments, the compound ((Z) - (R) -III) is substantially free of the compound ((Z) - (S) -III), ((E) - (R) -III) or ((E) - (S) -III).
In some embodiments, compound III is a (Z) -isomer having an allylic carbon atom with a hydroxyl group, having an (S) -enantiomer, and the compound has the structure:in some embodiments, the compound ((Z) - (S) -III) is substantially free of the compound ((Z) - (R) -III), ((E) - (R) -III) or ((E) - (S) -III).
In some embodiments, compound I is an (E) -isomer (or trans) having an allylic carbon atom with a hydroxyl group, having an (R) -enantiomer, and the compound has the structure:in some embodiments, the compounds((E) - (R) -III) is substantially free of compounds ((E) - (S) -III), ((Z) - (R) -III) or ((Z) - (S) -III).
In some embodiments, compound III is an (E) -isomer having an allylic carbon atom, having an (S) -enantiomer, and the compound has the structure: In some embodiments, the compound ((E) - (S) -III) is substantially free of the compound ((E) - (R) -III), ((Z) - (R) -III) or ((Z) - (S) -III).
5.2.2. A compound of formula (B)
In some embodiments, the compounds of the present invention are compounds of formula (B):
or a pharmaceutically acceptable salt, solvated ester, amide, or prodrug thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C3-C 7 Cycloalkyl groups;
x is-CH 2 OH、-COH、-COOCH 2 CONR 4 R 5 、-SO 3 H、
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
In some embodiments, the compound of formula (B) is a racemate or a mixture of enantiomers. In some embodiments, the compound of formula (B) has the olefin isomer configuration of (Z) or (E).
In some embodiments, the compound of formula (B) is a (Z) -isomer (or cis) and has the structure:in some embodiments, the compound of formula (B) is the (Z) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (E) -isomer).
In some embodiments, the compound of formula (B) is the (E) -isomer (or trans) and has the structure:in some embodiments, the compound of formula (B) is the (E) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z) -isomer).
In some embodiments of the compounds of formula (B), each R 1 And R is 2 independently-C 1 -C 6 An alkyl group. In some embodiments, each R 1 And R is 2 independently-C 1 -C 3 An alkyl group. In some embodiments, each R 1 And R is 2 Independently methyl.
In some embodiments of the compounds of formula (B), X is-CH 2 OH, -COH or-COOCH 2 CONR 4 R 5 . In some embodiments, X is-CH 2 OH。
In some embodiments of the compounds of formula (B), R 3 is-C 1 -C 6 An alkyl group. In some embodiments, R 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
In some embodiments of the compounds of formula (B), n is 0, 1, 2 or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.
5.2.2.1. Compound II
In some embodiments, the compound of the invention is compound II having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
In some embodiments, compound II has the olefin isomer configuration of (Z) or (E).
In some embodiments, compound II is the (Z) -isomer (or cis) and has the structure:in some embodiments, compound II is the (Z) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (E) -isomer).
In some embodiments, compound II is the (E) -isomer (or trans) and has the structure:in some embodiments, compound II is the (E) -isomer and is substantially free of its corresponding other olefin configuration (i.e., (Z) -isomer). />
5.2.3. A compound of formula (C)
In some embodiments, the compounds of the present invention are compounds of the following formula (C):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is phenyl, naphthyl, pyridyl, thienyl, furyl or quinolinylOr benzothienyl, either of which is unsubstituted or C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
R 2 is C 2-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl or C substituted by phenyl, naphthyl or pyridyl 1-6 Alkyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
a is oxygen, sulfur or NR 9 Wherein R is 9 Is hydrogen or C 1-8 An alkyl group;
x is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy or hydroxy substituted and having 0 or 1 double bond;
y is C (=O), C (=N-OR 10 )、CH(OR 11 ) Ch=ch, c≡c or C (=ch 2 ) Wherein R is 10 And R is 11 Each hydrogen or C 1-8 An alkyl group;
R 3 、R 4 and R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl; optionally, wherein R 3 、R 4 And R is 5 At least one of which is other than hydrogen;
b is CH or nitrogen;
z is oxygen or sulfur;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In the formula (C), examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isobutyl, butyl, isobutyl, tert-butyl and pentyl.
Examples of the alkyl group having 1 to 8 carbon atoms and halogen substituents include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl substituted with 1 to 3 halogens such as fluorine, chlorine and bromine. Examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and pentoxy.
Examples of the alkoxy group having 1 to 8 carbon atoms and a halogen substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom or bromine atom. Including trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy.
Examples of alkenyl groups having 2 to 8 carbon atoms include vinyl and allyl.
Examples of alkynyl groups having 2 to 8 carbon atoms include propargyl.
Examples of 3-7 membered cycloalkyl groups include cyclohexyl and cyclopentyl.
Examples of alkyl groups having 1 to 8 carbon atoms and 3 to 7 membered cycloalkyl substituents include cyclohexylmethyl and cyclopentylmethyl.
The compounds of formula (C) may exist in the form of geometric isomers (e.g. cis and trans) and optical isomers. These isomers are included in the provided compounds. Furthermore, the compounds provided may be in the form of pharmaceutically acceptable salts, such as alkali metal salts, e.g. sodium or potassium salts.
In some embodiments, R X Is CH 2 OH, COH or COOCH 2 CONR 4 R 5 . In other embodiments, R X Is CH 2 OH。
In some embodiments, the compound of formula (C) is
Or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
In some embodiments, the compound of formula (C) is a compound shown in table 1 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
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5.2.4. A compound of formula (D)
In some embodiments, the compounds of the present invention are compounds of formula (D):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 And R is 2 Each independently is hydrogen, halogen, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, optionally substituted C 6-10 Aryl, with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkyl moieties, heterocyclic groups or having C 1-8 A heterocycloalkyl group of an alkyl group;
R 3 、R 4 and R is 5 Each occurrence is independently hydrogen or C 1-8 An alkyl group;
a is an oxygen atom, a sulfur atom or NR 3 ；
X 1 、X 2 And Z are each independently C (=o), C (=o) NH, C (=n-OR 4 )、CH(OR 5 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c≡c, or a bond; and
y is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
R 1 And R is 2 Examples of the halogen atom of (c) include fluorine, chlorine and bromine.
R 1 、R 2 、R 3 、R 4 And R is 5 Examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
R 1 And R is 2 Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and pentoxy.
R 1 And R is 2 Examples of the alkyl group having 1 to 8 carbon atoms having 1 to 3 halogen substituents include chloromethyl, fluoromethyl, bromomethyl, chloroethyl, 2-fluoroethyl and trifluoromethyl.
R 1 And R is 2 Examples of the alkoxy group having 1 to 8 carbon atoms having 1 to 3 halogen substituents include chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy and trifluoroethoxy.
R 1 And R is 2 Examples of the alkenyl group having 2 to 8 carbon atoms include vinyl or allyl. Alkynyl groups having 2 to 8 carbon atoms may be, for example, propargyl. Cycloalkyl groups having 3 to 7 carbon atoms may be, for example, cyclohexyl or cyclopentyl. Having 3-7 membered cycloalkanesThe alkyl group of the radical substituent may be, for example, cyclohexylmethyl or cyclopentylmethyl.
For R 1 And R is 2 Optionally substituted aryl groups of (a), the aryl groups may be, for example, phenyl or naphthyl.
Examples of the aralkyl group optionally having a substituent include benzyl and phenethyl.
For the heterocyclic group optionally having a substituent, examples of the heterocyclic group include 5-7 membered cyclic groups having 1-4 hetero atoms (e.g., nitrogen, oxygen, sulfur) which form a ring. For example, pyridyl, thienyl and furyl groups may be included. In addition, benzene rings (e.g., quinolinyl, benzothienyl) fused to heterocyclic groups may be included.
Examples of the heterocyclic group for the optionally substituted heterocyclic-alkyl group (the alkyl moiety has 1 to 8 carbon atoms) may be the same as described above for the optionally substituted heterocyclic group. The alkyl group preferably has 1 to 3 carbon atoms.
For the substituent of the optionally substituted aryl group, the optionally substituted aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 8 carbon atoms), the optionally substituted heterocyclic group and the optionally substituted heterocyclic-alkyl group (the alkyl moiety has 1 to 8 carbon atoms), the substituent may be a halogen atom (e.g., chlorine, bromine or fluorine), a nitro group, a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms (e.g., methylamino or ethylamino), a dialkylamino group having 2 to 10 carbon atoms (e.g., dimethylamino), an alkyl group having 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl or butyl), an alkoxy group having 1 to 8 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy or butoxy), an alkyl group having 1 to 3 halogen substituents having 1 to 8 carbon atoms (e.g., chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl or trifluoromethyl), an alkoxy group having 1 to 8 carbon atoms (e.g., chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy or trifluoromethoxy), an alkenyl group having 2 to 8 carbon atoms (e.g., vinyl or allyl), an alkyl group having 2 to 8 carbon atoms (e.g., alkynyl) having 2 to 8 carbon atoms (e.g., propyl), cycloalkyl groups having 3 to 7 carbon atoms (e.g. cyclohexyl or cyclopentyl), alkyl groups having 3 to 7 carbon atoms (e.g. cyclohexylmethyl or cyclopentylmethyl, phenyl or pyridyl).
In some embodiments, the compound of formula (D) is a compound shown in table 2, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.5. Compounds of formula (E)
In some embodiments, the compounds of the present invention are compounds of formula (E):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 and R is 12 Each independently is hydrogen, halogen, nitro, hydroxy, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl group, C with 1 to 3 halogens 1-8 Haloalkoxy groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, or phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolinyl or benzothienyl groups optionally having substituents which are halogen atoms, nitro groups, hydroxyl groups, amino groups, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl group, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl groupA group, phenyl or pyridyl;
X 1 and Z 1 Each independently is C (=o), C (=o) NH, C (=n-OR 14 )、CH(OR 15 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c=c or bond, wherein R 14 And R is 15 Each hydrogen or C 1-8 An alkyl group;
Y 1 is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, R 11 Or R is 12 The halogen atom of (C1-8), the alkoxy group having 1-8 carbon atoms, the alkyl group having 1-8 carbon atoms having 1-3 halogen substituents, the alkoxy group having 1-8 carbon atoms having 1-3 halogen substituents, the alkenyl group having 2-8 carbon atoms, the alkynyl group having 2-8 carbon atoms, the cycloalkyl group having 3-7 carbon atoms, the alkyl group having 1-8 carbon atoms of the cycloalkyl group having 3-7 carbon atoms may be R of formula (D) 1 And R is 2 Halogen atoms, alkoxy groups, alkyl groups having 1 to 8 carbon atoms with halogen substituents, halogen radicalsAlkoxy groups having 1 to 8 carbon atoms, alkenyl groups, alkynyl groups, cycloalkyl groups and alkyl groups having 1 to 8 carbon atoms of cycloalkyl groups having 3 to 7 carbon atoms.
In some embodiments, R 11 、R 12 、R 14 And R is 15 The alkyl group having 1 to 8 carbon atoms of (C) may be R of formula D 1 、R 2 、R 3 、R 4 And R is 5 Alkyl groups as described.
At R 11 Or R is 12 In the case of phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienyl, furyl, quinolinyl or benzothienyl, these rings may in some embodiments have such substituents: halogen atoms (e.g. chlorine, bromine or fluorine), nitro groups, hydroxyl groups, amino groups, alkylamino groups having 1 to 8 carbon atoms (e.g. methylamino or ethylamino groups), dialkylamino groups having 2 to 10 carbon atoms (e.g. dimethylamino groups), alkyl groups having 1 to 8 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl or butyl groups), alkoxy groups having 1 to 8 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy or butoxy groups), alkyl groups having 1 to 3 halogen substituents having 1 to 8 carbon atoms (e.g. chloromethyl, fluoromethyl, bromomethyl, 2-chloroethyl, 2-fluoroethyl or trifluoromethyl groups), alkoxy groups having 1 to 8 carbon atoms (e.g. chloromethoxy, fluoromethoxy, bromomethoxy, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy groups), alkenyl groups having 2 to 8 carbon atoms (e.g. vinyl or allyl groups), alkynyl groups having 2 to 8 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy or butoxy groups), alkyl groups having 1 to 3 halogen substituents having 1 to 8 carbon atoms (e.g. chloromethyl, bromomethyl, 2-chloroethoxy, 2-fluoroethoxy, or trifluoromethoxy groups having 1 to 8 carbon atoms (e.g. cyclohexyl) or cyclopentyl groups having 3 carbon atoms).
The compounds provided may be stereoisomers (e.g., cis or trans) or optical isomers. These isomers are encompassed by the present invention.
The provided compounds include pharmaceutically acceptable salts, such as alkali metal salts (e.g., sodium or potassium salts). Furthermore, the compounds provided may be in the form of pharmaceutically acceptable salts, such as alkali metal salts (e.g., sodium and potassium salts).
In some embodiments, the compound of formula (E) is a compound shown in table 3 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.6. A compound of formula (F)
In some embodiments, the compounds of the present invention are compounds of formula (F):
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or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is O, S or NR 7 Wherein R7 is hydrogen or C 1-8 An alkyl group;
B 1 is CW or N, wherein W is hydrogen or a bond; b (B) 2 O, S or NR 8 Wherein R is 8 Is hydrogen or C 1-8 An alkyl group;
X 1 and X 2 Each O, S, NH, NHC (=o), C (=n-OR 9 )、CH(OR 10 ) C= C, C ≡c or bond, wherein R 9 And R is 10 Each hydrogen or C 1-8 An alkyl group;
y is C 1-8 Alkylene which is unsubstituted or C 1-8 Alkyl or C with 1-3 halogens 1-8 Haloalkyl substitution;
Z is NH, O or S;
R 1 is aryl (the aryl group being unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl or halogen substitution), or having a substituent comprising 1 to 3A heterocyclic group of five to eight membered rings of heteroatoms (wherein each heteroatom is independently nitrogen, oxygen or sulfur and the other atoms are carbon), optionally wherein a benzene ring is fused to the heterocyclic ring;
R 2 is C 2-8 Alkyl, C with 1-3 halogens 1-8 Haloalkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl (which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl or halogen substituted) substituted C 1-4 Alkyl, or C substituted with a heterocyclic group having a five-to eight-membered ring containing 1 to 3 heteroatoms each of which is independently nitrogen, oxygen or sulfur 1-4 An alkyl group;
R 3 is halogen, trifluoromethyl, C 1-8 Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl;
R 4 and R is 5 Each is hydrogen, C 1-8 Alkyl or C with 1-3 halogens 1-8 A haloalkyl group;
z and R 3 Each being attached to a benzene ring, and X 2 Not attached to the benzene ring;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In formula (F), R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Substituents of the alkylene chain of Y, R 3 Substituents for aryl and heterocyclyl radicals, R 2 Substituents of aryl-substituted alkyl groups, and R 2 The substituent of the alkyl group substituted with a heterocyclyl group may in some embodiments be an alkyl group having 1 to 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
In some embodiments, R 2 May be an alkyl group having 2 to 8 carbon atoms. Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
In some embodiments, R 2 、R 4 、R 5 Substituents of the alkylene chain of Y, R 1 Substituents of aryl or heterocyclic radicals, R 2 Substituents of aryl-substituted alkyl groups, and R 2 The substituent of the alkyl group substituted with a heterocyclic group may be an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogens. Examples of haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl substituted with 1-3 halogens (e.g., fluorine, chlorine, bromine). In some embodiments, the group is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-fluoroethyl.
In some embodiments, R 2 And R is 3 An alkenyl group having 2 to 8 carbon atoms may be used. Examples of alkenyl groups include vinyl and allyl. R is R 2 And R is 3 An alkynyl group having 2 to 8 carbon atoms is possible. Examples of alkynyl groups include propargyl.
In some embodiments, R 3 May be a halogen atom. Examples of halogen atoms include fluorine, chlorine and bromine.
In some embodiments, R 2 May be a cycloalkyl group having 3 to 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, and cyclohexyl.
In some embodiments, R 1 Substituents of aryl or heterocyclic radicals, R 2 Substituents of aryl-substituted alkyl groups, and R 2 The substituent of the alkyl group substituted with a heterocyclic group may be an alkoxy group having 1 to 8 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy.
In some embodiments, R 1 R is as follows 2 The aryl moiety of the aryl substituted with alkyl may be an aryl group. Examples of aryl groups include phenyl and naphthyl. R is R 1 R is as follows 2 The substituent of the alkyl group of (a) may be a heterocyclic group having a 5 to 8 membered ring. Examples of heterocyclic groups include pyridyl, thienyl, furyl, thiazolyl and quinolinyl.
In some embodiments, R 1 There may be a heterocyclic group having a five to eight membered ring, the heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur and other atoms composed of carbon. The benzene ring may be fused to the heterocycle. Examples of condensed rings include quinoline rings and benzothiophene rings
In some embodiments, Y may be an alkylene chain having 1 to 8 carbon atoms. Examples of alkylene chains include methylene and ethylene.
In some embodiments, R 3 May be 1 to 3 groups. In some embodiments, R 3 May be different from each other.
In some embodiments, R6 may be an alkyl group having 1 to 8 carbon atoms substituted with an amino group. Examples of aminoalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl substituted with amino groups such as piperidinyl, pyrrolidinyl, dimethylamino and diethylamino.
In some embodiments, the compound of formula (F) may be in the form of a pharmaceutically acceptable salt, such as an alkali metal salt (e.g., sodium and potassium salts).
In some embodiments, the compound of formula (F) is a compound shown in table 4 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.7. Compounds of the formulae (G), (H) and (J)
In some embodiments, the compounds of the present invention are compounds of the following formula (G):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 and R is 4 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 2 is hydrogen;
R 3 is C 1-8 Alkyl, or R 3 And R is R 2 Bonding forms=o or=c (R 7 )(R 8 ) Wherein R is 7 And R is 8 Are identical or different and are each hydrogen or C 1-8 An alkyl group;
R 5 and R is 6 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl, C 1-8 A haloalkyl group.
X and Y are the same or different and each represents CH or N;
z is oxygen or sulfur;
a is a 5-membered heterocyclic group which is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or substituted C 1-8 Alkyl substitution, the substituent being C 1-8 Alkyl, 3Cycloalkyl of from about 7 members, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-to 7-membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 An aralkyl group of an alkylene moiety, or a 5-or 6-membered heterocyclyl group;
b is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution, in the case where the alkylene group has 2 to 6 carbon atoms, the alkylene group optionally has a double bond;
q is 0, 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of formula (H):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 and R is 13 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 12 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 14 and R is 15 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 1 CH or N;
Z 1 is oxygen or sulfur;
when bond a is present, W 1 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 1 OH;
q is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently an alkyl, aryl or heteroaryl groupA base; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of the following formula (J):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 and R is 23 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 22 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 24 and R is 25 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 2 CH or N;
Z 2 is oxygen or sulfur;
when bond a is present, W 2 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 2 OH;
r is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In relation to formula (G), R may be 1 、R 3 、R 4 、R 5 、R 6 、R 7 Examples of the substituent of the 5-membered heterocyclic group of A, or the substituent of the alkylene chain having 2 to 6 carbon atoms of B, the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl.
May be R 1 、R 4 Examples of the alkenyl group having 2 to 8 carbon atoms which is a substituent of the 5-membered heterocyclic group of a, or a substituent of the alkylene chain having 2 to 6 carbon atoms of B include vinyl and allyl.
May be R 1 、R 4 Examples of the alkynyl group having 2 to 8 carbon atoms of the substituent of the 5-membered heterocyclic group of a, or the substituent of the alkylene chain having 2 to 6 carbon atoms of B include propargyl groups.
Examples of the 3-to 7-membered cycloalkyl group which may be a substituent of the 5-membered heterocyclic group of A or a substituent of the alkylene chain having 2 to 6 carbon atoms of B include cyclopropyl, cyclopentyl and cyclohexyl.
May be R 1 、R 4 Examples of the alkoxy group having 1 to 8 carbon atoms of the substituent of the 5-membered heterocyclic group of A, or the substituent of the alkylene chain having 2 to 6 carbon atoms of B include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy.
May be R 1 、R 4 Or B has 2 to 6 carbon atoms of alkylene chain substituents including fluorine, chlorine, bromine.
May be R 1 、R 4 、R 5 、R 6 Examples of the alkyl group having 1 to 8 carbon atoms and halogen atom substituents of the substituent of the 5-membered heterocyclic group of a, or the substituent of the alkylene chain having 2 to 6 carbon atoms of B include methyl, ethyl, propyl, isobutyl, butyl and tert-butyl having, for example, 1 to 3 fluorine, chlorine, bromine atom substituents. In some embodiments, the alkyl group having 1 to 8 carbon atoms and halogen atom substituents is trifluoromethyl, chloromethyl, chloroethyl, 2-bromoethyl, or 2-fluoroethyl.
May be R 1 、R 4 Examples of the alkoxy group having 1 to 8 carbon atoms and halogen atom substituents of the substituent of the 5-membered heterocyclic group of a, or the substituent of the alkylene chain having 2 to 6 carbon atoms of B include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy having, for example, 1 to 3 fluorine, chlorine or bromine atom substituents. In some embodiments, the alkoxy group having 1 to 8 carbon atoms and halogen atom substituents is trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy, or 2-fluoroethoxy.
May be R 1 Or R is 4 Examples of the acyl group having 2 to 8 carbon atoms include acetyl and propionyl.
May be R 1 、R 4 Or an aryl group having 6 to 10 carbon atoms as a substituent of the 5-membered heterocyclic group of a includes phenyl.
May be R 1 、R 4 Or a 5-or 6-membered heterocyclic group of a substituent of a 5-membered heterocyclic group of AExamples of groups include pyridyl.
Examples of the alkyl group having 1 to 8 carbon atoms and 3 to 7 membered cycloalkyl group substituents which may be substituents of the 5 membered heterocyclic group of a include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups having cyclopropyl, cyclopentyl or cyclohexyl substituents.
Examples of the aralkyl group (which has an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms) which may be a substituent of the 5-membered heterocyclic group of a include benzyl and phenethyl.
Examples of the alkyl group having 1 to 8 carbon atoms and a 5-or 6-membered heterocyclic group which may be a substituent of the 5-membered heterocyclic group of a include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl having a pyridyl substituent.
R may be of formula (H) 11 Or R is 13 Or R of formula (J) 21 Or R is 23 Examples of alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, halogen atoms, alkyl groups having 1 to 8 carbon atoms and halogen atom substituents, alkoxy groups having 1 to 8 carbon atoms and halogen atom substituents, acyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms and 5-or 6-membered heterocyclic groups are R of the above formula (G) 1 And R is 4 Those described.
R may be of formula (H) 12 Or R of formula (J) 22 An alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a 3-to 7-membered cycloalkyl group substituent, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent, an aryl group having 6 to 10 carbon atoms, a 5-or 6-membered heterocyclic group, an alkoxy group having 6 to 10 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and a halogen atom substituent Examples of the aralkyl group of the aryl moiety of carbon atom and the alkylene moiety of 1 to 8 carbon atoms, and the alkyl group having 1 to 8 carbon atoms and a 5-or 6-membered heterocyclic substituent include those described as substituents of the 5-membered heterocyclic group of A of the above formula (G).
R may be of formula (H) 14 Or R is 15 Or R of formula (J) 24 Or R is 25 Examples of the alkyl group having 1 to 8 carbon atoms and halogen atom substituents include R of the above formula (G) 5 And R is 6 Those described.
R in formula (G) 1 R in formula (H) 11 And R in formula (J) 21 May be attached to the benzene ring or the like in a single or plural number (1 to 3). If R is 1 、R 11 And R is 21 Each present in a plurality of amounts, the plurality of groups may be the same or different.
R in formula (G) 4 R in formula (H) 13 And R in formula (J) 23 May be attached to the benzene ring or the like in a single or plural number (1 to 3). If R is 4 、R 13 And R is 23 Each present in a plurality of amounts, the plurality of groups may be the same or different.
A substituent group of a 5-membered heterocyclic group of A in the formula (G), R in the formula (H) 12 And R in formula (J) 22 May be attached to the heterocycle in single or multiple numbers (1 or 2). If the substituent group of the 5-membered heterocyclic group of A, R 12 And R is 22 Each present in a plurality of amounts, the plurality of groups may be the same or different.
The compounds of formulae (G), (H) and (J) may be pharmacologically acceptable salts, for example alkali metal salts (e.g. sodium, potassium or lithium salts).
The compounds of formulae (G), (H) and (J) may exist in optically active form and in the form of optical isomers (e.g. compounds in racemic form) or geometric isomers (e.g. compounds in cis or trans form).
In some embodiments, the compound of formula (G), (H), or (J) is a compound shown in table 5, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
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5.2.8. A compound of formula (K)
In some embodiments, the compounds of the present invention are compounds of the following formula (K):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is CH or nitrogen;
when bond a is present, B is oxygen or C (R 8 )(R 9 ) Wherein R is 8 And R is 9 Each independently is hydrogen or C 1-8 An alkyl group; when bond a is absent, B is OH;
W 1 is a bond, C (=O) or (C (R) 10 )(R 11 )) m Wherein R is 10 And R is 11 Each independently is hydrogen or C 1-8 An alkyl group and m is 1, 2 or 3;
x and Y are different from each other and are each an oxygen atom, a sulfur atom, a nitrogen atom or CR 12 Wherein R is 12 Is hydrogen or C 1-8 An alkyl group;
Z 1 is a bond, oxygen, sulfur or C (R) 13 )(R 14 ) Wherein R is 13 And R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
R 1 、R 2 and R is 3 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 4 and R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 A haloalkyl group;
r is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In formula (K), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 And R is 14 Examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
R 1 、R 2 、R 3 、R 6 And R is 7 Examples of the alkenyl group having 2 to 8 carbon atoms include vinyl and allyl.
R 1 、R 2 、R 3 、R 6 And R is 7 Is provided with (1)Examples of alkynyl groups having 2 to 8 carbon atoms include propargyl.
R 1 、R 2 And R is 3 Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy.
R 1 、R 2 And R is 3 Examples of the halogen atom of (c) include fluorine, chlorine and bromine.
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Examples of the alkyl group having 1 to 8 carbon atoms substituted with a halogen atom include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine and bromine). In one embodiment, the substituent is trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl or 2-fluoroethyl.
R 1 、R 2 And R is 3 Examples of the alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine or bromine). In one embodiment, the substituent is trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-fluoroethoxy.
R 1 、R 2 And R is 3 Examples of the acyl group having 2 to 8 carbon atoms include acetyl and propionyl.
R 1 、R 2 And R is 3 Examples of the aryl group having 6 to 10 carbon atoms include phenyl.
R 1 、R 2 And R is 3 Examples of the 5-or 6-membered heterocyclic group of (2) include pyridyl.
R in formula (K) 1 、R 2 And R is 3 May be attached to a benzene ring or the like in an amount of 1 to 3, wherein the same or different groups may be attached to the same ring.
The compounds represented by formula (K) provided herein may be in the form of pharmacologically acceptable salts, such as alkali metal salts (e.g., sodium, potassium, and lithium salts).
The compounds provided herein may be in optically active form, and may be in the form of optical isomers (e.g., racemic forms of the compounds) or geometric isomers (e.g., cis or trans forms of the compounds).
In some embodiments, the compound of formula (K) is a compound shown in table 6 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.9. A compound of formula (L)
In some embodiments, the compounds of the present invention are compounds of formula (L):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, B is oxygen; when bond a is absent, B is OH;
W 2 is a bond, C (=O) or CH 2 ；
Z 2 Is oxygen or sulfur;
R 21 、R 22 and R is 23 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 24 and R is 25 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In formula (L), R 21 、R 22 And R is 23 An alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a 5-or 6-membered heterocyclic group may be R in formula (K) in some embodiments 1 、R 2 And R is 3 Those described.
In formula (L), R 24 And R is 25 The alkyl groups having 1 to 8 carbon atoms and the alkyl groups having 1 to 8 carbon atoms substituted with halogen atoms may be R in formula (K) in some embodiments 4 And R is 5 Those described.
R in formula (L) 21 、R 22 And R is 23 May be attached to a benzene ring or the like in an amount of 1 to 3, wherein the same or different groups may be attached to the same ring.
The compounds represented by formula (L) provided herein may be in the form of pharmacologically acceptable salts, such as alkali metal salts (e.g., sodium, potassium, and lithium salts).
The compounds provided herein may be in optically active form, and may be in the form of optical isomers (e.g., racemic forms of the compounds) or geometric isomers (e.g., cis or trans forms of the compounds).
5.2.10. Compounds of formulae (M) and (N)
In some embodiments, the compounds of the present invention are compounds of the following formula (M):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is nitrogen or CH;
x is nitrogen or CH;
y is oxygen or sulfur;
z is a bond, oxygen, sulfur or NR 5 Wherein R is 5 Is hydrogen or C 1-8 An alkyl group;
R 1 and R is 2 Each independently is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl radical of alkylene, or C with 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 3 and R is 4 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
a is a 5-membered heterocyclic ring which is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, cycloalkyl substituted with 3-to 7-membered ringC of radicals 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
b is a bond or C 1-8 Alkylene group, C 1-8 Alkylene is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 1-8 Substituted by alkoxy or halogen substituents, optionally wherein C 1-8 Alkylene has a double bond or a triple bond;
r is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of formula (N):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 3 is nitrogen or CH;
Z 1 is oxygen or sulfur;
R 11 and R is 12 Each independently is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Haloalkoxy groups;
R 13 and R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
A 1 is a five-membered heterocyclic ring which is pyrazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution;
m is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments of the compounds of formula (M), R 1 、R 2 、R 3 、R 4 、R 5 An alkyl group having 1 to 8 carbon atoms, a substituent attached to a 5-membered heterocyclic ring of a (when present), and a substituent attached to an alkylene chain having 1 to 8 carbon atoms may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl.
In one embodiment, R 1 、R 2 Alkenyl groups having 2 to 8 carbon atoms, and the substituent is attached to the 5-membered heterocyclic ring of a and is vinyl or allyl.
In one embodiment, R 1 、R 2 Alkynyl 1 group having 2 to 8 carbon atoms, wherein the substituent is attached to the 5 membered heterocycle of a and is propargyl.
In one embodiment, R 1 、R 2 3-to 7-membered cycloalkyl groups of (c), wherein the substituents are attached to the 5-membered heterocycle of a. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is cyclopentyl or cyclohexyl.
In one embodiment, R 1 、R 2 An alkoxy group having 1 to 8 carbon atoms, wherein the substituent is attached to the 5-membered heterocyclic ring of a. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy.
In one embodiment, R 1 And R is 2 Is halogen, and the substituent is attached to the 5-membered heterocyclic ring of A. In another embodiment, the substituent is attached to an alkylene chain having 1 to 8 carbon atoms and is fluorine, chlorine or bromine.
In one embodiment, R 1 、R 2 、R 5 An alkyl group having 1 to 8 carbon atoms and a halogen substituent, wherein the substituent is attached to the 5-membered heterocyclic ring of a and is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl having 1 to 3 halogen substituents. In another embodiment, the substituents are selected from trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
In one embodiment, R 1 、R 2 Alkoxy groups having 1 to 8 carbon atoms and halogen substituents, wherein the substituents are attached to the 5-membered heterocyclic ring of A and are methoxy, ethoxy, propoxy, isopropoxy, butoxy having 1 to 3 halogen substituents (e.g. fluorine, chlorine or bromine)A radical or a tert-butoxy radical. In one embodiment, the substituents are selected from trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy.
In one embodiment, R 1 、R 2 Is an aryl group having 6 to 10 carbon atoms, and the substituent is attached to the 5-membered heterocyclic ring of a and is phenyl.
In one embodiment, R 1 、R 2 And the substituent is attached to the 5-or 6-membered heterocyclic group of a and is pyridinyl.
In one embodiment, R 1 、R 2 And the substituent is attached to the 5-membered heterocycle of a and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl having a cyclopropyl substituent, a cyclopentyl substituent or a cyclohexyl substituent.
In one embodiment, R 1 、R 2 An aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms, and a substituent attached to the 5-membered heterocycle of a and is benzyl or phenethyl.
In one embodiment, R 1 、R 2 An alkyl group having 1 to 8 carbon atoms and a 5-or 6-membered heterocyclic group, and the substituent is attached to the 5-membered heterocyclic ring of a and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl having a pyridyl substituent.
In one embodiment, the 5-membered heterocyclic ring of a which may have a substituent is a pyrazole or thiophene having a substituent. In another embodiment, the pyrazole has substituents.
In one embodiment, the substituted alkylene chain of B having 1 to 8 carbon atoms is an alkylene chain having 1 to 4 carbon atoms. In another embodiment, the alkylene chain is an ethylene chain or a propylene chain.
In one embodiment, n is 0.
In some embodiments of the compounds of formula (N),R 11 and R is 12 The halogen atom of (C1-C8) alkyl group, the alkoxy group of (C1-C8) alkyl group of (C1-C8) and halogen substituent, and the alkoxy group of (C1-C8) and halogen substituent may be R of (M) Wen Zhongshi 1 And R is 2 Those described.
In one embodiment, R 13 And R is 14 The alkyl group having 1 to 8 carbon atoms of (C) may be R at upper Wen Zhongshi (M) 3 And R is 4 Those described.
In one embodiment, A in formula (N) 1 The halogen atoms of (a) and (b), the alkyl groups having 1 to 8 carbon atoms, the alkoxy groups having 1 to 8 carbon atoms, the alkyl groups having 1 to 8 carbon atoms and halogen substituents, and the alkoxy groups having 1 to 8 carbon atoms and halogen substituents attached to pyrazole or thiophene are those described as substituents attached to the 5-membered heterocyclic ring of a above Wen Zhongshi (M).
In one embodiment, R of formula (M) 1 And R of formula (N) 11 The benzene ring, etc. may have 1 to 3R's, which may be the same or different in number from each other 1 Or R is 11 . In another embodiment, the benzene ring and the like may have 1 to 3 substituents other than hydrogen atoms.
In one embodiment, R of formula (M) 2 And R of formula (N) 12 The benzene ring, benzisoxazole ring, etc. may have 1 to 3R's in the same or different numbers from each other 2 Or R is 12 . In another embodiment, the benzene ring of the benzisoxazole ring or the like may have 1 to 3 substituents other than hydrogen atoms.
In one embodiment, the substituents of formula (M) attached to the 5-membered heterocyclic ring of a and the substituents of formula (N) attached to the pyrazole or thiophene of A1 may be present in 1 or 2 numbers identical to or different from each other.
The compounds represented by formulas (M) and (N) provided herein may be in the form of pharmacologically acceptable salts, such as alkali metal salts (e.g., sodium, potassium, and lithium salts).
The compounds provided herein may be in optically active form, and may be in the form of optical isomers (e.g., racemic forms of the compounds) or geometric isomers (e.g., cis or trans forms of the compounds).
In some embodiments, the compound of formula (M) or (N) is a compound shown in table 7, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.11. Compounds of formula (O), (P) and (Q)
In some embodiments, the compounds of the present invention are compounds of the following formula (O):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or nitrogen;
x is NR 5 Or CR (CR) 6 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C 3-7 Cycloalkyl, quilt C 3-7 Cycloalkyl-substituted C 1-8 Alkyl, C substituted by phenyl 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl, and R 6 And R is 7 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 8 R 9 ) r Wherein R is 8 And R is 9 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4; or alternatively
X and Y combine to form CR 10 ＝CR 11 Or ethynylene group, wherein R 10 And R is 11 Each independently is hydrogen or C 1-8 An alkyl group;
when bond a is present, G is O, S or CR 12 R 13 Wherein R is 12 And R is 13 Each independently is hydrogen or C 1-8 An alkyl group; when bond a is absent, G is OH;
a is a five membered heterocycle which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocycle is unsubstituted or C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl or five-membered or six-membered heterocyclic groups;
b is C 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 Alkynylene chain wherein the chain is unsubstituted or C 1-8 Alkyl, C 3-7 Cycloalkyl, C 1-8 Alkoxy or halogen substitution;
R 1 and R is 2 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl, or five-or six-membered heterocyclic groups;
R 3 and R is 4 Each independently is hydrogen or C 1-8 An alkyl group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
/>
Each R X4 And R is X5 Independently an alkyl group, an aryl group or a hetero-groupAn aryl group; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of formula (P):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, G a Is O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G a Is OH;
A a is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B a is C 1-8 Alkylene or C 2-8 Alkenylene chains;
R 1a and R is 2a Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of formula (Q):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
When bond a is present, G b O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G b OH;
A b is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B b is C 1-8 Alkylene or C 2-8 Alkenylene chains;
R 1b and R is 2b Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R 3b is hydrogen or C 1-8 An alkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, in formula (O), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 A substituent of a five-membered heterocyclic ring represented by A and C represented by B 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 The substituent of the alkynylene chain may be C 1-8 An alkyl group. C (C) 1-8 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
In one embodiment, R 1 、R 2 、R 5 And the substituent of the five-membered heterocyclic ring represented by A may be C 2-8 Alkenyl groups. C (C) 2-8 Examples of alkenyl groups include vinyl and allyl.
In one embodiment, R 1 、R 2 And the substituent of the five-membered heterocyclic ring represented by A may be C 2-8 Alkynyl groups. C (C) 2-8 Examples of alkynyl groups include propargyl.
In one embodiment, R 1 、R 2 A substituent of a five-membered heterocyclic ring represented by A and C represented by B 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 The substituent of the alkynylene chain may be C 1-8 An alkoxy group. C (C) 1-8 Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy.
In one embodiment, R 1 、R 2 A substituent of a five-membered heterocyclic ring represented by A and C represented by B 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 The substituent of the alkynylene chain may be halogen. Examples of halogen include fluorine, chlorine and bromine.
In one embodiment, R 1 、R 2 、R 5 And the substituent of the five-membered heterocyclic ring represented by A may be C substituted with halogen 1-8 An alkyl group. C substituted by halogen 1-8 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl groups substituted with 1-3 halogens (e.g., fluorine, chlorine, bromine). Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
In one embodiment, R 1 、R 2 And the substituent of the five-membered heterocyclic ring represented by A may be C substituted with halogen 1-8 An alkoxy group.
C substituted by halogen 1-8 Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups substituted with 1 to 3 halogen atoms (for example, fluorine atom, chlorine atom or bromine atom). In one embodiment, R 1 、R 2 And the substituents of the five-membered heterocyclic ring are trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy.
In one embodiment, R 1 、R 2 、R 5 And the substituent of the five-membered heterocyclic ring represented by A may be C 2-8 An acyl group. C (C) 2-8 Examples of acyl groups include acetyl and propionyl.
In one embodiment, R 1 、R 2 And the substituent of the five-membered heterocyclic ring represented by A may be C 6-10 Aryl groups. C (C) 6-10 Examples of aryl groups include phenyl.
In one embodiment, R 1 、R 2 And the substituent of the five-membered heterocyclic ring represented by a may be a five-membered or six-membered heterocyclic group. Examples of five-or six-membered heterocyclic groups include pyridyl.
In one embodiment, R 5 May be C 1-8 Alkoxy substituted C 1-8 An alkyl group.
Quilt C 1-8 Alkoxy substituted C 1-8 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy.
In one embodiment, R 5 Cycloalkyl groups which may be three to seven membered rings. Examples of cycloalkyl groups of three to seven membered rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In one embodiment, R 5 May be C substituted by cycloalkyl of three to seven membered rings 1-8 An alkyl group. C substituted by cycloalkyl of three-to seven-membered ring 1-8 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In one embodiment, R 5 May be C substituted by phenyl 1-8 An alkyl group.
C substituted by phenyl 1-8 Examples of alkyl groups include benzyl, phenethyl, and the like.
In one embodiment, C represented by B 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 The substituents of the alkynylene chain may be cycloalkyl groups of three to seven membered rings. Examples of cycloalkyl groups of three to seven membered rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In some embodiments, in formula (P), R 1a 、R 2a From A a The substituents of the five-membered heterocyclic ring represented may be C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, C substituted by halogen 1-8 Alkoxy and C 2-8 An acyl group. Examples thereof and R in formula (O) 1 、R 2 The same as the examples of the substituents of the five-membered heterocyclic ring represented by A.
In some embodiments, in formula (Q), R 1b 、R 2b From A b The substituents of the five-membered heterocyclic ring represented may be C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, C substituted by halogen 1-8 Alkoxy and C 2-8 An acyl group. Examples thereof and R in formula (O) 1 、R 2 The same as the examples of the substituents of the five-membered heterocyclic ring represented by A.
In one embodiment, in formula (Q), R 3b Can be C 1-8 An alkyl group. Examples and R in formula (O) 5 The same as the examples of (a).
In one embodiment, each R in formula (O) 1 、R 2 Each R in formula (P) 1a 、R 2a Each R in formula (Q) 1b And R is 2b There may be one to three groups attached to a ring (e.g., benzene ring). Two or three groups may be different from each other.
The compounds of formulae (O), (P) and (Q) may be present in the form of pharmaceutically acceptable salts. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
The compounds of formulae (O), (P) and (Q) may also exist in the form of optical isomers (e.g. enantiomers or racemates) or geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
In some embodiments, the compound of formula (O), (P), or (Q) is a compound shown in table 8, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.12. Compounds of formula (R) and (S)
In some embodiments, the compounds of the present invention are compounds of formula (R):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or N;
x is NR 3 Or CR (CR) 4 R 5 Wherein R is 3 Is C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, C substituted by phenyl groups 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
R 4 and R is 5 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 6 R 7 ) r Wherein R is 6 And R is 7 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4;
a is a 5 or 6 membered heterocyclic group (which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine) or a phenyl group, wherein the 5 or 6 membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl, 3-7 membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-7 membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5 or 6 membered heterocyclic group containing C 6-10 Aryl group and C 1-8 Aralkyl groups of alkyl groups, or C substituted by 5-or 6-membered heterocyclic groups 1-8 Alkyl group substitution;
B is a bond or C 1-8 Alkylene group, C 1-8 Alkylene being unsubstituted or C 1-8 Alkyl, 3-7 membered cycloalkyl group, C 1-8 Alkoxy or halogen substituted, and when the number of carbons of the alkylene chain is 2 or more, it may have a double bond or a triple bond;
d is N or CH;
e is O or S;
R 1 and R is 2 Each independently H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, nitro, C 2-8 Acyl, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, the compounds of the present invention are compounds of the following formula (S):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
A 1 is a 5-or 6-membered heterocyclic group (which is thiazole, oxazole, pyridine or pyrimidine) or a phenyl group, wherein the 5-or 6-membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl or C 1-8 Haloalkyl substitution;
B 1 is C 2-4 An alkylene group;
R 11 and R is 12 Each independently H, C 1-8 Alkyl, halogenOr C 1-8 A haloalkyl group;
R 13 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 13 The attached N is attached to the 6 th position of the benzisoxazole;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments of the compounds having formula (R), W 1 And W is 2 Are CH.
In some embodiments of compounds having formula (R), X is CR 4 R 5 、CH 2 Or NR (NR) 3 And R is 3 Is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 3 Is a methyl group.
In some embodiments of compounds having formula (R), Y is CH 2 。
In some embodiments of compounds having formula (R), Z is a carboxyl group.
In some embodiments of compounds having formula (R), a is a thiazole or oxazole which may have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an aryl group having 6 to 10 carbon atoms, or a 5 or 6 membered heterocyclic group; the pyrazole may have a substituent selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent, an aryl group having 6 to 10 carbon atoms, or a 5-or 6-membered heterocyclic group.
In some embodiments of the compounds having formula (R), B is an ethylene chain.
In some embodiments of the compounds having formula (R), D is N.
In some embodiments of compounds having formula (R), E is O.
In some embodiments of the compounds having formula (R), R 1 And R is 2 Each independently is H, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
In some embodiments of compounds having formula (R), m is 0.
In some embodiments of the compounds having formula (S), R 13 Is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 13 Is a methyl group.
In some embodiments of the compounds having formula (S), p is 1.
In some embodiments of the compounds having formula (S), A 1 Is a thiazole, oxazole or phenyl group which may have a substituent selected from an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, A 1 Is a thiazole which may have an alkyl group having 1 to 8 carbon atoms as a substituent.
In some embodiments of the compounds having formula (S), B 1 Is an ethylene chain.
In some embodiments of the compounds having formula (S), R 11 Is 1 withAn alkyl group of up to 8 carbon atoms, a halogen atom or an alkyl group having substituents of 1 to 8 carbon atoms and halogen atoms.
In some embodiments of the compounds having formula (S), R 12 Is H, an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and halogen atom substituents.
The compounds of formulae (R) and (S) may also exist as optical isomers (e.g. enantiomers or racemates) or as geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
The compounds of formulae (R) and (S) may be present in the form of pharmaceutically acceptable salts. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
In some embodiments, the compound of formula (R) or (S) is a compound shown in table 9 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.13. Compounds of formula (T)
In some embodiments, the compounds of the present invention are compounds of formula (I):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
B 2 is C 2-4 An alkylene group;
R 20 is C 1-8 An alkyl group;
R 21 and R is 22 Each independently H, C 1-8 Alkyl, halogen or C 1-8 A haloalkyl group;
R 23 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 23 Connected toThe N-terminus is attached to the 6-position of the benzisoxazole;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
In some embodiments, R 23 Is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and halogen atom substituents. In another embodiment, R 23 Is a methyl group.
In some embodiments, n is an integer from 1 to 4. In some embodiments, n is 1.
In some embodiments, R 20 Is an alkyl group having 1 to 8 carbon atoms. In another embodiment, R 20 Is a methyl group.
In some embodiments, B 2 Is an alkylene chain having 2 to 4 carbon atoms. In another embodiment, B 2 Is an ethylene chain.
In some embodiments, R 21 And R is 22 Each independently is H, an alkyl group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In another embodiment, R 21 Is an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent. In yet another embodiment, R 22 Is H, an alkane having 1 to 8 carbon atomsAn alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
In some embodiments, N (R 23 )((CH 2 ) n -R x ) To the 6-position of benzisoxazole.
The compounds of formula (T) may also exist in the form of optical isomers (e.g. enantiomers or racemates) or geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
The compounds of formula (T) may be present in the form of pharmaceutically acceptable salts. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
5.2.14. Compounds of formula (U)
In some embodiments, the compounds of the present invention are compounds of formula (U):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 Is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 2 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 3 、R 4 、R 5 and R is 6 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
x is oxygen, sulfur or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl having C 6-10 Aryl moiety and C 1-8 Aralkyl group of alkylene moiety, C 2-8 Acyl or C 2-8 Alkenyl groups;
y is oxygen, sulfur, NR 8 Or a bond, wherein R 8 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
p is 0 or 1;
when bond a is present, A is oxygen CH 2 、N-NH 2 OR N-OR 9 Wherein R is 9 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, a is OH;
in the case of p=1, B is a benzene ring with or without substituents halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, or having C 6-10 An aryl moiety and an aralkyl group of a C1-C8 alkylene moiety of 1-8 carbon atoms, and, in the case of p=0, B is a fused ring which is indole, benzofuran, benzisoxazole or 1, 2-benzisothiazole, wherein the fused ring is with or without a substituent which is
Halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C with C1-C8 alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy groups, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
y is bonded with the benzene ring of B;
(C(R 3 )(R 4 )) m a fused ring to B is bonded at its 3 position;
m is an integer from 1 to 4;
n is 0, 1, 2, 3, 4 or 5;
in the case of n=0, Y is a bond;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In some embodiments, R 1 Represents hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, alkyl groups having 1 to 8 carbon atoms, 3-to 7-membered cycloalkyl groups, alkenyl groups having 2 to 8 carbon atomsAn alkynyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7 membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having 1 to 8 alkoxy substituents, an alkoxy group having 1 to 8 carbon atoms and having halogen substituents, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a 5-or 6-membered heterocyclic group, an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and 5 or 6 membered heterocyclic substituents.
In some embodiments, R 2 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7 membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, R 3 、R 4 、R 5 And R is 6 Each independently represents hydrogen, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and having a halogen substituent.
In some embodiments, X is oxygen, sulfur, or NR 7 ，R 7 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms or an alkenyl group having 2 to 8 carbon atoms.
In some embodiments, Y is oxygen, sulfur, NR or a bond, R 8 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms, a halogen substituent having 1 to 8 carbon atomsAn alkyl group having 2 to 8 carbon atoms, an acyl group, or an alkenyl group having 2 to 8 carbon atoms.
In some embodiments, p is 0 or 1.
In some embodiments, A is oxygen, CH 2 、N-NH 2 OR N-OR 9 ，R 9 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, where p=1, B represents a benzene ring, with or without substituents selected from halogen, hydroxyl, nitro, amino, alkyl groups having 1-8 carbon atoms, 3-to 7-membered cycloalkyl groups, alkenyl groups having 2-8 carbon atoms, alkynyl groups having 2-8 carbon atoms, alkoxy groups having 1-8 carbon atoms, alkyl groups having 1-8 carbon atoms and having 3-to 7-membered cycloalkyl substituents, alkyl groups having 1-8 carbon atoms and having halogen substituents, alkyl groups having 1-8 carbon atoms and having alkoxy substituents having 1-8 carbon atoms, alkoxy groups having 1-8 carbon atoms and having halogen substituents, acyl groups having 2-8 carbon atoms, aryl groups having 6-10 carbon atoms, or aralkyl groups having aryl moieties of 6-10 carbon atoms and alkylene moieties of 1-8 carbon atoms, and, in the case of p=0, the fused ring is selected from the group consisting of indole, benzofuran, benzisoxazole and 1, 2-benzisothiazole, wherein the fused ring is with or without an alkyl group selected from the group consisting of halogen, hydroxy, nitro, amino, 1-8 carbon atoms, 3-to 7-membered cycloalkyl group, 2-8 carbon atoms alkenyl group, 2-8 carbon atoms alkynyl group, 1-8 carbon atoms alkoxy group, 1-8 carbon atoms alkyl group with 3-to 7-membered cycloalkyl substituent, and, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an alkyl group having 1 to 8 carbon atoms and having an alkoxy substituent having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a substituent of an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, Y is bonded to the benzene ring of B.
In some embodiments, - (C (R) 3 )(R 4 )) m -a fused ring with B is bonded at its 3-position.
In some embodiments, m is an integer from 1 to 4.
In some embodiments, n is an integer from 0 to 5.
In some embodiments, Y is a bond in the case of n=0.
The compounds of formula (U) may also exist in the form of optical isomers (e.g. enantiomers or racemates) or geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
The compounds of formula (U) may be present in the form of pharmaceutically acceptable salts. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
5.2.15. Compounds of formula (V)
In some embodiments, the compounds of the present invention are compounds of formula (V):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 12 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 13 、R 14 、R 15 and R is 16 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 1 is oxygen, sulfur and NR 18 Or a bond, wherein R 18 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
when bond a is present, A 1 Is oxygen CH 2 、N-NH 2 OR N-OR 19 Wherein R is 19 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, A 1 OH;
Q 1 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
r is 1, 2, 3 or 4;
s is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In some embodiments, R 11 Represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7-membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having halogen substituents, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a 5-or 6-membered heterocyclic group, an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and 5-or 6-membered heterocyclic substituents.
In some embodiments, R 12 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7 membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents having 1 to 8 carbon atomsA group, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, R 13 、R 14 、R 15 And R is 16 Each independently represents hydrogen, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and having a halogen substituent.
In some embodiments, Y 1 Is oxygen, sulfur and NR 18 Or a bond, R 18 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2 to 8 carbon atoms, or an alkenyl group having 2 to 8 carbon atoms.
In some embodiments, a 1 Is oxygen CH 2 、N-NH 2 OR N-OR 19 ，R 19 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, Q 1 Represents hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7-membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents of 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having halogen substituents, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms.
In some embodiments, r is an integer from 1 to 4.
In some embodiments, s is an integer from 1 to 5.
The compounds of formula (V) may also exist in the form of optical isomers (e.g. enantiomers or racemates) or geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
The compounds of formula (V) may be present in the form of pharmaceutically acceptable salts. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
In some embodiments, the compound of formula (V) is a compound shown in table 10, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.16. A compound of formula (W)
In some embodiments, the compounds of the present invention are compounds of the following formula (W):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 22 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 23 、R 24 、R 25 and R is 26 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 2 Is oxygen, sulfur and NR 28 Or a bond, wherein R 28 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
Q 2 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
t is 1, 2, 3 or 4;
u is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently an alkaneA group, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In some embodiments, R 21 Represents hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, an alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7-membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having halogen substituents, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, a 5-or 6-membered heterocyclic group, an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms, or an aralkyl group having 1 to 8 carbon atoms and 5-or 6-membered heterocyclic substituents.
In some embodiments, R 22 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7 membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having an aryl moiety having 6 to 10 carbon atoms and an alkylene moiety having 1 to 8 carbon atoms.
In some embodiments, R 23 、R 24 、R 25 And R is 26 Each independently represents hydrogen, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and having a halogen substituent.
In some embodiments, Y 2 Is oxygen, sulfur and NR 28 Or a bond, R 28 Represents hydrogen, an alkyl group having 1 to 8 carbon atoms and having a halogen substituent, an acyl group having 2 to 8 carbon atoms, or an alkenyl group having 2 to 8 carbon atoms.
In some embodiments, Q 2 Represents hydrogen, halogen, hydroxyl, nitro, amino, an alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and having 3 to 7-membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and having halogen substituents, an alkyl group having 1 to 8 carbon atoms and having alkoxy substituents of 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms and having halogen substituents, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having an aryl moiety of 6 to 10 carbon atoms and an alkylene moiety of 1 to 8 carbon atoms.
In some embodiments, t is an integer from 1 to 4.
In some embodiments, u is an integer from 1 to 5.
The compounds of formula (W) may also exist in the form of optical isomers (e.g. enantiomers or racemates) or geometric isomers (e.g. cis or trans). Isomers of these compounds are also provided.
The compound having formula (W) may be present in the form of a pharmaceutically acceptable salt. Examples of the salt include alkali metal salts (e.g., sodium salt, potassium salt, and lithium salt).
In some embodiments, the compound of formula (W) is a compound shown in table 11, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof.
5.2.17. Compounds of formula (X)
In some embodiments, the compounds of the present invention are compounds of formula (X):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
In some embodiments, the compound is("Compound VI") or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
5.2.18. A compound of formula (Y)
In some embodiments, the compounds of the present invention are compounds of formula (Y):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl group) Wherein aryl and heteroaryl are unsubstituted or substituted by halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
5.2.19. Compounds of formula (Z)
In some embodiments, the compounds of the present invention are compounds of formula (Z):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
5.2.20. Compounds of formula (AA)
In some embodiments, the compounds of the invention are compounds of the following formula (AA):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
l is (CH) 2 ) 5 Which is unsubstituted or substituted by one methyl group;
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
R 2 Is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 0 or 1;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
R 3 is C 1-4 Haloalkyl, NO 2 CN, halogen or C (O) O (C) 1-4 An alkyl group);
R 20 is hydrogen, halogen or C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
5.2.21. Other Compounds
In some embodiments, the compounds of the present invention are
("Compound VII") or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
In some embodiments, the compounds of the present invention are
("Compound VIII") or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
5.3. Compositions of the invention
In some embodiments, the compositions of the present invention comprise (i) an effective amount of a compound of the present invention and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of a racemate of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of an enantiomeric mixture of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I has an allylic carbon atom with a hydroxyl group, has the (R) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I has an allylic carbon atom with a hydroxyl group, has an (R) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (S) -enantiomer of compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I has an allylic carbon atom with a hydroxyl group, has the (S) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I has an allylic carbon atom with a hydroxyl group, has an (S) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (R) -enantiomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of a non-racemic mixture of the (R) -enantiomer and the (S) -enantiomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-racemic mixture has an excess of the (R) -enantiomer relative to the (S) -enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S) -enantiomer relative to the (R) -enantiomer.
In some embodiments, the compositions of the present invention comprise (I) an effective amount of the (Z) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of the (Z) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (E) -isomer of compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of the (E) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of the (E) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (Z) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of an unequal mixture of the (Z) -isomer and the (E) -isomer of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equal mixture has an excess of (Z) -isomer relative to (E) -isomer. In some embodiments, the non-equal mixture has an excess of (E) -isomer relative to (Z) -isomer.
In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound I is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((Z) - (S) -I), ((E) - (R) -I), or ((E) - (S) -I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound I is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((Z) - (R) -I), ((E) - (R) -I), or ((E) - (S) -I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound I is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds (E) - (S) -I), ((Z) - (R) -I), or ((Z) - (S) -I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound I is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having the (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (I) an effective amount of compound I or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound I is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having the (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((E) - (R) -I), ((Z) - (R) -I), or ((Z) - (S) -I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound II or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (II) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (Z) -isomer of compound II, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (II) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (Z) -isomer of compound II, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (II) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (E) -isomer of compound II, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (E) -isomer of compound II, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (II) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (E) -isomer of compound II, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (II) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (Z) -isomer of compound II, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of an unequal mixture of the (Z) -isomer and the (E) -isomer of compound II, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (II) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equal mixture has an excess of (Z) -isomer relative to (E) -isomer. In some embodiments, the non-equal mixture has an excess of (E) -isomer relative to (Z) -isomer.
In some embodiments, the compositions of the invention comprise (i) an effective amount of compound III or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of a racemate of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the invention comprise (i) an effective amount of an enantiomeric mixture of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III has an allylic carbon atom with a hydroxyl group, has the (R) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III has an allylic carbon atom with a hydroxyl group, has an (R) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (S) -enantiomer of compound III, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III has an allylic carbon atom with a hydroxyl group, has the (S) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III has an allylic carbon atom with a hydroxyl group, has an (S) -enantiomer, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (R) -enantiomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof. In some embodiments, the compositions of the invention comprise (i) an effective amount of a non-racemic mixture of the (R) -enantiomer and the (S) -enantiomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-racemic mixture has an excess of the (R) -enantiomer relative to the (S) -enantiomer. In some embodiments, the non-racemic mixture has an excess of the (S) -enantiomer relative to the (R) -enantiomer.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (Z) -isomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (Z) -isomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (E) -isomer of compound III, or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (E) -isomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of the (E) -isomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of the (Z) -isomer of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of an unequal mixture or pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof of the (Z) -isomer and the (E) -isomer of compound III and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the non-equal mixture has an excess of (Z) -isomer relative to (E) -isomer. In some embodiments, the non-equal mixture has an excess of (E) -isomer relative to (Z) -isomer.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III is the (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((Z) - (S) -III), ((E) - (R) -III), or ((E) - (S) -III), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III is the (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III is a (Z) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((Z) - (R) -III), ((E) - (R) -III), or ((E) - (S) -III), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having the (R) -stereochemistry, (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds (E) - (S) -III), ((Z) - (R) -III), or ((Z) - (S) -III), or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein compound III is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having the (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle. In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound III, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein compound III is the (E) -isomer and has an allylic carbon atom with a hydroxyl group, said carbon atom having the (S) -stereochemistry, and (ii) a pharmaceutically acceptable carrier or vehicle, wherein the composition is substantially free of compounds ((E) - (R) -III), ((Z) - (R) -III), or ((Z) - (S) -III), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound IV or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound V or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound VI, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound VIa, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound VIb, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the invention comprise (i) an effective amount of compound VII or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention comprise (i) an effective amount of compound VIII or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, and (ii) a pharmaceutically acceptable carrier or vehicle.
In some embodiments, the compositions of the present invention further comprise another therapeutically active agent.
The composition of the invention further comprising another therapeutically active agent is a "combination of the invention". The present invention provides a combination of the present invention. The combination of the invention may comprise one or more therapeutically active agents.
In some embodiments, the other therapeutically active agent is a lipid lowering drug, statin, cholesterol absorption inhibitor, anti-PCSK 9 antibody, siRNA PCSK9, anti-fibrotic agent, thyroid hormone, selective thyroid receptor- β agonist, apoptosis signal-regulating kinase 1 (ASK 1) inhibitor, acetyl Coa Carboxylase (ACC) inhibitor, integrin antagonist or non-steroidal Farnesoid X Receptor (FXR) agonist.
In some embodiments, the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, etoxytheophylline, pirfibrate, bisfibrate, tocofibrate or pemafibrate. In some embodiments, the lipid-lowering drug is gemfibrozil, fenofibrate, bezafibrate, or baclofen Ma Beite.
In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin (dihydroompactin) or cerivastatin, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the statin is atorvastatin, simvastatin, pravastatin, or rosuvastatin, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the cholesterol absorption inhibitor is ezetimibe.
In some embodiments, the anti-PCSK 9 antibody is allo You Shan anti-aliskirab, bococizumab, 1D05-IgG2 (Merck), RG7652 (Genentech), LY3015014 (Eli Lilly), or LGT-209 (Novartis/Cyon Therapeutics). In some embodiments, the antibody to PCSK9 is an allo You Shan antibody or an aliskiren.
In some embodiments, the siRNA PCSK9 is an siRNA that interferes with PCSK9 production, e.g., inclisiran.
In some embodiments, the anti-fibrotic agent is nitazoxanide, tizoxanide, or tizoxanide glucuronide, nidanib, imatinib, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the selective thyroid receptor-beta agonist is VK2809 (Viking Therapeutics), MGL-3196 (Madrigal Pharmaceuticals), MGL-3745 (Madrigal Pharmaceuticals), SKL-14763, sobetirome, BCT304 (ITL Pharma), ZYT1 (ZydusCadila)), MB-0781 (Metabasis), or irinotecan (epothilone).
In some embodiments, the ASK1 inhibitor is ste Long Se (selonsertib).
In some embodiments, the ACC inhibitor is first ocostat.
In some embodiments, the integrin antagonist is an α5β1 inhibitor or a ubiquitin inhibitor. In some embodiments, the integrin antagonist is IDL-2965 (Indalo Therapeutics). In some embodiments, the integrin antagonist is CLT-28643 (ClanoTech AB).
In some embodiments, the integrin antagonist is 3- (6-methoxypyridin-3-yl) -3- (4- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -2- (((benzyloxy) carbonyl) amino) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -2H-indazol-2-yl) propionic acid; 3-phenyl-3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -2H-indazol-2-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (6- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -2H-indazol-2-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (6- ((2-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -2H-indazol-2-yl) propanoic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (6- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -2H-indazol-2-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (6- (2- (2-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) ethyl) -2H-indazol-2-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) pyrazolo [4,3-b ] pyridin-1-yl) propionic acid; 3- (5- (2- ((4, 5-dihydroimidazol-2-yl) amino) ethoxy) -1H-indazol-1-yl) -3- (6-methoxypyridin-3-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -2- ((2, 4, 6-trimethylphenyl) sulfonamide) propanoic acid; 2- (((benzyloxy) carbonyl) amino) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (quinoxalin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (quinoxalin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (quinoxalin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3, 5-dichlorophenyl) -3- (4- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -propyl) -1H-indazol-1-yl) propionic acid; 3- (quinoxalin-2-yl) -3- (4- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; 3- (3, 5-dichlorophenyl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -propyl) -1H-indazol-1-yl) propionic acid; 3- (quinoxalin-2-yl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; 3- (3- (dimethylcarbamoyl) phenyl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; 3- (3- (dimethylcarbamoyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propionic acid; 3- (dibenzo [ b, d ] furan-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propionic acid; 3- (3- ((dimethylamino) methyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propanoic acid; 3- (quinoxalin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propionic acid; 3- (3, 5-dichlorophenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -ethyl) -1H-indazol-1-yl) propionic acid; 3- (3- (dimethylcarbamoyl) phenyl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (dibenzo [ b, d ] furan-3-yl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 6, 6-trifluoro-3- (4- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) hexanoic acid; 3- (3, 5-dichlorophenyl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -ethoxy) -1H-indazol-1-yl) propionic acid; 3- (quinoxalin-2-yl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3- (dimethylcarbamoyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -2- (((benzyloxy) carbonyl) amino) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-indazol-1-yl) propionic acid; (R) -3- (3- (dimethylcarbamoyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (3- (dimethylcarbamoyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 2- (((benzyloxy) carbonyl) amino) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5-chloropyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3, 5-dichlorophenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3-fluoro-4-methoxyphenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3-cyclopropyl-3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) octanoic acid; 3- (2, 3-dihydrobenzofuran-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (quinolin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid (48); 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (thiophen-2-yl) propionic acid; 3- (pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3-cyanophenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5-fluoropyridin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (dibenzo [ b, d ] furan-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (4, 6-dimethylpyrimidin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2-methylbenzo [ d ] thiazol-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (4-phenoxyphenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3-morpholinophenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3- (1H-pyrrol-1-yl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3- ((dimethylamino) methyl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propanoic acid; 3- (pyridin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3- (2-oxopyrrolidin-1-yl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1-propylpyrazol-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -2H-indazol-2-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (6- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -2H-indazol-2-yl) propionic acid; 3- (2-methylpyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (6-methoxypyridin-3-yl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -2H-indazol-2-yl) propionic acid; 3- (3, 5-dimethylpyrazol-1-yl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 4- (4- (benzyloxy) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) butanoic acid; 3- (6-methoxypyridin-3-yl) -3- (3-methyl-5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (3S) -3- (6-methoxypyridin-3-yl) -3- (6- (2- (1, 2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -2H-indazol-2-yl) propionic acid; 4-phenyl-2- ((5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) methyl) butanoic acid; 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (pyridin-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 2- (1- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) cyclopropyl) acetic acid; 3- (2-ethoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 4- (4-fluorophenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) butanoic acid; 3- (5-methoxypyrazin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (quinoxalin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (quinolin-3-yl) -3- (6- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -2H-indazol-2-yl) propionic acid; (S) -3- (6- ((2-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) methyl) -2H-indazol-2-yl) -3- (quinolin-3-yl) propionic acid; (3S) -3- (quinolin-3-yl) -3- (6- (2- (1, 2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) -ethyl) -2H-indazol-2-yl) propionic acid; (S) -3- (3- (2-oxopyrrolidin-1-yl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (3- (2-oxopyrrolidin-1-yl) phenyl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5-fluoro-6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (quinolin-3-yl) -3- (6- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -2H-indazol-2-yl) propionic acid; (3S) -3- (quinolin-3-yl) -3- (6- (3- (1, 2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) -propyl) -2H-indazol-2-yl) propionic acid; 3- (5- (hydroxymethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6- (2-hydroxy-2-methylpropyloxy) -5-methylpyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2-methoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2- (2-oxopyrrolidin-1-yl) pyridin-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (isoquinolin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (pyrido [2,3-b ] pyrazin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1, 8-naphthyridin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -2- (((benzyloxy) carbonyl) amino) -3- (5- ((5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) methoxy) -2H-indazol-2-yl) propionic acid; (R) -3- (5- (hydroxymethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (hydroxymethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1, 8-naphthyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2-oxopyrrolidin-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (1- (tetrahydro-2H-pyran-2-yl) pyrazolo [3,4-b ] pyridin-5-yl) propionic acid; 3- (5- (1, 3-dioxolan-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- ((dimethylamino) methyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (2-ethoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (2-ethoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (benzo [ d ] thiazol-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2-morpholinpyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2- (methylamino) pyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propyl) -1H-pyrazolo [4,3-b ] pyridin-1-yl) propionic acid; 3- (6-methoxypyridazin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- ([ 1,2,4] triazolo [4,3-a ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (2-methoxypyrimidin-5-yl) -3- (6- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -2H-indazol-2-yl) propionic acid; 3- (2- (azetidin-1-yl) pyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (oxazol-5-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (7-ethyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (((tert-butoxycarbonyl) amino) methyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5-morpholinpyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (methylsulfonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (3-methyl-3H-imidazo [4,5-b ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (pyrrolidin-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (pyrido [2,3-b ] pyrazin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (pyrido [2,3-b ] pyrazin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- ([ 1,2,4] triazolo [4,3-a ] pyridin-7-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (aminomethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- ([ 1,3] dioxolan-4, 5-b ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (1, 3-dioxolan-2-yl) -6-methoxypyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6- (1H-pyrazol-1-yl) pyridin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1- (pyridin-4-yl) -1H-pyrazol-4-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (2-methyl-2H-pyrazolo [4,3-b ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1-methyl-1H-pyrazolo [4,3-b ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (1, 3-dioxolan-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (1, 3-dioxolan-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (1-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (1H-pyrazol-5-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6-morpholinpyrazin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2-hydroxy-prop-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (2-hydroxypropan-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (2-hydroxypropan-2-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (2-methoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (2-methoxypyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (6-methoxypyrazin-2-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (2-oxopyrrolidin-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (2-oxopyrrolidin-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (morpholine-4-carbonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (dimethylcarbamoyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (4-methylpiperazine-1-carbonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5-cyclopropylpyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (4-methylpiperazin-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (azetidine-1-carbonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- ((2- (dimethylamino) ethyl) carboxamido) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (2-methylpyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (2-methylpyrimidin-5-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (1H-pyrazol-1-yl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) hexanoic acid; 3- (5- (dimethylamino) pyridin-3-yl) -3- (5- (2 (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3-cyclohexyl-3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (methylsulfonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (methylsulfonyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) -ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (((methoxycarbonyl) amino) methyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (((methoxycarbonyl) amino) methyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (((methoxycarbonyl) amino) methyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (methylsulfonylaminomethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propanoic acid; 3- (5- (acetamidomethyl) pyridin-3-yl) -3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) propionic acid; 3- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-3-yl) propionic acid; 4- ((6- (2-carboxy-1- (5- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) ethyl) pyrazin-2-yl) amino) butyric acid; 3- (6-methoxypyridin-3-yl) -3- (4- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) -1H-indazol-1-yl) propionic acid; (R) -3- (5- (2- ((R) -7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (2-methylpyrimidin-5-yl) propionic acid; (S) -3- (5- (2- ((R) -7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (2-methylpyrimidin-5-yl) propionic acid; (R) -3- (5- (2- ((S) -7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (2-methylpyrimidin-5-yl) propionic acid; (S) -3- (5- (2- ((S) -7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) -1H-indazol-1-yl) -3- (2-methylpyrimidin-5-yl) propionic acid; 3- (6-methoxypyridin-3-yl) -3- (5- (2- (1-methyl-1, 2,3, 4-tetrahydropyrido [2,3-b ] pyrazin-6-yl) ethoxy) -1H-indazol-1-yl) propionic acid; (S) -3- (5- (2- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-6-yl) ethoxy) -1H-indazol-1-yl) -3- (6-methoxypyridin-3-yl) propionic acid; and (R) -3- (5- (2- (3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazin-6-yl) ethoxy) -1H-indazol-1-yl) -3- (6-methoxypyridin-3-yl) propionic acid; or a pharmaceutically acceptable salt thereof. See US2019/0256496, the entire contents of which are incorporated herein by reference.
In some embodiments, the integrin antagonist is (S) -3- (3- (2-methoxyethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butanoic acid; (S) -3- (3- ((R) -2-methoxypropoxyphenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid, (S) -3- (3- ((S) -2-methoxypropoxyphenyl) -4-4R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; (S) -3- (3- (2-methoxy-2-methylpropyloxy) phenyl) -44 (R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butanoic acid; 3- (3- (((S) -1-methoxypropan-2-yl) oxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; (S) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) -3- (3- (((S) -tetrahydrofuran-3-yl) oxy) phenyl) butanoic acid; (S) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) -3- (3- (((R) -tetrahydrofuran-3-yl) oxy) phenyl) butanoic acid; (S) -3- (3, 5-bis (2-methoxyethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; (3S) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) -3- (3- (tetrahydrofuran-3-yl) phenylbutyric acid, (S) -3- (3- ((1-methoxy-2-methylpropan-2-yl) oxy) phenyl) -4-4R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; (S) -3- (3- (((R) -1-methoxypropan-2-yl) oxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butanoic acid; (S) -3- (3- (2-isopropoxyethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; (S) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) -3- (3- (((R) -tetrahydrofuran-2-yl) methoxy) phenyl) butanoic acid; (S) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) -3- (3- (((S) -tetrahydrofuran-2-yl) methoxy) phenyl) butanoic acid; (S) -3- (2-fluoro-5- (2-methoxyethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid; 3- (3- ((1, 3-dimethoxyprop-2-yloxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid, 3- (3- (2-fluoroethoxy) -5- (2-methoxyethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid, 3- (3- (3-methoxypropoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid, or 3- (3- (oxetan-3-ylmethoxy) phenyl) -4- ((R) -3- (2- (5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl) butyric acid, or a pharmaceutically acceptable salt thereof, is incorporated herein by reference in its entirety, 2012309.
In some embodiments, the integrin antagonist has the following structure
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Or a pharmaceutically acceptable salt thereof. See U.S. patent No. 10,214,522, which is incorporated by reference herein in its entirety.
In some embodiments, the integrin antagonist has the following structure
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Or a pharmaceutically acceptable salt thereof. See US 2018/0074684, the entire contents of which are incorporated herein by reference.
In some embodiments, the non-steroidal Farnesoid X Receptor (FXR) agonist is cilofexor.
In some embodiments, the combination of the invention comprises grossezia, firsostat, or cilofaxor. In some embodiments, the combination of the invention comprises a spirotetramat and a first ocostat. In some embodiments, the combination of the invention comprises a miltonian and a cilofexor. In some embodiments, the combination of the invention comprises ficosostat and cilofexor. In some embodiments, the combination of the invention comprises grossezia, firsostat, and cilofaxor.
In some embodiments, the pharmaceutically acceptable carrier or vehicle includes, but is not limited to, a binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, colorant, dye-migration inhibitor, sweetener, or flavoring agent.
The binder or granulating agent imparts cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, irish moss extract, panwar gum, gum ghatti, isabgol shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), magnesium aluminum silicate (Veegum), larch arabinogalactan, tragacanth powder and guar gum; cellulose, such as ethylcellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC); microcrystalline cellulose, for example, AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., marcus Hook, pa.); and mixtures thereof.
Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder is hydroxypropyl cellulose.
The binder or filler may be present in an amount of about 2% to about 49% by weight of the composition of the invention or any range within these values. In some embodiments, the binder or filler is present in about 5% to about 15% by weight of the composition of the invention. In some embodiments, the binder or filler is present in the compositions of the present invention at about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 8 wt%, about 10 wt%, about 11 wt%, 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt%, or any range within any of these values.
Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starches, and powdered sugar. When present in sufficient amounts, certain diluents (e.g., mannitol, lactose, sorbitol, sucrose, and inositol) can impart properties to some compressed tablets that allow disintegration in the mouth by chewing. Such compressed tablets may be used as chewable tablets. In some embodiments, the diluent is lactose monohydrate. In some embodiments, the diluent is lactose monohydrate Fast-Flo 316NF.
The compositions of the present invention may comprise a diluent, for example, from about 5% to about 49% by weight of the composition or any range between any of these values. In some embodiments, the diluent is present at about 15% to about 30% by weight of the composition of the invention. In some embodiments, the diluent is present in the compositions of the present invention at about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 18 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, or about 30 wt%, or any range within any of these values.
Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methyl cellulose and carboxymethyl cellulose; a wood product; natural sponge; a cation exchange resin; alginic acid; gums such as guar gum and magnesium aluminum silicate HV; citrus pulp (citrus pulp); crosslinked celluloses, such as crosslinked carboxymethyl cellulose; crosslinked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, pregelatinized starch, etc.; clay; alignment (alignns); and mixtures thereof. The amount of disintegrant in the compositions of the present invention can vary. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium NF (Ac-Di-Sol).
The compositions of the present invention may comprise a disintegrant, for example, from about 0.5% to about 15% by weight or from about 1% to about 10% by weight of the disintegrant. In some embodiments, the compositions of the present invention comprise a disintegrant in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 8 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt% of the composition, or within any range of any of these values.
Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc powder; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; stone pine nuts; silica or silica gel, e.g.200 (W.R. Grace Co., baltimore, MD) and +.>(Cabot co.of Boston, MA); and mixtures thereof. In some embodiments, the lubricant is magnesium stearate.
The compositions of the present invention may comprise a lubricant, for example, from about 0.1 to about 5 weight percent lubricant. In some embodiments, the compositions of the present invention comprise a lubricant in an amount of about 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 0.8 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt% or 3.0 wt% of the composition or within any range of any of these values.
Suitable glidants include colloidal silicon dioxide,(Cabot co.of Boston, MA) and talc, including asbestos-free talc.
Colorants include any approved, certified water-soluble FD & C dyes and water-insoluble FD & C dyes suspended on hydrated alumina, as well as lakes and mixtures thereof.
Flavoring agents include natural flavors extracted from plants (e.g., fruits), and synthetic blends of compounds that provide a pleasant taste sensation, such as peppermint and methyl salicylate.
Sweeteners include sucrose, lactose, mannitol, syrups, glycerol, sucralose, and artificial sweeteners (e.g., saccharin, stevioside (Stevia), and aspartame).
Suitable emulsifiers include gelatin, gum arabic, tragacanth, bentonite and surfactants (e.g. polyoxyethylene sorbitan monooleate @20 Polyoxyethylene sorbitan monooleate 80 ()>80 And triethanolamine oleate). Suspending and dispersing agents include sodium carboxymethyl cellulose, pectin, tragacanth, magnesium aluminum silicate, acacia, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl parahydroxybenzoates, benzoic acid addition, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
Solvents include glycerin, sorbitol, ethanol and syrup.
Examples of nonaqueous liquids for emulsions include mineral oil and cottonseed oil. The organic acid includes citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.
The compounds of the invention and the compositions of the invention may be formulated for administration in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles by a variety of means including oral, parenteral, by inhalation spray, topical or rectal. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular and intraarterial injection by a variety of infusion techniques. Intra-arterial and intravenous injection as used herein includes administration through a catheter.
The compounds of the present invention and the compositions of the present invention may be formulated according to conventional procedures suitable for the desired route of administration. Thus, the compositions of the present invention may take the form of suspensions, solutions or emulsions, such as in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds of the present invention and the compositions of the present invention may be formulated into formulations suitable for implantation or injection. Thus, for example, the compositions of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). The compounds of the invention and the compositions of the invention may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in remington: the Science and Practice of Pharmacy, a.gennaro, ed.,20th edition,Lippincott,Williams&Wilkins,Philadelphia,PA.
In some embodiments, the compositions of the present invention are suitable for oral administration. These compositions may comprise solid, semi-solid, gel matrix or liquid dosage forms suitable for oral administration. Oral administration, as used herein, includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, troches, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the present invention suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compositions of the present invention are in the form of tablets. In some embodiments, the compositions of the present invention are in the form of capsules. In some embodiments, the compounds of the invention are contained in capsules.
In some embodiments, the capsule is an immediate release capsule. Non-limiting examples of capsules areHard gelatin capsules.
The compositions of the present invention may be in the form of compressed tablets, tablet grind, chewing gum lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated tablets, or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestinal tract, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets that are coated with a sugar coating, which can be advantageous in masking unpleasant tastes or odors and protecting the tablets from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of water soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating may impart the same general characteristics as the sugar coating. Multiple compressed tablets refer to compressed tablets made by more than one compression cycle, including layered tablets and compression coated or dry coated tablets.
In some embodiments, the coating is a film coating. In some embodiments, the film coating comprises Opadry White and simethicone emulsion 30% usp.
In some embodiments, the compounds of the present invention are contained in a tablet. In some embodiments, the compounds of the present invention are contained in compressed tablets. In some embodiments, the compounds of the present invention are contained in film coated compressed tablets. In some embodiments, the compositions of the present invention are in the form of film coated compressed tablets.
In some embodiments, the compositions of the present invention are prepared by fluid bed granulation of a compound of the present invention with one or more pharmaceutically acceptable carriers, vehicles, or excipients. In some embodiments, the compositions of the present invention prepared by the fluid bed granulation step may provide tablet formulations having good flowability, good compressibility, rapid dissolution, good stability, and/or minimal to no breakage. In some embodiments, the fluid bed granulation step allows for the preparation of formulations having high drug loading (e.g., greater than 70% or greater than 75% of the compound of the invention).
The composition of the present invention may be in the form of a soft capsule or a hard capsule, which may be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as Dry Filled Capsules (DFCs), may comprise two parts, one part sliding over the other, thereby completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft spherical shells (e.g. gelatin shells) which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parahydroxybenzoates and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent No. 4,328,245;4,409,239; and 4,410,545. The capsules may also be coated as known to those skilled in the art in order to alter or maintain dissolution of the active ingredient.
The compositions of the present invention may be in liquid or semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion may be a two-phase system in which one liquid is dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may comprise a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier and a preservative. The suspension may comprise a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcohol solution may comprise a pharmaceutically acceptable acetal, such as a di- (lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" refers to an alkyl group having 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal; and water miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweetened, and hydroalcoholic solutions. Syrups may be concentrated aqueous solutions of a sugar (e.g., sucrose) and may contain a preservative. For liquid dosage forms, for example, the solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement of administration.
The compositions of the present invention for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms may be prepared as described in U.S. Pat. No. 6,350,458.
The compositions of the present invention may be provided as non-effervescent or effervescent agents, granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and carbon dioxide sources.
Coloring and flavoring agents may be used in all of the above-described dosage forms. Also, flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.
The compositions of the present invention may be formulated in immediate or modified release dosage forms including delayed release, extended release, pulsatile release, controlled release, targeted release and programmed release forms.
In some embodiments, the compositions of the present invention comprise a film coating.
The compositions of the present invention may contain another active ingredient that does not impair the therapeutic or prophylactic efficacy of the composition, or may contain substances that enhance or supplement the efficacy of the composition.
Tablet dosage forms may contain the compounds of the present invention in powder, crystalline or granular form and may further contain carriers or vehicles described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents or colorants.
In some embodiments, the compositions of the present invention may further comprise excipients, such as diluents, disintegrants, wetting agents, binders, glidants, lubricants, or any combination thereof. In some embodiments, the tablet comprises a binder. Also, in some embodiments, the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxymethyl cellulose, or any combination thereof. In other embodiments, the tablet comprises a disintegrant. In other embodiments, the disintegrant comprises croscarmellose sodium, sodium starch glycolate, or any combination thereof. In other embodiments, the tablet comprises a lubricant. Also, in some embodiments, the lubricant comprises magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
In some embodiments, the compositions of the present invention are in the form of tablets comprising a binder, such as any of the binders described herein.
In some embodiments, the compositions of the present invention are in the form of tablets comprising a disintegrant, such as any of the disintegrants described herein.
In some embodiments, the compositions of the present invention are in the form of tablets comprising a lubricant, such as any of the lubricants described herein.
In some embodiments, the compositions of the present invention may be in a modified release or controlled release dosage form. In some embodiments, the compositions of the present invention may comprise particles that exhibit a particular release profile. For example, the compositions of the present invention may comprise a compound of the present invention in immediate release form, together with a statin or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof in modified release form, both compressed into a single tablet. Other combinations and modifications of the release profile may be implemented as will be appreciated by those skilled in the art. Examples of modified release dosage forms suitable for the pharmaceutical compositions of the present invention are described in, but are not limited to, U.S. Pat. nos. 3,845,770;3,916,899;3,536,809;3,598,123;4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5,739,108;5,891,474;5,922,356;5,972,891;5,980,945;5,993,855;6,045,830;6,087,324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,376,461;6,419,961;6,589,548;6,613,358; and 6,699,500.
In some embodiments, the compositions of the present invention are matrix controlled release dosage forms. In some embodiments, the release profiles of the compounds of the invention and the other pharmaceutically active agents are the same or different. Suitable matrix controlled release dosage forms are described, for example, in Takada et al, "Encyclopedia of Controlled Drug Delivery," Vol.2, mathiowitz ed., wiley, 1999.
In some embodiments, the matrix controlled release form comprises an erodible matrix comprising a water swellable, erodible or soluble polymer including synthetic polymers and naturally occurring polymers and derivatives (e.g., polysaccharides and proteins).
In some embodiments, the erodible matrix in a matrix controlled release form comprises chitin, chitosan, dextran, or pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum or scleroglucan; starches, such as dextrins or maltodextrins; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; an alginate; propylene glycol alginate; gelatin; collagen; cellulose, such as Ethyl Cellulose (EC), methyl Ethyl Cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose Acetate (CA), cellulose Propionate (CP), cellulose Butyrate (CB), cellulose Acetate Butyrate (CAB), cellulose Acetate Phthalate (CAP), cellulose Acetate Trimellitate (CAT), hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), or ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; a glycerol fatty acid ester; polypropylene (PP) Enamides; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acidRohm America, inc., piscataway, NJ); poly (2-hydroxyethyl methacrylate); polylactic acid; copolymers of L-glutamic acid and ethyl L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D- (-) -3-hydroxybutyric acid; or other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl acrylate, 2-dimethylaminoethyl methacrylate or (trimethylaminoethyl) methacrylate chloride; or any combination thereof.
In other embodiments, the compositions of the present invention are matrix-controlled modified release forms comprising a non-erodable matrix. In some embodiments, the statin(s) (compounds of the invention) are dissolved or dispersed in an inert matrix and, once administered, are released primarily by diffusion through the inert matrix. In some embodiments, the non-erodable matrix in the matrix controlled release form comprises an insoluble polymer such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, vinyl chloride-vinyl acetate copolymer, vinylidene chloride, ethylene or propylene, ionomers polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/ethyleneoxy ethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, or a hydrophilic polymer such as ethylcellulose, cellulose acetate, cross-linked povidone, cross-linked partially hydrolyzed polyvinyl acetate; fatty compounds, such as carnauba wax, microcrystalline wax or triglycerides; or any combination thereof.
The compositions of the present invention in modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.
In some embodiments, the compositions of the present invention comprise an in-capsule tablet system, which may be a multi-function and multi-unit system of universal mini-tablets contained in hard gelatin capsules. The mini-tablets may be fast-release, extended-release, pulsed, delayed-action extended-release mini-tablets, or any combination thereof. In some embodiments, a combination of minitablets or a combination of minitablets and minibeads comprising multiple active agents may each have a specific lag time, release-multiplexed pulse Drug Delivery System (DDS), site-specific DDS, slow-fast DDS, fast/slow DDS, and zero order DDS.
In some embodiments, the compositions of the present invention are osmotic controlled release dosage forms.
In some embodiments, the osmotic controlled release device comprises a one-compartment system, a two-compartment system, an Asymmetric Membrane Technology (AMT), an Extruded Core System (ECS), or any combination thereof. In some embodiments, such devices comprise at least two components: (a) a core containing one or more active agents; and (b) a semipermeable membrane encapsulating the core having at least one delivery port. The semipermeable membrane controls the flow of water from the aqueous environment of use into the core, thereby causing drug release by extrusion through one or more delivery ports.
In some embodiments, the core of the osmotic device optionally includes an osmotic agent that generates a driving force for transporting water from the environment of use into the core of the device. One class of penetrants that may be used in the compositions of the invention include water swellable hydrophilic polymers, also referred to as "osmopolymers" or "hydrogels," including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, copolymers of PVA/PVP with hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethyl cellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.
Another class of osmotic agents useful in the compositions of the present invention include osmotic agents that are capable of absorbing water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable penetrants include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof.
Osmotic agents of different dissolution rates may be used to influence how rapidly the compounds of the present invention dissolve after administration. For example, amorphous sugars (e.g., mannogemez (spicharm, lewes, DE)) may be included to provide faster delivery during the first few hours (e.g., about 1 to about 5 hours) to rapidly produce a prophylactic or therapeutic effect. And gradually and continuously releasing the remaining amount to maintain a desired level of therapeutic or prophylactic effect over a longer period of time. In some embodiments, the compounds of the invention are released from the compositions of the invention at a rate that replaces the amount of the compounds of the invention that are metabolized or excreted by the subject.
The core may also include a variety of other excipients and carriers described herein to enhance the performance of the dosage form or to promote stability or processing.
Materials used to form the semipermeable membrane include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water permeable and insoluble at physiologically relevant pH or that readily become insoluble by chemical changes (e.g., crosslinking). Examples of suitable polymers that may be used to form the coating include plasticized, unplasticized and enhanced Cellulose Acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose Acetate Butyrate (CAB), CA urethane, CAP, CA methyl carbamate, CA succinic acid, cellulose Acetate Trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methylsulfonate, CA butylsulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, β -glucan acetate, β -glucan triacetate, dimethyl glyoxylate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acids and esters, and poly (methacrylic) acids and esters and copolymers thereof, starches, glucans, dextrins, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyethylene esters and ethers, natural waxes and synthetic waxes.
The semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with gas and are not wetted by the aqueous medium, but are permeable to water vapor, as disclosed in us patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers (e.g., polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural and synthetic waxes).
One or more delivery ports on the semipermeable membrane may be formed after coating by mechanical or laser drilling. The one or more delivery ports may also be formed in situ by eroding a plug of water-soluble material or by rupture of a thinner portion of the membrane over a recess in the core. In addition, the delivery ports may be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. nos. 5,612,059 and 5,698,220.
The total amount and release rate of the compounds of the present invention released can be substantially regulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.
In some embodiments, the pharmaceutical composition of the osmotic controlled release dosage form may further comprise additional conventional excipients as described herein to facilitate performance or processing of the formulation.
Osmotic controlled Release dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: the Science and Practice of Pharmacy, supra; santus and Baker, J. Controlled Release 1995,35,1-21; verma et al, drug Development and Industrial Pharmacy 2000,26,695-708; verma et al, J. Controlled Release 2002,79,7-27).
In some embodiments, the pharmaceutical compositions provided herein are formulated as Asymmetric Membrane Technology (AMT) controlled release dosage forms comprising an asymmetric osmotic membrane coating a core comprising one or more active ingredients and other pharmaceutically acceptable excipients. See U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled release dosage forms may be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, dip coating, and the like.
In some embodiments, the pharmaceutical compositions provided herein are formulated as controlled-release dosage forms of ESCs comprising a permeable membrane coating a core comprising a compound of the invention, hydroxyethylcellulose, and other pharmaceutically acceptable excipients.
In some embodiments, the compositions of the present invention are modified release dosage forms manufactured as multiparticulate controlled release dosage forms comprising a plurality of particles, granules or pellets, microparticles, beads, microcapsules, and microtablets ranging in diameter from about 10 μm to about 3mm, from about 50 μm to about 2.5mm, or from about 100 μm to 1 mm.
Multiparticulate controlled release dosage forms can provide extended release dosage forms with improved bioavailability. Suitable carriers for maintaining the release rate of the compounds of the present invention include, but are not limited to, ethylcellulose, HPMC-phthalate, colloidal silica and Eudragit-RSPM.
The composition of the invention in the form of a pill may comprise 50-80% (w/w) of the drug and 20-50% (w/w) of microcrystalline cellulose or other polymer. Suitable polymers include, but are not limited to, microcrystalline waxes, pregelatinized starches, and maltodextrins.
The beads can be prepared into capsules and tablet formulations. Beads in a tablet dosage form exhibit a slower dissolution profile than microparticles in a capsule dosage form. Particulate fillers suitable for the compositions and methods of treatment or prevention of the present invention include, but are not limited to, sorbitan monooleate (Span 80), HPMC, or any combination thereof. Suitable dispersions for the controlled release latex include, for example, ethyl acrylate and methyl acrylate.
In some embodiments, the compositions of the present invention are in the form of microcapsules and/or microtablets. In some embodiments, the microcapsules comprise extended release polymeric microcapsules containing a statin and a compound of the invention having various solubility characteristics. Extended release polymeric microcapsules can be prepared in an aqueous environment using a colloidal polymer dispersion. In other embodiments, microcapsules suitable for use in the compositions and methods provided herein may be prepared using conventional microencapsulation techniques (Bodmeier & Wang, 1993).
Such multiparticulates may be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, rolling, melt coagulation, and by spraying the seed core. See, e.g., multiparticulate Oral Drug Delivery; marcel Dekker 1994; and Pharmaceutical Pelletization Technology; marcel Dekker 1989. Excipients of such technology are commercially available and described in the united states pharmacopeia.
Other excipients described herein may be mixed with the compositions of the present invention to aid in processing and formation of multiparticulates. The resulting particles may themselves comprise multiparticulate dosage forms or may be coated with various film-forming materials, such as enteric polymers, water-swellable or water-soluble polymers. The multiparticulates may be further processed into capsules or tablets.
In other embodiments, the compositions of the present invention are dosage forms having an immediate release component and at least one delayed release component and are capable of providing discontinuous release of the compound in the form of at least two consecutive pulses (time interval from 0.1 hour to 24 hours).
In some embodiments, the compositions of the present invention comprise from about 1mg to about 1000mg of a compound of the present invention or any amount within these values. In some embodiments, the compositions of the present invention comprise from about 1mg to about 500mg of a compound of the present invention or any amount within these values. In some embodiments, the compositions of the present invention comprise from about 1mg to about 400mg of a compound of the present invention or any amount within these values.
In other embodiments, the compositions of the present invention comprise the compounds of the present invention in an amount of about 1mg to about 1000mg molar equivalents of the compounds of the present invention or in any amount within these values. In other embodiments, the compositions of the present invention comprise an amount of the compound of the present invention in a molar equivalent of from about 1mg to about 500mg or any amount within these values. In other embodiments, the compositions of the present invention comprise the compounds of the present invention in an amount of about 1mg to about 400mg molar equivalents of the compounds of the present invention or in any amount within these values.
In some embodiments, the compositions of the present invention comprise the compounds of the present invention in an amount of about 10wt% to about 99wt% of the total weight of the composition of the present invention.
5.4. The method of the invention
The present invention provides methods for treating or preventing liver disorders, dyslipidemia, kidney disease, a glucose metabolism disorder, a lipid metabolism disorder, a saccharin (glucose) metabolism disorder, a cardiovascular disease, a vascular disease, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorders, sepsis, thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders associated with neovascularization, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, tumor diseases, muscle atrophy, cholestasis, mitochondrial dysfunction, ocular diseases, lysosomal storage diseases, or impotence, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The invention provides methods of treating or preventing kidney disease (e.g., acute kidney injury) comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
In some embodiments, the invention provides methods for treating or preventing liver disorders comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis, or proliferation of hepatocytes. In some embodiments, the liver disorder is liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
In some embodiments, the invention provides methods for reducing abnormally high concentrations of alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, gamma-glutamyltransferase (GGT), L-Lactate Dehydrogenase (LD), prothrombin Time (PT), creatinine, or total protein in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the invention provides methods for increasing abnormally low concentrations of albumin or total protein in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The "abnormally high concentration" of ALT in the plasma or serum of a subject is greater than 56 units/liter. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of ALT in the plasma or serum of a subject ranges from about 7 units/liter to about 56 units/liter.
The "abnormally high concentration" of AST in the plasma or serum of a subject is greater than 48 units/liter. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of AST in the plasma or serum of a subject ranges from about 8 units/liter to about 48 units/liter.
The "abnormally high concentration" of ALP in the plasma or serum of a subject is greater than 129 units/liter. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of ALP in the subject's plasma or serum ranges from about 40 units/liter to about 129 units/liter.
The "abnormally low concentration" of albumin in the plasma or serum of a subject is less than 3.5g/dL. In some embodiments, the increase is to a normal concentration. In some embodiments, the normal concentration of albumin in the subject's plasma or serum ranges from about 3.5g/dL to about 5.0g/dL.
"abnormally high concentrations" of bilirubin in the plasma or serum of a subject are greater than 1.2mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of bilirubin in the subject's plasma or serum ranges from about 0.1mg/dL to about 1.2mg/dL.
The "abnormally high concentration" of GGT in the plasma or serum of a subject is greater than 61 units/liter. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of GGT in the plasma or serum of a subject ranges from about 8 units/liter to about 61 units/liter.
The "abnormally high concentration" of LD in the plasma or serum of a subject is greater than 222 units/liter. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of LD in the plasma or serum of a subject ranges from about 122 units/liter to about 222 units/liter.
The "abnormally high concentration" of PT in the plasma or serum of the subject is greater than 12.5 seconds. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of PT in the subject's plasma or serum ranges from about 9.4 seconds to about 12.5 seconds.
The "abnormally high concentration" of creatinine in the plasma or serum of a subject is greater than 1.5mg/dL, which corresponds to a Glomerular Filtration Rate (GFR) of about 30mL/min and indicates renal failure. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of creatinine in the subject's plasma or serum ranges from about 0.84mg/dL to about 1.21mg/dL. (about 74.3. Mu. Mol/L to about 107. Mu. Mol/L).
The "abnormally high concentration" of total protein in the plasma or serum of the subject is greater than 7.9g/dL. The "abnormally low concentration" of total protein in the plasma or serum of the subject is less than 6.3g/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the increase is to increase the normal concentration. In some embodiments, the normal concentration range of total protein in the subject's plasma or serum is about 6.3g/dL to about 7.9g/dL.
In some embodiments, the invention provides methods for treating or preventing NAFLD or NASH comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
In some embodiments, the invention provides methods for treating or preventing dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the dyslipidemia is hyperlipidemia or an abnormally low concentration of high density lipoprotein cholesterol (HDL-C) in the plasma or serum of a subject. The term "dyslipidemia" refers to disorders that result in or appear as abnormal levels of circulating lipids.
In some embodiments, the invention provides methods for restoring plasma or serum concentrations of total cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, or free triglycerides to normal or recommended concentrations or ratios. Thus, to the extent that lipid levels in plasma or serum are abnormally high, the compounds of the invention or the compositions of the invention may be administered to patients to restore normal levels. Normal levels of lipids are well known to those skilled in the art. For example, normal blood levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, free triglycerides, and other parameters related to lipid metabolism can be found on the websites of the american heart association, national lipid association, and national cholesterol education programs of the national institute of heart, lung and blood. In some embodiments, the recommended concentration of HDL-C in plasma or serum is greater than 35mg/dl. In some embodiments, the recommended concentration of LDL-C in plasma or serum is less than 100mg/dl. In some embodiments, the recommended LDL-C to HDL-C ratio in plasma or serum is less than 5:1, in some embodiments less than 3.5:1. In some embodiments, the recommended concentration of free triglycerides in plasma or serum is less than 200mg/dl.
In some embodiments, the present invention provides methods for treating or preventing hyperlipidemia comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial mixed hyperlipidemia. In some embodiments, hyperlipidemia is characterized by abnormally reduced or absent levels or activities of lipoprotein lipase in the plasma or serum of a subject, or abnormally high concentrations of ketone bodies, lipoprotein (a) cholesterol (Lp (a) -C), low-density lipoprotein (LDL), very low-density lipoprotein cholesterol (VLDL-C), or non-esterified fatty acids (NEFA) in the plasma or serum of a subject. In some embodiments, the reduced or absent lipoprotein lipase level or activity is the result of a lipoprotein lipase mutation. In some embodiments, the reduced or absent lipoprotein lipase level or activity is the result of a mutation in a gene encoding a lipoprotein lipase.
Non-limiting examples of ketone bodies include acetoacetate, beta-hydroxybutyrate, and acetone. The "abnormally high concentration" of ketone bodies in the plasma or serum of a subject is 1mg/dL or higher (< 0.1 mmol/L). In some embodiments, the invention provides methods for reducing abnormally high concentrations of ketone bodies in the plasma or serum of a subject, wherein the concentration is 1mg/dL or greater. In some embodiments, the decrease is to a normal level. In some embodiments, the normal level is less than 1mg/dL (< 0.1 mmol/L). See Devkota, B.P. et al, medical science, updated Oct.30,2015.
The "abnormally high concentration" of VLDL-C in the plasma or serum of a subject is greater than 30mg/dL (1.7 mmol/L). In some embodiments, the invention provides methods for reducing VLDL-C concentration in a subject's plasma or serum, wherein the VLDL-C concentration is greater than 30mg/dL. In some embodiments, the decrease is to a normal level. In some embodiments, the normal level ranges from 2mg/dL to 30mg/dL (0.1 to 1.7 mmol/L).
The "abnormally high concentration" of NEFA in the plasma or serum of the subject in the non-fasting state is 0.9mM or higher. The "abnormally high concentration" of NEFA in the plasma or serum of the subject in the fasting state is greater than 1.8mM. The "abnormally high concentration" of NEFA in the plasma or serum of the subject at 15 hours on an empty stomach is greater than 1.1nM. The "abnormally high concentration" of NEFA in the plasma or serum of the subject is greater than 1.3mM at 20 hours on an empty stomach. The "abnormally high concentration" of NEFA in the plasma or serum of the subject at 15 hours on an empty stomach is greater than 1.1nM. The "abnormally high concentration" of NEFA in the plasma or serum of the subject is greater than 1.8mM at 24 hours on an empty stomach. In some embodiments, the invention provides methods for reducing NEFA concentration in a subject's plasma or serum, wherein the NEFA concentration is greater than 0.9mM, in some embodiments greater than 1.1mM, in some embodiments greater than 1.5mM, and in some embodiments greater than 1.8mM. In some embodiments, the decrease is to a normal level. In some embodiments, the normal level is 1.8mM or less, in some embodiments 1.5mM or less, in some embodiments 1.1mM or less, and in some embodiments 0.9mM or less. See Horowitz, G.L.et al, medical science, updated July 25,2019.
In some embodiments, the invention provides methods for treating or preventing dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, dyslipidemia is characterized by an abnormally high concentration of LDL, apolipoprotein (a) or VLDL in the plasma or serum of the subject, or an abnormally low concentration of High Density Lipoprotein (HDL) or lipoprotein lipase in the plasma or serum of the subject. In some embodiments, the abnormally low concentration of lipoprotein lipase is associated with: mutations in lipoprotein lipase, hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial mixed hyperlipidemia. The term "dyslipidemia" refers to a disorder that results in or manifests as an abnormal concentration of circulating lipoproteins in the plasma or serum of a subject. To the extent that the concentration of lipoproteins in the plasma or serum is too high, the compounds of the invention or the compositions of the invention can be administered to a subject to restore normal lipoprotein concentration. In contrast, to the extent that the concentration of lipoproteins in the plasma or serum is too low, the compound of the present invention or the composition of the present invention can be administered to a subject to restore the normal concentration. The normal concentration of lipoproteins is reported in medical papers known to those skilled in the art.
In some embodiments, the invention provides methods for treating or preventing kidney disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the kidney disease is glomerular disease, tubular interstitial disease, acute or rapidly progressive renal failure, chronic renal failure, kidney stones or tumors. In some embodiments, the kidney disease is hypertension, renal sclerosis, microangiopathy hemolytic anemia, atherosclerotic kidney disease, diffuse cortical necrosis, or renal infarction.
In some embodiments, the glomerular disease is acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesions associated with systemic disease, goodpasture's syndrome (Goodpasture syndrome), multiple myeloma, diabetes, neoplasia, sickle cell disease, or chronic inflammatory disease. In some embodiments, the glomerulopathy associated with the systemic disease is systemic lupus erythematosus.
In some embodiments, the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, spongiform kidney, medullary cystic disease, nephrogenic diabetes, or tubular acidosis.
In some embodiments, the tubular interstitial disease is pyelonephritis, drug-or toxin-induced tubular interstitial nephritis, hypercalcemic nephropathy, or hypokalemic nephropathy.
In some embodiments, the tumor is a renal cell carcinoma or a wilms' tumor.
In some embodiments, the kidney disease is hypertension. In some embodiments, the hypertension is primary hypertension, hypertension (hyperpiesa), hyperpiesis, malignant hypertension, secondary hypertension, or white coat hypertension.
In some embodiments, the kidney disease (renal disease) is kidney disease (kidney disease).
In some embodiments, the present invention provides methods for treating or preventing a glucose metabolism disorder comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The term "glucose metabolism disorder" refers to disorders that result in or manifest as abnormal glucose storage and/or utilization. To the extent that the glucose metabolism index (i.e., insulin, glucose, or glycosylated hemoglobin in the subject's plasma or serum) is too high, the compounds of the invention or the compositions of the invention can be administered to the subject to restore normal levels. Normal indicators of glucose metabolism are reported in medical papers known to those skilled in the art. See US 7,709,682 B2.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of glucose in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The "abnormally high concentration" of glucose in the plasma or serum of the subject in the fasting state (10-16 hours without feeding) is greater than 5.6mmol/L (100 mg/dL). In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of glucose in the fasting state is less than 5.6mmol/L. In some embodiments, fasting glucose plasma or serum concentrations in the range of 5.6mmol/L to 6mmol/L (100-109 mg/dL) may be indicative of pre-diabetes. In some embodiments, fasting glucose plasma or serum concentrations in the range of 6.1mmol/L to 6.9mmol/L (110-125 mg/dL) may be indicative of diabetes. In some embodiments, a fasting glucose plasma or serum concentration of 7mmol/L (126 mg/dL) and above is indicative of diabetes.
In some embodiments, abnormally high concentrations of glucose in the plasma or serum of a subject are measured in a Glucose Tolerance Test (GTT).
An hour of "abnormally high concentration" of glucose in the plasma or serum of the subject in the GTT is greater than 10mmol/L (180 mg/dL). In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration in an hour of GTT is less than 10mmol/L (180 mg/dL).
In a two hour GTT at 75g intake, the "abnormally high concentration" of glucose in the subject's plasma or serum is greater than 7.8mmol/L (140 mg/dL), which indicates hyperglycemia. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration in the two hour GTT at 75g intake is less than 7.8mmol/L (140 mg/dL). In some embodiments, a concentration of glucose in the subject's plasma or serum of between 7.8mmol/L (140 mg/dL) and 11.1mmol/L (200 mg/dL) in a two hour GTT at 75g intake indicates impaired glucose tolerance. In some embodiments, a glucose concentration greater than 11.1mmol/L in a two hour GTT at 75g intake is indicative of diabetes.
In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the glucose concentration in the plasma or serum of the subject in the subject is greater than 7.8mmol/L (140 mg/dL) in the two-hour GTT. In some embodiments, the invention provides methods of treating or preventing a glucose metabolism disorder in a subject, wherein the glucose concentration in the subject's plasma or serum is in the range of 7.8mmol/L (140 mg/dL) to 11.1mmol/L (200 mg/dL) in a two hour GTT. In some embodiments, the invention provides methods for treating or preventing a glucose metabolic disorder in a subject, wherein the subject's glucose concentration in the subject's plasma or serum is greater than 11.1mmol/L (200 mg/dL) in a two hour GTT.
In some embodiments, the invention provides methods for reducing a subjectAbnormally high levels of HbA in plasma or serum 1c Comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Hemoglobin A1c (HbA) in the plasma or serum of a subject 1c ) The "abnormally high level" of (1) is 6.5% or higher (expressed in% NGSP units). In some embodiments, the decrease is to a normal level. In some embodiments, hbA 1c Is in the range of about 4% to about 5.9%. In some embodiments, the invention provides methods for reducing HbA in plasma or serum of a subject 1c Horizontal method, wherein HbA 1c The level is greater than 7%, greater than 8% or greater than 9%. See Horowitz, G.L.et al, medical science, updated July 25,2019.
In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject's HbA in the subject's plasma or serum 1c The level is 6.5% or higher and the fasting glucose concentration of the subject is 126mg/dL or higher (. Gtoreq.7.0 mmol/L). See Selvin, e.et al, ann international med. Published online June 18,2018.
In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject has HbA 1c Greater than or equal to 6.5%. In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject's HbA in the subject's plasma or serum 1c Greater than or equal to 6.5% and a fasting glucose concentration greater than or equal to 126mg/dL (7.0 mmol/L).
In some embodiments, the invention provides methods for reducing abnormally high concentrations of glucose in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention, wherein the subject is pregnant. The "abnormally high concentration" of glucose in the plasma or serum of a pregnant subject in the fasting state is greater than 5.3mmol/L (95 mg/dL).
In some embodiments, the invention provides a method for reducing abnormally high concentrations of glucose in the plasma or serum of a subject, comprising administering to a subject in need thereof (i) a glucose solution as part of a two-step gestational diabetes test (ii) an effective amount of a compound of the invention or a composition of the invention. In the two-step gestational diabetes test, the "abnormally high concentration" of glucose in the plasma or serum of a subject is greater than 10mmol/L (180 mg/dL) 1 hour after consumption of the glucose solution. In the two-step procedure, the first step is a glucose dose of 50 g. If it results in a blood glucose level exceeding 7.8mmol/L (140 mg/dL), then a 100g glucose dose is taken. "abnormally high concentration: 2 hours after consumption of the glucose solution in the two-step gestational diabetes test, the glucose in the subject's plasma or serum is greater than 8.6mmol/L (155 mg/dL). "abnormally high concentration: 3 hours after consumption of the glucose solution in the two-step gestational diabetes test, the glucose in the subject's plasma or serum is greater than 7.8mmol/L (140 mg/dL).
In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject has impaired glucose tolerance. In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject has diabetes. In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject has been demonstrated to have undiagnosed diabetes. In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject has gestational diabetes.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of insulin in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The "abnormally high concentration" of insulin in the plasma or serum of a subject in the fasting state is greater than 25mIU/L (> 174 pmol/L). In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of insulin in the plasma or serum of the subject in the fasting state is less than 25mIU/L (< 174 pmol/L). See Buppajarntham, s.et al, mediascape email, updated jan.2,2019.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of insulin in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
In some embodiments, the method further comprises administering glucose to the subject. In some embodiments, the method does not include administering glucose to the subject. In some embodiments, the subject is in a fasting state.
In some embodiments, there is an abnormal concentration of insulin in the plasma or blood glucose of the subject 30 minutes after administration of glucose. The "abnormally high concentration" of insulin in the plasma or serum of a subject at 30 minutes after administration of glucose is greater than 230mIU/L (> 1597 pmol/L). In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of insulin in the plasma or serum of the subject at 30 minutes after administration of glucose is in the range of about 30mIU/L to about 230mIU/L (208-1597 pmol/L). See Buppajarntham,2019.
In some embodiments, the subject has an abnormal concentration of insulin in the plasma or serum of the subject 1 hour after administration of glucose. The "abnormally high concentration" of insulin in the plasma or serum of a subject at 1 hour after administration of glucose is greater than 276mIU/L (> 1917 pmol/L). In some embodiments, the invention provides methods for reducing abnormally high concentrations of insulin in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of insulin in the plasma or serum of the subject 1 hour after administration of glucose is in the range of about 18mIU/L to about 276mIU/L (125-1917 pmol/L). See Buppajarntham,2019.
In some embodiments, the subject has an abnormal concentration of insulin in the plasma or blood glucose 2 hours after administration of glucose. The "abnormally high concentration" of insulin in the plasma or serum of a subject at 2 hours after administration of glucose is greater than 166mIU/L (> 1153 pmol/L). In some embodiments, the invention provides methods for reducing abnormally high concentrations of insulin in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the normal concentration of insulin in the plasma or serum of the subject at 2 hours after administration of glucose is in the range of about 16mIU/L to about 166mIU/L (111-1153 pmol/L). See Buppajarntham,2019.
In some embodiments, the subject has an abnormal concentration of insulin in the plasma or blood glucose 3 hours after administration of glucose. The "abnormally high concentration" of insulin in the plasma or serum of a subject at 3 hours after administration of glucose is greater than 25mIU/L (> 174 pmol/L). In some embodiments, the invention provides methods for reducing abnormally high concentrations of insulin in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the normal concentration of insulin in the subject's plasma or serum at 3 hours after or after administration of glucose is less than 25mIU/L (< 174 pmol/L). See Buppajarntham,2019.
In some embodiments, the invention provides methods for treating or preventing a glucose metabolism disorder in a subject, wherein the subject's insulin concentration in the subject's plasma or serum is greater than 25mIU/L in a fasting state or 3 hours after glucose administration. See Buppajarntham,2019.
In some embodiments, the disorder of glucose metabolism is impaired glucose tolerance; insulin resistance; insulin resistance-associated breast, colon or prostate cancer; diabetes mellitus; pancreatitis; hypertension; polycystic ovarian disease; or abnormally high concentrations of blood insulin or glucose in the plasma or serum of the subject. In some embodiments, the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin Dependent Diabetes Mellitus (IDDM), gestational Diabetes Mellitus (GDM), or juvenile onset adult-onset diabetes (MODY).
In some embodiments, the invention provides methods for treating or preventing metabolic syndrome (syndrome X) comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the invention provides methods for treating or preventing a symptom of metabolic syndrome (syndrome X), comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the symptom is impaired glucose tolerance, hypertension, dyslipidemia, or dyslipidemia.
In some embodiments, the invention provides methods for treating or preventing vascular disease or cardiovascular disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The term "cardiovascular disease" refers to a disease of the heart or circulatory system. In some embodiments, the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia reperfusion injury, myocardial infarction, or cerebral infarction.
In some embodiments, the invention provides methods for treating or preventing a PPAR-related disorder comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the PPAR-related disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer or prostate cancer. In some embodiments, the PPAR-related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structure disorder, a neuron activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a β -oxidation disease, or a metabolic disease. In some embodiments, the PPAR related disorder is an abnormally low concentration of HDL, an abnormally low concentration of apolipoprotein A-I (apo A-I), an abnormally high concentration of VLDL-C, an abnormally high concentration of low density lipoprotein cholesterol (LDL-C), an abnormally high concentration of triglycerides, an abnormally high concentration of apolipoprotein B (apo B), an abnormally high concentration of apolipoprotein C-III (apo C-III), or an abnormally reduced proportion of post-heparin hepatic lipase: lipoprotein lipase activity in the plasma or serum of the subject. In some embodiments, the PPAR-related disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo a-I in the lymph or brain fluid of the subject.
In some embodiments, the PPAR-related disorder is an abnormally low concentration of lipoprotein lipase activity in the post-heparin plasma of the subject (the subject's plasma after intravenous heparin injection). In some embodiments, the invention provides methods for increasing an abnormally low concentration of lipoprotein lipase activity in plasma after heparin, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The "abnormally low concentration" of lipoprotein lipase activity in plasma after heparin is below 30U/L. In some embodiments, the increase is to a normal concentration. In some embodiments, the normal concentration is in the range of about 30U/L to about 153U/L (see Nakajima et al Clin Chim acta.2018Dec; 487:54-59).
In some embodiments, the invention provides methods for treating or preventing a PPAR-related disorder in a subject, wherein the subject has less than 30U/L of lipoprotein lipase activity in the plasma after heparin.
In some embodiments, the subject is a male subject. "abnormally high concentrations" of HDL in a male subject are greater than 75mg/dL.
In some embodiments, the subject is a female subject. The "abnormally high concentration" of HDL in female subjects is greater than 90mg/dL.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of HDL in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration in a male subject is less than 75mg/dL. In some embodiments, the normal concentration in a female subject is less than 90mg/dL. In some embodiments, the invention provides methods for treating or preventing a PPAR-related disorder in a male subject, wherein the subject's HDL concentration in the subject's plasma or serum is greater than 75mg/dL. In some embodiments, the invention provides methods for treating or preventing a PPAR-related disorder in a female subject, wherein the subject has an HDL concentration in the subject's plasma or serum of greater than 90mg/dL. See Hassan, m.et al.glob Cardiol Sci practice.2016dec30; 2016 (4) e201634.
In some embodiments, the muscle disorder is a muscular dystrophy disorder. In some embodiments, the muscular dystrophy disease is duchenne muscular dystrophy, becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facial shoulder brachial muscular dystrophy, tonic muscular dystrophy, ocular pharyngeal muscular dystrophy, distal muscular dystrophy, or Emery-debifys muscular dystrophy (Emery-Dreifuss muscular dystrophy).
In some embodiments, the demyelinating disease is multiple sclerosis, charcot-Marie-Tooth disease (Charcot-Marie-Tooth disease), pelizaeus-Mibach disease (Pelizaeus-Merzbacher disease), encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy or Guillain-Barre syndrome (Guillian-Barre syndrome).
In some embodiments, the muscle structural disorder is Bethlem myopathy (Bethlem myopathy), central core heart disease (central core disease), congenital fibrotic imbalance, distal Muscular Dystrophy (MD), duchenne and beck-type MD (Duchenne & Becker MD), emery-Dreifuss MD (Emery-Dreifuss MD), facial shoulder arm MD, homogenized small body myopathy, limb band MD, muscle sodium channel disorder, tonic cartilage dystrophy, tonic myodystrophy, myotubular myopathy, line-like small body disease, ocular pharynx MD, or stress urinary incontinence.
In some embodiments, the neuron activation disorder is amyotrophic lateral sclerosis, charcot-marie-fig disease, gill-barre syndrome, lambert-Eaton syndrome (Lambert-Eaton syndrome), multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, delayed ulnar paralysis, or toxic muscular disorder.
In some embodiments, the muscle fatigue disorder is chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, friedreich's ataxia, intermittent claudication, lipid deposition myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like attacks) syndrome, mucopolysaccharidosis, pompe disease (Pompe disease), or thyrotoxic myopathy.
In some embodiments, the muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, fascial syndrome, critical myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus.
In some embodiments, the mitochondrial disorder is Alpers's disease, chronic progressive extraocular muscle paralysis (CPEO), kaens-sayer syndrome (KSS), leber Hereditary Optic Neuropathy (LHON), MELAS, myoclonus epilepsy, and broken red fiber disease (MERRF), neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, pearson syndrome (Pearson syndrome), mitochondrial dysfunction, or loss of mitochondrial function (e.g., due to drug effects).
In some embodiments, the mitochondrial dysfunction is drug-induced mitochondrial dysfunction.
In some embodiments, the beta oxidation disease is systemic carnitine transporter, carnitine Palmitoyl Transferase (CPT) II deficiency, very long chain acyl-coa dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium chain acyl-coa dehydrogenase (MCAD) deficiency, short chain acyl-coa dehydrogenase (SCAD) deficiency, or riboflavin-reactive beta-oxidation disorder (RR-MADD).
In some embodiments, the metabolic disease is hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypercholesterolemia, LDL hypercholesterolemia, HLD non-cholesterol, VLDL hyperproteinemia, dyslipidemia, apolipoprotein a-I hypoproteinemia, atherosclerosis, arteriosclerosis, cardiovascular disease, cerebrovascular disease, peripheral circulation disease, metabolic syndrome, syndrome X, obesity, diabetes, type I diabetes, type II diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, cardiac insufficiency, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, hair morbidity, inflammation, arthritis, asthma, irritable bowel syndrome, crohn's, ulcerative colitis, or pancreatic's.
In some embodiments, the invention provides methods for treating or preventing sepsis comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the sepsis is septic shock.
In some embodiments, the present invention provides methods for treating or preventing a thrombotic disorder comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the thrombotic disorder is a high concentration of fibrinogen, or promotes fibrinolysis, in the plasma or serum of the subject.
In some embodiments, the present invention provides methods for treating or preventing obesity comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the obesity is abdominal obesity. In some embodiments, the method for treating or preventing obesity further comprises promoting weight loss in the subject.
In some embodiments, the present invention provides methods for treating or preventing diabetic nephropathy comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the method for treating or preventing diabetic nephropathy further comprises treating or preventing nephropathy that develops as a result of diabetes. In some embodiments, the present invention provides methods for treating or preventing diabetes comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.
In some embodiments, the invention provides methods for treating or preventing diabetic retinopathy comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the method for treating or preventing diabetic retinopathy results in the treatment or prevention of diabetic complications that can cause or result in blindness.
In some embodiments, the present invention provides methods for treating or preventing a cerebrovascular disease comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the cerebrovascular disease is cerebral ischemia.
In some embodiments, the invention provides methods for treating or preventing a disorder associated with neovascularization comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the disorder associated with neovascularization is retinopathy or diabetes.
In some embodiments, the invention provides methods for treating or preventing hypertension comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the method for treating or preventing hypertension results in treating or preventing blood flow that occurs through the subject's blood vessels with greater than normal force.
In some embodiments, the invention provides methods for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the cancer is a human sarcoma or a human cancer. In some embodiments of the present invention, in some embodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, and cervical cancer squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cyst adenocarcinoma, medullary carcinoma, bronchus carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryo carcinoma, wilms ' tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, prostate cancer, cervical cancer astrocytomas, medulloblastomas, craniopharyngenomas, ependymomas, pineal tumors, angioblastomas, auditory neuromas, oligodendrogliomas, meningiomas, skin cancers, melanomas, neuroblastomas, retinoblastomas, leukemias, acute lymphoblastic B-cell leukemias, acute lymphoblastic T-cell leukemias, acute promyelocytic leukemias, acute monocytic leukemias, acute erythroleukemias, acute megakaryoblastic leukemias, acute myelomonocytic leukemias, acute non-lymphoblastic leukemias, acute undifferentiated leukemias, chronic granulocytic leukemias, hairy cell leukemias, lymphoblastic leukemias, myelogenous leukemias, polycythemia vera, multiple myeloma, lymphomas, hodgkin's disease, non-hodgkin lymphoma, fahrenheit macroglobulinemia (Waldenstrom's macroglobulinemia) or heavy chain disease.
In some embodiments, the leukemia is acute or chronic lymphocytic leukemia, granulocytic leukemia, lymphocytic leukemia, or myelogenous leukemia. In some embodiments, the myelogenous leukemia is acute and is myeloblasts, promyelocytes, myelomonocytes, monocytes, or leukemia cells.
In some embodiments, the lymphoma is hodgkin's lymphoma or non-hodgkin's lymphoma.
In some embodiments, the invention provides methods for treating or preventing an inflammatory disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the inflammatory disease is multiple sclerosis, chronic inflammatory disorders of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorders of the gums, tuberculosis, leprosy, inflammatory diseases of the kidneys, inflammatory disorders of the skin, inflammatory diseases of the central nervous system, systemic Lupus Erythematosus (SLE) or inflammatory diseases of the heart.
In some embodiments, the arthritis is rheumatoid arthritis or osteoarthritis.
In some embodiments, the inflammatory bowel disease is ileitis, ulcerative colitis, or crohn's disease.
In some embodiments, the inflammatory pulmonary disorder is asthma or chronic obstructive airways disease.
In some embodiments, the inflammatory disorder of the eye is corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathogenic ophthalmia, or endophthalmitis.
In some embodiments, the inflammatory disorder of the gums is periodontitis or gingivitis.
In some embodiments, the inflammatory disorder of the kidney is glomerulonephritis or kidney disease.
In some embodiments, the inflammatory disorder of the skin is acne, sclerodermatitis, psoriasis, eczema, photoaging or wrinkles.
In some embodiments, the inflammatory disease of the central nervous system is an AIDS-related neurodegenerative disease, stroke, neurotrauma, alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis.
In some embodiments, the inflammatory disease of the heart is cardiomyopathy.
In some embodiments, the invention provides methods for treating or preventing a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the neurodegenerative disease is alzheimer's disease or Huntington's disease.
In some embodiments, the invention provides methods for treating or preventing an autoimmune disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the autoimmune disease is immune complex vasculitis, systemic lupus, or erythema.
In some embodiments, the invention provides methods for treating or preventing a neoplastic disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the neoplastic disease is carcinogenesis.
In some embodiments, the invention provides methods for treating or preventing cholestasis comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
In some embodiments, cholestasis is an intrahepatic cholestasis disease or an extrahepatic cholestasis disease. In some embodiments, the intrahepatic cholestasis disease is primary cholangitis (PBC), primary Sclerosing Cholangitis (PSC), progressive Familial Intrahepatic Cholestasis (PFIC), or Alagille Syndrome (AS). In some embodiments, the method for treating or preventing an intrahepatic cholestatic disease results in preventing or reducing the risk of developing an intrahepatic cholestatic disease, e.g., results in clinical symptoms of an intrahepatic cholestatic disease not developing (i.e., preventing) in a subject who may have not experienced or exhibited symptoms of an intrahepatic cholestatic disease but is susceptible to an intrahepatic cholestatic disease. In some embodiments, the method for treating or preventing an intrahepatic cholestatic disease comprises inhibiting an intrahepatic cholestatic disease, e.g., preventing or reducing the progression of an intrahepatic cholestatic disease or reducing the number, frequency, duration, or severity of one or more clinical symptoms thereof.
In some embodiments, the invention provides methods for treating or preventing an ocular disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the ocular disease is dry eye, meibomian gland dysfunction, keratoconjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer. In some embodiments, the ocular disease is dry eye syndrome, corneal ulcers, superficial punctate keratitis, corneal epithelial erosion, ocular allergic diseases associated with keratopathy (e.g., vernal conjunctivitis), or atopic keratoconjunctivitis. In some embodiments, the ocular disease is high evaporative dry eye. In some embodiments, the ocular disease is corneal epithelial cell damage. In some embodiments, damage to corneal epithelial cells is associated with an endogenous disease (e.g., sjogren's syndrome, stevens-Johnson syndrome, keratoconjunctivitis sicca (dry eye), etc.). In some embodiments, damage to corneal epithelial cells is associated with an exogenous disease (e.g., post-surgery, drug use, trauma, corneal ulceration, meibomian gland inflammation, an exogenous disease during contact lens wear, etc.). In some embodiments, damage to corneal epithelial cells is associated with ocular allergic diseases (e.g., vernal conjunctivitis, atopic keratoconjunctivitis, etc.) that accompany keratopathy. In some embodiments, the ocular disease is superficial punctate keratitis and corneal epithelial erosion.
In some embodiments, the methods for treating or preventing an ocular disease result in promoting proliferation of meibomian gland epithelial cells and corneal epithelial cells.
In some embodiments, the invention provides methods for treating or preventing a lysosomal storage disorder, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the lysosomal storage disorder is neuronal ceroid lipofuscinosis, alzheimer's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), parkinson's disease, multiple System Atrophy (MSA), progressive Supranuclear Palsy (PSP), corticobasal degeneration (CBD), lewy body Dementia (DLB), autophagy pathway disorders, tay-Sach's disease, fabry disease, niemann-Pick disease (Niemann-Pick disease), gaucher disease (Gaucher disease), hunter's syndrome (Hunter syndonme), alpha-mannosidosis, aspartyl glucurosis, cholesterol ester storage disease, chronic aminohexosidase a deficiency, cystine disease, darone disease, farber disease, fucosidosis, semi-sialosis or batton disease (batton disease).
In some embodiments, the invention provides methods for treating or preventing kidney disease comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the kidney disease is renal ischemia reperfusion injury. In some embodiments, the kidney disease is acute kidney injury. In some embodiments, the method for treating or preventing kidney disease results in a reduced risk of acute kidney injury in a subject following coronary bypass grafting, transplantation, and/or valve surgery.
In some embodiments, the subject has AKI. In other embodiments, the subject is at risk of AKI.
AKI is characterized by a rapid decline in renal function, which may be caused by a variety of factors, such as reduced renal blood flow, glomerulonephritis, use of nephrotoxic antibiotics, use of anticancer agents, and sepsis.
For example, acute kidney injury may be diagnosed when a subject exhibits a change in one or more of serum creatinine levels, glomerular filtration rate, or urine output. For example, AKI is characterized by a serum creatinine level of at least 1.5 times the baseline, where baseline refers to a subject's serum creatinine level no more than 7 days ago. For example, the serum creatinine level of a patient with AKI may be 1.5 to 1.9 times the baseline, 2.0 to 2.9 times the baseline, or 3.0 or more times the baseline. Alternatively, AKI is characterized by an increase in serum creatinine of at least 0.3mg/dL or at least 0.4mg/dL, for example by an increase in serum creatinine of at least 0.3mg/dL over a 48 hour period.
Alternatively, AKI is characterized by a glomerular filtration rate of less than 90mL/min/1.73m 2 . For example, a subject with AKI may have 60-89mL/min/1.73m 2 、30-59mL/min/1.73m 2 、15-29mL/min/1.73m 2 Or less than 15mL/min/1.73m 2 Glomerular filtration rate of (2).
Alternatively, AKI is characterized by a subject having a urine output of less than 0.5mL/Kg in 6 hours, less than 0.5mL/Kg in 12 hours, less than 0.3mL/Kg in 12 hours, or no urine for 12 hours or more.
AKI can be categorized using the kdaigo standard (global outcome of renal disease improvement. Guidelines for clinical practice of kdaigo acute kidney injury, kidney International Supplements 2012; 2:1-138), as shown in table 12.
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AKI may be associated with specific kidney diseases (e.g., acute interstitial nephritis, acute glomerular and vasculitis kidney disease); nonspecific conditions (e.g., ischemia, toxic damage); and extra-renal pathologies (e.g., prerenal azotemia and acute postrenal obstructive nephropathy) occur together. More than one of these conditions may be present simultaneously in the same subject, and more importantly epidemiological evidence supports the notion that even mild, reversible AKI can have important clinical consequences, including increased risk of mortality. Furthermore, because AKI may behave very similarly (or even indistinguishably) to clinical consequences, regardless of whether the etiology is primarily in the kidney or is primarily from external stress on the kidney, AKI includes direct damage to the kidney as well as damage to acute function.
In some embodiments, a subject having or at risk of AKI has diabetes, potential renal insufficiency, nephritis syndrome, atherosclerotic disease, sepsis, hypotension, hypoxia, myoglobin-hematuria, or liver disease. In some embodiments, the subject is an elderly person, a pregnant person, a surgical patient, or has been exposed to a nephrotoxic agent. In particular embodiments, the subject suffering from or at risk of AKI is a surgical patient. Thus, in certain embodiments, the compounds of the present disclosure are administered to a surgical patient after surgery, e.g., after cardiovascular surgery (e.g., coronary Artery Bypass Graft (CABG) surgery and/or heart valve surgery).
In some embodiments, the subject has sepsis (e.g., associated with a gram-negative bacterial infection). In some embodiments, sepsis may be caused by intraperitoneal infection or be urine sepsis. Sepsis is a risk factor for AKI. Thus, in some embodiments, the subject may be at risk of AKI, e.g., due to sepsis.
In some embodiments, the subject has a shortened sequential organ failure assessment Score (SOFA) score of 1 to 4, e.g., a score of 1, 2, 3, or 4, prior to treatment with a compound of the disclosure (see Vincent et al 1996, intensive Care Med, 22:707-710).
In some embodiments, the subject has AKI secondary to or at risk for infection, e.g., a viral infection (e.g., covd-19).
In some embodiments, the subject suffering from or at risk of AKI has been exposed to a nephrotoxic agent. Nephrotoxic agents are drugs or chemicals that can cause AKI. Drugs or chemicals capable of causing AKI include, but are not limited to, cisplatin; gentamicin; pioneer mycin; cyclosporine; amphotericin; carbon tetrachloride; trichloroethylene; and dichloroacetylene.
In some embodiments, the invention provides methods for treating or preventing impotence comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the impotence is caused by nerve injury, arterial injury, smooth muscle injury, or fibrous tissue injury; diabetes mellitus; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or a neurological disease. In some embodiments, the method for treating or preventing impotence results in the treatment or prevention of erectile dysfunction.
The present invention provides a method for treating or preventing hyperlipidemia, hyperlipidaemia, hyperlipoproteinaemia, hypercholesteraemia, hypertriglyceridaemia or dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the hypercholesterolemia is homozygous familial hypercholesterolemia.
The present invention provides a method for treating a subject having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, or preventing a subject from having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, comprising administering to the subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The "abnormally high concentration" of lipoprotein cholesterol may depend on the number of risk factors and whether the treatment is primary or secondary prevention. As used herein, "primary prevention" refers to treatment intended to avoid a subject from developing or suffering from a disease or disorder. As used herein, "secondary prevention" refers to treatment intended to detect a disease or condition early and prevent the disease or condition from gradually worsening or progressing. Suggested concentrations of lipoprotein cholesterol can be found in guidelines issued by the national lipid association or the national institute of health national institute of cardiopulmonary blood (e.g., third Report of the Expert Panel on Detection, evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III Final Report), 2002). ATP III Final Report is incorporated by reference herein in its entirety for all purposes.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of apo B in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the "abnormally high concentration" of apo B in the plasma or serum of the subject is greater than 130mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of apo B in the plasma or serum of the subject is less than 130mg/dL. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject. In some embodiments, the invention provides methods for treating a subject having an apo B plasma or serum concentration greater than 130mg/dL. In some embodiments, the invention provides methods of treating a subject having an apo B plasma or serum concentration greater than 130mg/dL when the subject is at low risk for Coronary Heart Disease (CHD), which has 0-1 risk factors for CHD.
In some embodiments, the invention provides methods of treating a subject having an apo B plasma or serum concentration greater than 110mg/dL when the subject is at moderate risk for CHD with 2 or more CHD risk factors. In some embodiments, the "abnormally high concentration" of apo B in the plasma or serum of the subject is greater than 110mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. In some embodiments, the subject has CHD or a CHD risk equivalent. In some embodiments, the invention provides methods of treating a subject with apo B plasma or serum concentration greater than 90mg/dL when the subject has CHD or a CHD risk equivalent.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of Lp (a) in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. "abnormally high concentrations" of Lp (a) in the plasma or serum of a subject are greater than 10mg/dL. In some embodiments, an abnormally high concentration of Lp (a) is associated with an increase in cardiovascular risk. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of Lp (a) in the plasma or serum of a subject is less than 10mg/dL. In some embodiments, the normal concentration of Lp (a) in the plasma or serum of a subject is less than 50mg/dL (see, banach, M.J. Am Heart Assoc.2016Apr;5 (4): e 003597). In some embodiments, the invention provides methods for treating a subject having a Lp (a) plasma concentration of greater than 50mg/dL comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The present invention provides a method for treating a subject having an abnormally high apo B/apo a-I ratio in the plasma or serum of the subject or preventing a subject from having an abnormally high apo B/apo a-I ratio in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the invention provides methods for reducing abnormally high apo B/apo a-I ratios in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The "abnormally high" apo B/apo A-I ratio in the plasma or serum of the subject is greater than 0.9. In some embodiments, the decrease is to a normal level. In some embodiments, the normal apo B/apo a-I ratio in the plasma or serum of the subject is less than 0.9. In some embodiments, the normal apo B/apo a-I ratio in the plasma or serum of the subject is less than 0.7. In some embodiments, the subject has an apo B/apo a-I ratio in the subject's plasma or serum of greater than 0.9. In some embodiments, the subject has an apo B/apo a-I ratio in the subject's plasma or serum of greater than 0.7. See wallus, g.et al j international med.2006May;259 (5):493-519.
In some embodiments, primary prophylactic treatment of a male subject having an apo B/apo a-I ratio greater than 0.9 in the plasma or serum of the male subject is contemplated. In some embodiments, primary prophylactic treatment of a female subject having an apo B/apo A-I ratio greater than 0.8 in the plasma or serum of the female subject is contemplated. In some embodiments, the subject is a male subject and the apo B/apo a-I ratio in the subject's plasma or serum is greater than 0.9. In some embodiments, the subject is a female subject and the apo B/apo a-I ratio in the subject's plasma or serum is greater than 0.8. See wallus, 2006.
In some embodiments, it is contemplated that a secondary prophylactic treatment is performed on a male subject having an apo B/apo a-I ratio greater than 0.7 in the plasma or serum of the male subject. In some embodiments, secondary prophylactic treatment of a female subject having an apo B/apo a-I ratio greater than 0.6 in the plasma or serum of the female subject is contemplated. In some embodiments, the subject is a male subject and the apo B/apo a-I ratio in the subject's plasma or serum is greater than 0.7. In some embodiments, the subject is a female subject and the apo B/apo a-I ratio in the subject's plasma or serum is greater than 0.6. See wallus, 2006.
The present invention provides a method for treating a subject having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject or preventing a subject from having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The present invention provides a method for treating a subject having or preventing a subject having or having abnormally reduced or absent lipoprotein lipase concentration or activity in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the reduced or absent lipoprotein lipase level or activity is the result of a lipoprotein lipase mutation. In some embodiments, the reduced or absent lipoprotein lipase level or activity is the result of a mutation in a gene encoding a lipoprotein lipase.
In some embodiments, the invention provides methods for increasing an abnormally low concentration of lipoprotein lipase in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. The "abnormally reduced concentration" of lipoprotein lipase in the serum of the subject is less than 46ng/mL. In some embodiments, the subject is at increased risk of future coronary artery disease. In some embodiments, the increase is to a normal concentration. In some embodiments, the normal concentration of lipoprotein lipase in the serum of the subject is greater than 46ng/mL. In some embodiments, the invention provides a method for treating a subject having a lipoprotein lipase plasma or serum concentration of less than 46ng/mL, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. See Rip, j.et al, arterioscler Thromb Vasc biol.2006mar;26 (3) 637-42.Epub2005Dec 22.
The present invention provides methods for treating a subject having an abnormally high concentration of lipoprotein-associated phospholipase A in the plasma or serum of the subject 2 (Lp-PLA 2 ) Has an abnormally high concentration of lipoprotein-associated phospholipase a in the plasma or serum of the subject 2 (Lp-PLA 2 ) Comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Lp-PLA in plasma or serum of a subject 2 The "abnormally high concentration" of (2) is greater than 200ng/mL. In some embodiments, the subject is at risk for cardiovascular disease. In some embodiments, the risk is high.
In some embodiments, the invention provides methods for reducing abnormally high concentrations of Lp-PLA in a subject's plasma or serum 2 Comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the decrease is to a normal concentration. In some embodiments, lp-PLA is present in a subject's plasma or serum concentration 2 Is less than 200ng/mL. In some embodiments, the invention provides methods for treating disorders with Lp-PLA 2 A method of treating a subject having a plasma or serum concentration greater than 200ng/mL. See Davidson, m.h. et al, the American Journal of Cardiology,2008,101, s51.
The present invention provides a method for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with alzheimer's disease, or familial mixed hyperlipidemia, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The present invention provides a method for reducing abnormally high concentrations of triglycerides, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) (Lp (a)), the ratio of apolipoprotein B, HDL/(vldl+ldl), apolipoprotein C-II (apo C-II) or apolipoprotein C-III (apo C-III) in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The "abnormally high concentration" of triglycerides in the serum of a subject is greater than 150mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of triglycerides in the serum of a subject is less than 150mg/dL. In some embodiments, the invention provides methods for reducing serum triglyceride concentration in a subject, wherein the serum triglyceride concentration in the subject is greater than or equal to 200mg/dL. In some embodiments, the invention provides methods for reducing serum triglyceride concentration in a subject, wherein the serum triglyceride concentration in the subject is greater than or equal to 500mg/dL.
The "abnormally high concentration" of LDL-C in the plasma or serum of a subject for primary prophylaxis is greater than 100mg/dL. The "abnormally high concentration" of LDL-C in the plasma or serum of a subject for secondary prophylaxis in a subject having a risk factor is greater than 70mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of LDL-C in the plasma or serum of a subject is less than 100mg/dL, wherein primary prevention of the subject is contemplated. In some embodiments, the normal concentration of LDL-C in the plasma or serum of a subject is less than 70mg/dL. In some embodiments, the subject has a risk factor and is being considered for secondary prevention. See wallus, 2006.
In some embodiments, the "abnormally high concentration" of LDL-C in the plasma or serum of the subject is greater than 160mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of LDL-C in the plasma or serum of a subject is less than 160mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. In some embodiments, the invention provides methods for treating a subject having an LDL-C plasma or serum concentration greater than 160mg/dL. In some embodiments, the invention provides methods for treating a subject having an LDL-C plasma or serum concentration greater than 160mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. See wallus, 2006.
In some embodiments, the "abnormally high concentration" of LDL-C in the plasma or serum of the subject is greater than 130mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of LDL-C in the subject's plasma or serum is less than 130mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. In some embodiments, the invention provides methods for treating a subject having an LDL-C plasma or serum concentration greater than 130mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. See wallus, 2006.
In some embodiments, the "abnormally high concentration" of LDL-C in the plasma or serum of the subject is greater than 100mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of LDL-C in the plasma or serum of a subject is less than 100mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. In some embodiments, the invention provides methods for treating a subject having an LDL-C plasma or serum concentration greater than 100mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. See wallus, 2006.
The "abnormally high concentration" of apo C-III concentration in the plasma or serum of a subject is greater than 7.87mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of apo C-III concentration in the plasma or serum of the subject is less than 7.87mg/dL. In some embodiments, the invention provides methods for treating a subject, wherein the subject has an apo C-III plasma or serum concentration greater than 8 mg/dL. In some embodiments, the invention provides methods for treating a subject, wherein the subject has an apo C-III plasma or serum concentration greater than 7.9 mg/dL. In some embodiments, the invention provides methods for treating a subject, wherein the subject has an apo C-III plasma or serum concentration greater than 7.87mg/dL. In some embodiments, an abnormally high concentration of apo C-III is associated with a high risk of coronary artery disease. See Capelleven et al Arterioscler Thromb Vasc biol.2017Jun;37 (6):1206-1212.
The present invention provides a method for reducing abnormally high LDL-C/HDL-C ratios in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
In some embodiments, the "abnormally high rate" of LDL-C/HDL-C in the plasma or serum of a male subject for primary prevention is greater than 3.0. In some embodiments, the decrease is to a normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in the plasma or serum of a male subject is less than 3.0, wherein the subject is considered primary prophylaxis. In some embodiments, the invention provides methods for treating a male subject having an LDL-C/HDL-C ratio of greater than 3.0 in the plasma or serum of the subject. In some embodiments, the method is used for primary prevention.
In some embodiments, the "abnormally high rate" of LDL-C/HDL-C in the plasma or serum of a female subject for primary prevention is greater than 2.5. In some embodiments, the decrease is to a normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in the plasma or serum of a female subject is less than 2.5, wherein the subject is considered primary prophylaxis. In some embodiments, the invention provides methods for treating a female subject having an LDL-C/HDL-C ratio of greater than 2.5 in the plasma or serum of the subject. In some embodiments, the method is used for primary prevention. See wallus, 2006.
In some embodiments, the "abnormally high rate" of LDL-C/HDL-C in the plasma or serum of a male subject for secondary prophylaxis is greater than 2.5. In some embodiments, the decrease is to a normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in the plasma or serum of a male subject is less than 2.5, wherein secondary prevention of the subject is contemplated. In some embodiments, the invention provides methods for treating a male subject having an LDL-C/HDL-C ratio of greater than 2.5 in the plasma or serum of the subject. In some embodiments, the method is used for secondary prevention. See wallus, 2006.
In some embodiments, the "abnormally high rate" of LDL-C/HDL-C in the plasma or serum of a female subject for secondary prophylaxis is greater than 2.0. In some embodiments, the decrease is to a normal ratio. In some embodiments, the normal ratio of LDL-C/HDL-C in the plasma or serum of a female subject is less than 2.0, wherein secondary prevention of the subject is contemplated. In some embodiments, the invention provides methods for treating a female subject having an LDL-C/HDL-C ratio of greater than 2.0 in the plasma or serum of the subject. In some embodiments, the method is used for secondary prevention. See wallus, 2006.
The present invention provides a method for reducing abnormally high concentrations of non-HDL-C in the plasma or serum of a subject comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention.
In some embodiments, the "abnormally high concentration" of non-HDL-C in the plasma or serum of a subject is greater than 190mg/dL. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of non-HDL-C in the plasma or serum of a subject is less than 190mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. In some embodiments, the invention provides methods for reducing the concentration of non-HDL-C in the plasma or serum of a subject, wherein the concentration of non-HDL-C is greater than 190mg/dL. In some embodiments, the subject has 0-1 CHD risk factors. See wallus, 2006.
In some embodiments, the "abnormally high concentration" of non-HDL-C in the plasma or serum of a subject is greater than 160mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of non-HDL-C in the plasma or serum of a subject is less than 160mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. In some embodiments, the invention provides methods for reducing the concentration of non-HDL-C in a subject's plasma or serum, wherein the subject's non-HDL-C concentration is greater than 160mg/dL. In some embodiments, the subject has 2 or more CHD risk factors. See wallus, 2006.
In some embodiments, the "abnormally high concentration" of non-HDL-C in the plasma or serum of a subject is greater than 130mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of non-HDL-C in the plasma or serum of a subject is less than 130mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. In some embodiments, the invention provides methods for reducing the concentration of non-HDL-C in a subject's plasma or serum, wherein the subject's non-HDL-C concentration is greater than 130mg/dL. In some embodiments, the subject has CHD or a CHD risk equivalent. See wallus, 2006.
The present invention provides a method for increasing abnormally low concentrations of High Density Lipoprotein (HDL) -related protein, HDL-cholesterol (HDL-C), apolipoprotein A-I or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a composition of the present invention. In some embodiments, the HDL-related protein is an apolipoprotein A-I (apo A-I), an apolipoprotein A-II (apo A-II), an apolipoprotein A-IV (apo A-IV), or an apolipoprotein E (apo E).
In some embodiments, the "abnormally low concentration" of HDL-C in the plasma or serum of a subject is less than 40mg/dL. In some embodiments, the increase is to a normal concentration. In some embodiments, the normal concentration of HDL-C in the plasma or serum of a subject is greater than 40mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in the plasma or serum of a subject, wherein the HDL-C concentration of the subject is less than 40mg/dL. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.
In some embodiments, the "abnormally low concentration" of HDL-C in the plasma or serum of a male subject is less than 45mg/dL. In some embodiments, the normal concentration of HDL-C in the plasma or serum of a male subject is greater than 45mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in the plasma or serum of a male subject, wherein the HDL-C concentration of the subject is less than 45mg/dL.
In some embodiments, the "abnormally low concentration" of HDL-C in the plasma or serum of a female subject is less than 50mg/dL. In some embodiments, the normal concentration of HDL-C in the plasma or serum of a female subject is greater than 50mg/dL. In some embodiments, the normal concentration of HDL-C in the plasma or serum of a female subject is greater than 55mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in plasma or serum of a female subject, wherein the subject has an HDL-C concentration of less than 50mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in plasma or serum of a female subject, wherein the subject's HDL-C concentration is below 55mg/dL.
In some embodiments, the invention provides methods for increasing HDL-C concentration to 45mg/dL or greater in a subject's plasma or serum, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration to 50mg/dL or greater in a subject's plasma or serum, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration to 55mg/dL or greater in a subject's plasma or serum, wherein the subject's HDL-C concentration in the subject's plasma or serum is less than 40mg/dL.
In some embodiments, the invention provides methods for increasing HDL-C concentration in the plasma or serum of a male subject to 50mg/dL or greater, wherein the HDL-C concentration in the plasma or serum of the subject is less than 45mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in the plasma or serum of a female subject to 50mg/dL or greater, wherein the HDL-C concentration in the plasma or serum of the subject is less than 50mg/dL. In some embodiments, the invention provides methods for increasing HDL-C concentration in the plasma or serum of a female subject to 55mg/dL or greater, wherein the HDL-C concentration in the plasma or serum of the subject is less than 50mg/dL.
The present invention provides a method for promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention.
The present invention provides a method for increasing abnormally low glucose metabolism or increasing abnormally low lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the method for increasing abnormally low glucose metabolism increases insulin sensitivity or oxygen consumption in the subject. In some embodiments, the method for increasing abnormally low glucose metabolism reduces blood insulin, blood glucose, or glycosylated hemoglobin in the plasma or serum of the subject. In some embodiments, the method for increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the plasma or serum of a subject, or inhibits saponified or non-saponified fatty acid synthesis.
In some embodiments, a subject with abnormally low glucose metabolism has an abnormally high concentration of glucose or hemoglobin (Hb) in the subject's plasma or serum. In some embodiments, the invention provides methods for reducing abnormally high concentrations of glucose or hemoglobin in the plasma or serum of a subject. In some embodiments, the method increases abnormally low glucose metabolism. In a two hour GTT, the "abnormally high concentration" of glucose in the plasma or serum of the subject is greater than 7.8mmol/L (140 mg/dL). In some embodiments, the decrease is to a normal concentration. In some embodiments, the normal concentration of glucose in the plasma or serum of the subject is less than 7.8mmol/L (140 mg/dL) in a two hour GTT. In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in the plasma or serum of a subject, wherein the concentration of glucose in the plasma or serum of the subject is greater than 7.8mmol/L (140 mg/dL) in the two hour GTT of the subject. In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the concentration of glucose in the plasma or serum of the subject in a two hour GTT ranges from 7.8mmol/L (140 mg/dL) to 11.1mmol/L (200 mg/dL). In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the concentration of glucose in the plasma or serum of the subject is greater than 11.1mmol/L (200 mg/dL) in the subject for two hours of GTT.
In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject has impaired glucose tolerance. In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject has diabetes. In some embodiments, the invention provides methods for increasing abnormally low glucose metabolism in a subject, wherein the subject has gestational diabetes.
Low lipid metabolism is characterized by dyslipidemia (using LDL-C, TG, non-HDL-cholesterol, apo B, apo C-III or apoC-II values), but may also be elevated levels of transaminase. In some embodiments, the subject with low lipid metabolism also suffers from dyslipidemia.
The present invention provides a method for treating or preventing a symptom of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. In some embodiments, the arthritis is adjuvant arthritis or type II collagen-induced arthritis. In some embodiments, the symptom is nephritis, renal failure, or reduced renal function. In some embodiments, reduced renal function requires renal dialysis.
The present invention provides a method for reducing the fat content of livestock meat comprising administering to livestock an effective amount of a compound of the invention or a composition of the invention.
The present invention provides a method for reducing the cholesterol content of an avian egg comprising administering to an avian an effective amount of a compound of the present invention or a composition of the present invention.
In some embodiments, the methods of the invention provide a dosage form for administering the compounds of the invention or the compositions of the invention hourly, daily, weekly or monthly. The dosage forms and formulations of the present invention may be administered three times per day, twice per day or once per day. The dosage forms of the invention may be administered with or without food. The appropriate length of time, dosage and route of administration of the treatment may be determined and/or adjusted by the physician.
In some embodiments of the methods of the invention, the subject is a human subject.
5.5. Synthesis of Compounds of the invention
The compounds of the present invention may be synthesized by conventional methods. Exemplary methods for synthesizing the exemplary compounds of formulas (a) and (B) are described in examples 1-3 below. WO 2011/020001 describes PPAR modulator compounds (described therein as compounds of formulae (I) - (XX)) and methods for their synthesis, the contents of which are incorporated herein by reference in their entirety. The compounds of formulae (I) - (XX) described in WO 2011/020001 can be used as starting materials for the synthesis of the compounds of formulae (C) - (H) and (J) - (W), respectively, of the present invention. For example, compounds with ketones of WO 2011/020001 may be treated with reducing agents (e.g. NaBH 4 ) Optionally in a Lewis acid (e.g. CeCl) 3 ) In the presence of or in an alcoholic solvent (e.g., methanol) to provide for the conversion of ketone groups to hydroxyl groups. Similarly, the carboxylic acid group of the compound of WO 2011/020001 may use a reducing agent (e.g. LiAlH 4 ) Reduction to hydroxymethyl groups is followed by aqueous acid work-up to provide the compounds of the present invention.
WO 2017/062468, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds (described therein as compounds of formulae (I) - (III)) and methods for their synthesis. The compounds of formulae (I) - (III) described in WO 2017/06246 may be used as starting materials for the synthesis of the compounds of formulae (X) - (Z), respectively, of the present invention. The carboxylic acid groups of the compounds of WO 2017/06246 may use reducing agents (e.g. LiAlH 4 ) Reduction to hydroxymethyl groups followed by acidPost-treatment of aqueous solutions to provide the compounds of the present invention.
WO 2017/180818, the contents of which are incorporated herein by reference in their entirety, describes PPAR modulator compounds, described therein as compounds of formula (I), and methods of synthesis thereof. The compounds of formula (I) described in WO 2017/180818 may be used as starting materials for the synthesis of the compounds of formula (AA) of the present invention. The carboxylic acid groups of the compounds of WO 2017/180818 may use a reducing agent (e.g. LiAlH 4 ) Reduction to hydroxymethyl groups is followed by aqueous acid work-up to provide the compounds of the present invention.
WO 2018/067857 describes PPAR modulator compounds (described therein as compounds A, B and C) and methods of synthesis thereof, the contents of which are incorporated herein by reference in their entirety. Compounds B and C described in WO 2018/067857 can be used as starting materials for the synthesis of compounds VII and VIII. The carboxylic acid groups of the compounds of WO 2017/180818 may use a reducing agent (e.g. LiAlH 4 ) Reduction to hydroxymethyl groups is followed by aqueous acid work-up to provide the compounds of the present invention.
In order to selectively reduce carboxylic acids in compounds having ketone and carboxylic acid groups (e.g. some of the compounds described in WO 2011/020001), the ketone may be protected, for example, by reacting the compound with ethylene glycol in the presence of a catalytic acid (e.g. 0.1M HCl) to form an acetal compound. The acetals may be removed after reduction of the carboxylic acid groups, for example by post-treatment with aqueous acid solutions. For the selective reduction of ketones in compounds having ketone and carboxylic acid groups (e.g. some of the compounds described in WO 2011/020001) it is possible to use a less reactive reducing agent such as NaBH 4 To selectively reduce the ketone.
6. Examples
6.1. EXAMPLE 1 Synthesis of Compound I
(Z) -2- (2, 6-dimethyl-4- (3- (4- (methylsulfanyl) phenyl) -3-oxoprop-1-en-1-yl) phenoxy) -2-methylpropanoic acid ("Compound A") was synthesized according to US2006/0142611. Then using a reducing agent (e.g., naBH 4 ) Optionally in a Lewis acid (e.g. CeCl) 3 ) Reducing compound a in the presence of or in an alcoholic solvent (e.g., methanol) to provide the compound I racemate. The racemate of compound I is then resolved using chiral high performance liquid chromatography to provide its (S) -and (R) -enantiomers, each of which is substantially free of its corresponding opposite enantiomer.
6.2. EXAMPLE 2 Synthesis of Compound II
Acetal compound B is synthesized from compound a and ethylene glycol in the presence of a catalytic acid (e.g., 0.1M HCl). See, e.g., dong, J-l., et al acs Omega,2018,3,4974 for acetal formation on α, β -unsaturated ketones. Subsequently using a reducing agent (e.g. LiAlH 4 ) The carboxyl group of compound B is reduced to a hydroxymethyl group, followed by an aqueous acid post-treatment which removes the acetal to provide compound II.
6.3. EXAMPLE 3 Synthesis of Compound III
Using reducing agents (e.g. NaBH 4 ) Optionally in a Lewis acid (e.g. CeCl) 3 ) Reducing compound II in the presence of or in an alcoholic solvent (e.g. methanol) to provide the racemate of compound III. The racemate of compound III is then resolved using chiral high performance liquid chromatography to provide its (S) -and (R) -enantiomers, each of which is substantially free of its corresponding opposite enantiomer.
6.4. Example 4 liver and peripheral insulin sensitivity effects in rats fed a high fat/medium fructose diet (western diet)
After 8 weeks on a high fat diet, treatment with pioglitazone (10 mg/kg), metformin (50 mg/kg), exemplary compounds of the invention (3 and 10 mg/kg), alone or in combination with metformin (50 mg/kg), and GW501516 (2- [ 2-methyl-4- [ [ 4-methyl-2- [4- (trifluoromethyl) phenyl ] -1, 3-thiazol-5-yl ] methylsulfanyl ] phenoxy ] acetic acid) (10 mg/kg; ligand/GSK) for 5 weeks. Metformin reduces body weight and this effect is emphasized when used in combination with an exemplary compound of the invention at a dose of 10 mg/kg. After 17 days of treatment, rats were allowed to empty stomach for 4 hours and blood samples were taken.
After 21 days of treatment, glucose tolerance was assessed by oral glucose loading performed after 6 hours of fasting.
After 5 weeks of treatment, a euglycemic-hyperinsulinemic clamp procedure was performed in conscious rats. Two doses of insulin were infused with 3H-glucose: 0.2U/kg/h was infused to assess the effect on Hepatic Glucose Production (HGP), and 0.8U/kg/h was infused to inhibit HGP, then the effect on systemic glucose utilization was assessed.
6.4.1. Animal model
Male Sprague Dawley (SD) rats (250-275 g) were first fed a western diet during 8 weeks to induce insulin resistance. The first set of rats underwent an Oral Glucose Tolerance Test (OGTT) (half rats/arm-set) 3 weeks after treatment, the second set underwent OGTT (half rats/arm-set) and histological studies (3 rats/set) also after 3 weeks of treatment.
Rats from each pool were screened and randomized into groups based on their fasting (4 h) plasma glucose, insulin levels (for insulin resistance steady state model assessment (HOMA-IR) calculations) and body weight. Rats that did not respond to western diet were excluded from the study.
Homogeneous mildly obese and insulin resistant rats were assigned to different treatment groups and the western diet was continued until the end of the experiment. In view of this, the beginning of the 2 series is spaced one week apart.
6.4.2. Treatment of
Dosing regimen: in the morning, rats were treated by the oral route once daily. The duration of treatment is between 5 and 5.5 weeks.
6.4.3. Test set
Group 1: medium (n=12)
Group 2: pioglitazone, 10mg/kg (n=12)
Group 3: metformin, 50mg/Kg (n=12)
Group 4: exemplary Compounds of the invention, 3mg/Kg (n=12)
Group 5: exemplary Compounds of the invention, 10mg/Kg (n=12)
Group 6: exemplary Compounds of the invention, 3 mg/Kg+metformin 50mg/Kg (n=12)
Group 7: exemplary Compounds of the invention, 10 mg/Kg+metformin 50mg/Kg (n=12)
Group 8: GW501216, 10mg/kg (n=12)
6.4.4. Condition of empty stomach
OGTT and fasting conditions for forceps procedures: food is removed from the cage and the litter is replaced prior to light-off (between 7:30 and 8:00 am). Each experiment was then started after about 6 hours of empty stomach (between 1:30 and 2:00 pm).
Fasting conditions of plasma parameters: food was removed from the cages and the litter was replaced 4 hours after light off (between 11:30 am and noon). Blood collection was then started after 4 hours of fasting (4:00 pm).
6.4.5. Oral glucose tolerance test
After 3 weeks of treatment, rats were allowed to empty for 6 hours and subjected to oral glucose loading (2.5 g/kg body weight). Blood glucose was measured 30 minutes before glucose loading and at 0, 15, 30, 60, 90 and 120 minutes.
6.4.6. Euglycemic-hyperinsulinemic 2-step jaw with 3H-glucose
After 4 weeks of treatment, catheters were implanted into femoral veins under isoflurane anesthesia and required a recovery period of 5-6 days. Rats with unrecovered body weight were excluded from the study. Acceptable weight loss estimated on the day of infusion was fixed at 5% in the group where treatment should not affect body weight (as seen during body weight follow-up) (vehicle, pioglitazone and exemplary compounds of the invention, mg/kg group) and at 10% in the group where treatment reduced body weight (other 5 groups). In the morning of the clamping procedure, rats were treated and fasted for 6 hours, and then infused with tracer, glucose and insulin. The initiation of the clamping operation is performed in the middle of the dark cycle.
Euglycemic-hyperinsulinemic 2-step insulin clamps were performed using 0.2U/kg/H and 0.8U/kg/H insulin infusion in combination with 3H-glucose infusion. The following parameters were thereafter evaluated:
whole body glucose utilization
Hepatic glucose production
Glucose infusion rate
Systemic glycogen and glycolysis rates
6.4.7. In vivo glucose utilization
During the clamping operation, a bolus (30. Mu. Ci) of D- [3-3H ] glucose was first injected, followed by an infusion rate of 4. Mu. Ci/min/kg throughout the experiment to ensure a detectable enrichment of plasma D [3-3H ] glucose. Bolus insulin (100 mU) was injected first, then insulin was infused at 0.2U/kg/h for the first 2 hours and at a rate of 0.8U/kg/h from 120 minutes to 210 minutes.
Throughout the infusion process, blood glucose was assessed from the tail vein tip with a glucometer, if needed. Euglycemia was maintained by adjusting the variable infusion of 30% glucose periodically (every 10 minutes). In the stationary phase, 10 μl of blood was sampled every 20 minutes from the tip of the tail vein during the first step from 60 to 120 minutes and during the second step from 150 to 210 minutes, and plasma glucose concentration and D- [3-3H ] glucose specific activity were measured.
For glucose turnover measurement, D- [3-3H]Glucose enrichment is by Zn (OH) 2 Precipitation deproteinized and then assayed from whole blood. Briefly, aliquots of the supernatant were evaporated to dryness to determine the radioactivity of the corresponding D-3-3H. In a second aliquot of the same supernatant, the glucose concentration is estimated by the glucose oxidase method (biomerieux, france).
6.4.8. Calculation of
The calculation of glucose turnover rate measurements was performed from the parameters obtained during infusion at steady state conditions (60-120 and 160-210 minutes). Briefly, the specific activity of D- [3-3H ] glucose is calculated by dividing the D- [3-3H ] glucose enrichment by the plasma glucose concentration. Systemic glucose turnover was calculated by dividing the D3-3H glucose rate by the D3-3H glucose plasma specific activity. For each rat, an average value was calculated and averaged with the values of the same group of rats. The whole-body glycolysis rate was measured by evaluating the amount of tritiated water accumulated in blood during 3H-glucose infusion, and the whole-body glycogen synthesis rate was calculated by the difference between the whole-body glucose turnover rate and the whole-body glycolysis rate.
6.4.9. Blood, tissue collection and biochemistry
At the end of the clamping operation (9.5 hours on empty stomach), perirenal, retroperitoneal, epididymal and inguinal fat pads and liver weights were recorded. Blood was collected from the cardiac puncture and plasma was stored at-80 ℃ for further determination when needed (depending on the radioactive state of the sample). Liver triglyceride content (enzyme colorimetric) and liver and adipose tissue TNF-alpha content (enzyme linked immunosorbent assay (ELISA)) were assessed. See US2011/0092517, the entire contents of which are incorporated herein by reference.
6.5. Example 5 activation of PPAR transcription in mice and rats in a cell-based transactivation assay
GAL4-PPAR chimeric receptor assay
6.5.2. Receptor expression plasmids
The relative transcriptional activity of the receptor subtypes was compared using the established chimeric receptor system (Lehmann J M et al J Biol chem 1997;272 (6): 3406-10). From Chinesemedicine (hs) (NM-006238, NM-015869, NM-001001928), macaque (mm) (NM-001033029, XM-001116676, NM-001032860), mouse (m) (NM-01144, U10375, NM) — 011146 Mammalian expression vectors pSG5-GAL4-PPARα, pSG5-GAL4-PPARγ and pSG5-GAL4-PPARδ, which express human PPARα (amino acids 167-468, amino acids 167-467, m, amino acids 176-477, amino acids 204-505, m and mm, from PPARγ) and Ligand Binding Domain (LBD) of PPARδ (amino acids 139-441, amino acids 139-440, m, from PPARγ) were cloned, each fused to the yeast transcription factor GAL4 DNA binding domain (amino acids 1-147) and human glucocorticoid receptor (amino acids 1-76), and (r) from brown mice (r) (NM-013141, NM-01396, NM-013124).
Reporter plasmid: MH 100X 4-tk-luc (Forman BM et al cell 1995 81 (4): 541-50) was used as reporter plasmid.
6.5.12. Transient transfection assay
The African green monkey kidney cell line CV-1 was used in transfection assays. CV-1 cells were plated at 0.5X10 per well 5 Individual cells were seeded in 24-well plates and cultured for 24 hours. The chimeric receptor transfection mixture contained 30ng of receptor expression plasmid, 120ng of reporter plasmid, 350ng of pCMX-beta-galactosidase (. Beta.GAL) expression plasmid as a control for transfection efficiency, 250ng of pGEM4 vector plasmid and 2. Mu.L of Lipofectamine 2000, invitrogen. These mixtures were added to cells and incubated for 5 hours according to the manufacturer's instructions. Following transfection, cells were incubated for an additional 40 hours in the presence of various concentrations of the exemplary compound of the invention or each reference compound. Cell lysates were prepared with lysis buffer (passive lysis buffer, promega) and used in luciferase and beta GAL assays. Luciferase and beta GAL activity were measured with a luciferase assay system (E4030, promega) and with a beta GAL enzyme assay system (E2000, promega). The GAL 4-chimeras were assayed in triplicate. Experiments were repeated at least three times.
6.5.1.3. Calculation of relative PPAR transactivation Activity
Each point of relative PPAR transcriptional activity and maximum activity was calculated from the following values:
With positive control (hPPARα 10) -5 M GW-590735, hPPARgamma 3.times.10 -5 Rosiglitazone maleate M and hPPAR delta of 10 -5 M GW-501516) as maximum activity and luciferase activity of cells treated with 0.1% DMSO as minimum activity.
6.5.1.4.EC 50 Calculation of values
EC 50 Values are defined as the concentration of exemplary compounds of the invention and GW-501516 that produced 50% of the maximum reporter activity recalculated with Prism software (Graphpad Software).
6.5.1.5. Experiments with 10% serum versus 0.1% serum.
Experiments at 2 serum concentrations: 10% and 0.1%. EC50 was calculated as described previously.
First, an assay was established and GAL 4-chimeras/reporter plasmids were validated using the homo sapiens sequences of different PPARs. Experiments were performed in 10% and 0.1% serum with GW501516 (pparδ agonist).
The plasmid is referenced as in US2011/0092517, which is incorporated herein by reference in its entirety.
6.6. EXAMPLE 6 Synthesis of Compound IV
Acetal compound B is synthesized from compound a (see WO 2011/020001;US 7,265,137) and ethylene glycol in the presence of a catalytic acid (e.g. 0.1M HCl). Subsequently using a reducing agent (e.g. LiAlH 4 ) The carboxyl group of compound B is reduced to an alcohol, followed by an aqueous acid post-treatment which removes the acetal to provide compound IV.
6.7. EXAMPLE 7 Synthesis of Compounds V, va and Vb
Compound V is synthesized from compound a (see WO 2011/020001;US 7,265,137) by using a reducing agent (e.g. LiAlH 4 ) Reduction of carboxylic acid and ketone groups to the corresponding alcohols provides compound V. Compound V was then resolved using chiral high performance liquid chromatography to provide its (S) -and (R) -enantiomers, each of which was substantially free of its corresponding opposite enantiomer.
6.8. EXAMPLE 8 Metabolic profile of the Compounds of the invention in cryopreserved hepatocytes
6.8.1. Purpose(s)
The purpose of this study was to investigate the formation of metabolites of the compounds of the invention, including the specific compounds of formulas (a) - (H) and (J) - (AA), compound IV, compound V, compound VI, compound Va, compound Vb, compound VI, compound VII and compound VIII described in section 5.2 (including sub-parts thereof), incubated in human and cynomolgus monkey cryopreserved hepatocytes.
6.8.2. Description of the assay
The compounds of the invention (each "test" for assay purposes) were incubated in cryopreserved hepatocytes from humans and cynomolgus monkeys to provide comparative data for phase I and phase II liver metabolites.
6.8.2.1. Material
The following materials were used:
CNC-00X
Human liver hepatocytes, men
Cynomolgus monkey liver hepatocytes, males
Dulbecco's Modified Eagle's Medium (DMEM)
ITS+1 solution, dexamethasone (Sigma)
Liver cell hatching medium (Xenotech)
7-ethoxycoumarin and 7-hydroxycoumarin (Sigma)
Mass spectrometer with LC sample injection system
6.8.2.2. Step (a)
Each sample consisted of 10 μm of a compound of the invention (diluted from a 10mM DMSO stock, 0.2% DMSO in final incubation) and cryopreserved hepatocytes at a final concentration of 100,000 viable cells per well, with a final volume of 100 μl. The incubation buffer of human hepatocytes was supplemented with DMEM (dexamethasone, 3.3mM; insulin and transferrin, 5. Mu.g/mL each; selenium, 5 ng/mL). The incubation buffer of monkey hepatocytes is a hepatocyte incubation medium without additional supplementation. Samples were in 96-well plates at 37℃in 95% air/5% CO 2 Is incubated in a humidified incubator with gentle shaking. At t=0, 60 or 120 minutes, 100 μl of acetonitrile containing internal standard (metoprolol) was added to stop the reaction. Positive controls 7-ethoxycoumarin and 7-hydroxycoumarin were incubated in the same manner as each of the evaluation compounds.
The samples were centrifuged prior to LC-MS analysis using electrospray ionization and SIM monitoring. Positive control 7-hydroxycoumarin was measured using a fluorescence plate reader.
Metabolite identification was performed for up to 5 days using LC/MS methods.
Metabolite analysis is based on mass spectra of the relevant components of the test article.
LC/MS sensitivity of the test article metabolites was presumed to be the same as the test article.
6.8.3. Results
The compounds of the present invention are found to be metabolized to compounds having PPAR agonist activity and/or metabolites thereof.
7. Detailed description of the preferred embodiments
7.1. Detailed description of the invention, group 1
Various aspects of the disclosure are described in the numbered embodiments set forth in the numbered paragraphs below, wherein references to previously numbered embodiments refer to previously numbered embodiments in this section 7.1.
1. A compound of formula (a):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C 3 -C 7 Cycloalkyl groups;
x is-CH 2 OH、-COOH、-COH、-COOR 3 、-COOCH 2 CONR 4 R 5 、-SO 3 H、
/>
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
2. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a racemate or a mixture of enantiomers or diastereomers.
3. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -stereochemistry and having the structure
4. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom having (S) -stereochemistry and having the structure/>
5. A compound of embodiment 3 or 4 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding opposite stereoisomer.
6. The compound of any one of embodiments 3-5, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein the compound has the olefin isomer configuration of (Z) or (E).
7. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound wherein said compound is a (Z) -isomer and has the structure
8. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound wherein said compound is an (E) -isomer and has the structure
9. A compound of embodiment 7 or 8 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding other olefinic configuration.
10. A compound of any one of embodiments 7-9 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -or (S)) -stereochemistry.
11. The compound of any one of embodiments 1-10 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein each R 1 And R is 2 Independently is-C 1 -C 3 An alkyl group.
12. The compound of any one of embodiments 1-10 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein each R 1 And R is 2 Independently methyl.
13. The compound of any one of embodiments 1-12 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein X is-CH 2 OH、-COOH、-COH、-COOR 3 or-COOCH 2 CONR 4 R 5 。
14. The compound of any one of embodiments 1-12 or a pharmaceutically acceptable salt of the compoundSalts, solvates, esters, amides or prodrugs thereof, wherein X is-CH 2 OH or-COOH.
15. A compound of any one of embodiments 1-14 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein n is 0 or 1.
16. A compound of formula (B):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
each R 1 And R is 2 independently-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl; alternatively, R 1 And R is 2 And R is R 1 And R is 2 The carbon atoms to which they are attached together form C 3 -C 7 Cycloalkyl groups;
x is-CH 2 OH、-COH、-COOCH 2 CONR 4 R 5 、-SO 3 H、
R 3 is-C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl, -C 2 -C 6 Alkynyl, phenyl or benzyl;
each R 4 And R is 5 Independently alkyl, aryl or heteroaryl; alternatively, R 4 And R is 5 And R is R 4 And R is 5 The attached carbon atoms together form a heterocycle;
each R 6 And R is 7 Independently H, -C 1 -C 6 Alkyl, -C 2 -C 6 Alkenyl or-C 2 -C 6 Alkynyl; and n is 0, 1, 2, 3 or 4.
17. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a mixture of (Z) -and (E) -isomers.
18. The compound of embodiment 16 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound wherein said compound is a (Z) -isomer and has the structure
19. The compound of embodiment 16 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound wherein said compound is an (E) -isomer and has the structure
20. A compound of embodiment 18 or 19 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding other olefinic configuration.
21. The compound of any one of embodiments 16-20 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein each R 1 And R is 2 Independently is-C 1 -C 3 An alkyl group.
22. The compound or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of any one of embodiments 16-20, wherein each R 1 And R is 2 Independently methyl.
23. The compound of any one of embodiments 16-22 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein X is-CH 2 OH, -COH or-COOCH 2 CONR 4 R 5 。
24. Any of embodiments 16 through 22A compound of one aspect or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, wherein X is-CH 2 OH。
25. A compound of any one of embodiments 16-24 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein n is 0 or 1.
26. A compound having the structure:
or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
27. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a racemate or a mixture of enantiomers.
28. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom has (R) -stereochemistry, and said compound has the structure
29. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom has (S) -stereochemistry, and said compound has the structure
30. A compound of embodiment 28 or 29 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding opposite enantiomer.
31. The compound of any one of embodiments 28-30, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein the compound has the olefin isomer configuration of (Z) or (E).
32. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a (Z) -isomer and has the structure
33. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is an (E) -isomer and has the structure
34. A compound of embodiment 32 or 33 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding other olefinic configuration.
35. The compound of any one of embodiments 32-34, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -or (S) -stereochemistry.
36. A compound having the structure:
or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
37. A compound of embodiment 36 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a mixture of (Z) -and (E) -isomers.
38. Embodiment 36 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, wherein the compound is a (Z) -isomer and has the structure
39. The compound of embodiment 36 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of said compound wherein said compound is an (E) -isomer and has the structure
40. A compound of embodiment 38 or 39 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding other olefinic configuration.
41. A compound having the structure:
or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
42. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a racemate or a mixture of enantiomers.
43. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom has (R) -stereochemistry, and said compound has the structure
44. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom has (S) -stereochemistry, and said compound has the structure
45. A compound of embodiment 43 or 44 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding opposite enantiomer.
46. The compound of any one of embodiments 43-45 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein the compound has the olefin isomer configuration of (Z) or (E).
47. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is a (Z) -isomer and has the structure
48. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is an (E) -isomer and has the structure
49. A compound of embodiment 47 or 48 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein the compound is substantially free of its corresponding other olefinic configuration.
50. The compound of any one of embodiments 47-49 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein the compound has an allylic carbon atom with a hydroxyl group, said carbon atom having (R) -or (S) -stereochemistry.
51. A composition comprising an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, and a pharmaceutically acceptable carrier or vehicle.
52. The composition of embodiment 51, further comprising another therapeutically active agent.
53. The composition of embodiment 52, wherein the additional therapeutically active agent is a lipid lowering agent, a statin, a cholesterol absorption inhibitor, an anti-PCSK 9 antibody, siRNA PCSK9, an anti-fibrotic agent, a thyroid hormone, a selective thyroid receptor- β agonist, an inhibitor of apoptosis signal-regulating kinase 1 (ASK 1), an inhibitor of Acetyl Coa Carboxylase (ACC), an integrin antagonist, or a non-steroidal Farnesoid X Receptor (FXR) agonist.
54. The composition of embodiment 53, wherein:
the lipid lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, ethoxyhylline, pirfibrate, bisfibrate, tocofibrate or peg Ma Beite;
the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin or cerivastatin, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof;
the cholesterol absorption inhibitor is ezetimibe;
the anti-PCSK 9 antibody is ebo You Shan anti-aliskirumab, bococizumab, 1D05-IgG2, RG7652, LY3015014 or LGT-209;
siRNA PCSK9 is inclisiran;
the anti-fibrotic agent is a nitrozolamide, a tizoxanide, or a tizoxanide glucuronide, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof;
the selective thyroid receptor-beta agonist is VK2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT, ZYT1, MB-0781 or irinotecan;
ASK1 inhibitor is ste Long Se;
the ACC inhibitor is first ocostat;
integrin antagonists are α5β1 inhibitors or ubiquitin inhibitors; or alternatively
The FXR agonist is cilofexor.
55. A method for treating or preventing liver disorders, dyslipidemia, a kidney disease, a glucose metabolic disorder, a lipid metabolic disorder, a carbohydrate metabolic disorder, a cardiovascular disease, a vascular disease, a metabolic syndrome, a complication associated with a metabolic syndrome, a PPAR-related disorder, sepsis, a thrombotic disorder, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, a cerebrovascular disease, a disorder associated with neovascularization, hypertension, cancer, inflammation, an inflammatory disease, a neurodegenerative disease, an autoimmune disease, a neoplastic disease, muscle atrophy, cholestasis, mitochondrial dysfunction, an ocular disease, a lysosomal storage disease, kidney disease, or impotence, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
56. The method of embodiment 55, wherein the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis, or proliferation of hepatocytes.
57. The method of embodiment 55, wherein the liver disorder is liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
58. The method of embodiment 55, wherein the dyslipidemia is hyperlipidemia or abnormally low concentrations of high density lipoprotein cholesterol (HDL-C) in the plasma or serum of the subject.
59. The method of embodiment 58, wherein the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia or familial mixed hyperlipidemia.
60. The method of embodiment 58, wherein the hyperlipidemia is characterized by abnormally decreased or absent levels or activities of lipoprotein lipase in the plasma or serum of the subject, or abnormally high concentrations of ketone bodies, lipoprotein (a) cholesterol (Lp (a) -C), low-density lipoprotein (LDL), very low-density lipoprotein cholesterol (VLDL-C), or non-esterified fatty acids in the plasma or serum of the subject.
61. The method of embodiment 60, wherein the reduced level or activity of lipoprotein lipase or the absence of is the result of a mutation in a gene encoding lipoprotein lipase.
62. The method of embodiment 55, wherein the dyslipidemia is characterized by an abnormally high concentration of LDL, apolipoprotein (a) or VLDL in the plasma or serum of the subject, or an abnormally low concentration of High Density Lipoprotein (HDL) or lipoprotein lipase in the plasma or serum of the subject.
63. The method of embodiment 62, wherein the abnormally low concentration of lipoprotein lipase is compared to: mutations in lipoprotein lipase, hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial mixed hyperlipidemia.
64. The method of embodiment 55, wherein the kidney disease is glomerular disease, tubular interstitial disease, acute or rapidly progressive renal failure, chronic renal failure, kidney stones or tumors.
65. The method of embodiment 64, wherein:
glomerular diseases are acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesions associated with systemic diseases, goodpasture's syndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease or chronic inflammatory diseases;
the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, medullary sponge kidney, medullary cystic disease, nephrogenic diabetes or tubular acidosis;
the renal tubule interstitial disease is nephropyelitis, drug or toxin induced renal tubule interstitial nephritis, hypercalcemic nephropathy or hypokalemic nephropathy; or alternatively
The tumor is renal cell carcinoma or nephroblastoma.
66. The method of embodiment 65, wherein the glomerulopathy associated with the systemic disease is systemic lupus erythematosus.
67. The method of embodiment 55, wherein the kidney disease is hypertension, renal sclerosis, microangiopathy hemolytic anemia, atherosclerotic kidney disease, diffuse cortical necrosis, or renal infarction.
68. The method of embodiment 67, wherein the hypertension is primary hypertension, hyperpiersis, malignant hypertension, secondary hypertension, or white coat hypertension.
69. The method of embodiment 55, wherein the glucose metabolism disorder is impaired glucose tolerance; insulin resistance; insulin resistance-associated breast, colon or prostate cancer; diabetes mellitus; pancreatitis; hypertension; polycystic ovarian disease; or abnormally high concentrations of blood insulin or glucose in the plasma or serum of the subject.
70. The method of embodiment 69, wherein the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin Dependent Diabetes Mellitus (IDDM), gestational Diabetes Mellitus (GDM), or juvenile onset adult-onset diabetes (MODY).
71. The method of embodiment 55, wherein the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia reperfusion injury, myocardial infarction, or cerebral infarction.
72. The method of embodiment 55, wherein the PPAR related disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer, or prostate cancer.
73. The method of embodiment 55, wherein the PPAR related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structure disorder, a neuron activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a β -oxidation disease, or a metabolic disease.
74. The method of embodiment 73, wherein:
muscle disease is muscular dystrophy;
demyelinating diseases are multiple sclerosis, summer-Mary-Chart disease, pet Li Zawu S-Mzhibach disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy or Guillain-Barre syndrome;
muscle structural disorders are bezame myopathy, central nuclear heart disease, congenital fiber imbalance, distal Muscular Dystrophy (MD), duchenne and beck MD, emery-derifer MD, facial scapular MD, homogeneous body myopathy, limb band MD, muscle sodium channel disorder, tonic cartilage dystrophy, tonic muscular dystrophy, myotube myopathy, line-like body disorders, ocular pharynx MD or stress urinary incontinence;
the neuronal activation disorder is amyotrophic lateral sclerosis, mary-Chart disease, guillain-Barre syndrome, lanbert-Eton syndrome, multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve paralysis, or toxic muscular disorder;
Muscle fatigue disorders are chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, friedel's ataxia, intermittent claudication, lipid deposition myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like attacks) syndrome, mucopolysaccharidosis, pompe disease or thyrotoxic myopathy;
muscle mass disorders are cachexia, cartilage degeneration, cerebral palsy, fascial syndrome, critical myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy or systemic lupus erythematosus;
mitochondrial diseases are alper's disease, chronic progressive extraocular muscle paralysis (CPEO), kanns-sal syndrome (KSS), leber Hereditary Optic Neuropathy (LHON), MELAS, myoclonus epilepsy and broken red fiber disease (MERRF), neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, pearson syndrome, mitochondrial dysfunction or loss of mitochondrial function;
beta oxidation disease is systemic carnitine transporter, carnitine Palmitoyl Transferase (CPT) II deficiency, very long chain acyl-coa dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium chain acyl-coa dehydrogenase (MCAD) deficiency, short chain acyl-coa dehydrogenase (SCAD) deficiency or riboflavin-reactive beta-oxidation disorder (RR-MADD); or alternatively
Metabolic diseases are hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypercholesterolemia, LDL hypercholesterolemia, HLD non-cholesterol blood, VLDL hyperproteinemia, dyslipidemia, apolipoprotein a-I hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulation diseases, metabolic syndrome, syndrome X, obesity, diabetes mellitus type I, diabetes type II, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, cardiac insufficiency, myocardial infarction, cardiomyopathy, hypertension, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), thrombosis, alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, hair morbidity, inflammation, arthritis, asthma, allergic bowel syndrome, ulcerative colitis, or pancreatitis.
75. The method of embodiment 74, wherein the muscular dystrophy is duchenne muscular dystrophy, becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facial shoulder humeral muscular dystrophy, tonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, or emery-debifs muscular dystrophy.
76. The method of embodiment 55, wherein the PPAR related disorder is abnormally low concentration of HDL, abnormally low concentration of apolipoprotein A-I (apo A-I), abnormally high concentration of VLDL-C, abnormally high concentration of low density lipoprotein cholesterol (LDL-C), abnormally high concentration of triglycerides, abnormally high concentration of apolipoprotein B (apo B), abnormally high concentration of apolipoprotein C-III (apo C-III), or abnormally reduced proportion of post-heparin hepatic lipase: lipoprotein lipase activity in the plasma or serum of the subject.
77. The method of embodiment 55, wherein the PPAR related disorder is an abnormally high concentration of HDL or an abnormally low concentration of apo A-I in the lymph or cerebral fluid of the subject.
78. The method of embodiment 55, wherein the obesity is abdominal obesity.
79. The method of embodiment 55, wherein the cerebrovascular disease is cerebral ischemia.
80. The method of embodiment 55, wherein the disorder associated with neovascularization is retinopathy or diabetes.
81. The method of embodiment 55, wherein the cancer is human sarcoma or human carcinoma.
82. The method of embodiment 55, wherein the step of, wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary gland cancer, cyst gland cancer, medullary carcinoma, bronchi cancer, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma medulloblastoma, craniopharyngeal medulloma, ependymoma, pineal tumor, angioblastoma, auditory neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphoblastic leukemia, acute undifferentiated leukemia, chronic myelogenous leukemia, hairy cell leukemia, lymphoblastic leukemia, granulocytic leukemia, lymphoblastic leukemia, myelogenous leukemia, polycythemia vera, multiple myeloma, lymphoma, hodgkin's disease, non-hodgkin's lymphoma, megaloblastic Fahrenheit or heavy chain disease.
83. The method of embodiment 82, wherein the leukemia is acute or chronic lymphocytic leukemia, myelogenous leukemia, lymphocytic leukemia or myelogenous leukemia.
84. The method of embodiment 83, wherein the myelogenous leukemia is acute and is myeloblasts, promyelocytes, myelomonocytes, monocytes or leukemia cells.
85. The method of embodiment 83, wherein the lymphoma is hodgkin's lymphoma or non-hodgkin's lymphoma.
86. The method of embodiment 55, wherein the inflammatory disease is multiple sclerosis, chronic inflammatory disorders of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorders of the gums, tuberculosis, leprosy, inflammatory diseases of the kidneys, inflammatory disorders of the skin, inflammatory diseases of the central nervous system, systemic Lupus Erythematosus (SLE) or inflammatory diseases of the heart.
87. The method of embodiment 86, wherein:
arthritis is rheumatoid arthritis or osteoarthritis;
inflammatory bowel disease is ileitis, ulcerative colitis or crohn's disease;
inflammatory pulmonary disorders are asthma or chronic obstructive airways diseases;
Inflammatory disorders of the eye are corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathogenic ophthalmia, or endophthalmitis;
inflammatory disorders of the gums are periodontitis or gingivitis;
inflammatory disorders of the kidney are glomerulonephritis or kidney disease;
inflammatory disorders of the skin are acne, sclerodermatitis, psoriasis, eczema, photoaging or wrinkles;
inflammatory diseases of the central nervous system are AIDS-related neurodegenerative diseases, stroke, neurotrauma, alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis; or alternatively
The inflammatory disease of the heart is cardiomyopathy.
88. The method of embodiment 55, wherein the neurodegenerative disease is Alzheimer's disease or Huntington's disease.
89. The method of embodiment 55, wherein the autoimmune disease is immune complex vasculitis, systemic lupus, or erythema.
90. The method of embodiment 55, wherein the neoplastic disease is carcinogenesis.
91. The method of embodiment 55, wherein cholestasis is an intrahepatic cholestasis disease or an extrahepatic cholestasis disease.
92. The method of embodiment 91, wherein the intrahepatic cholestasis disease is primary cholangitis (PBC), primary Sclerosing Cholangitis (PSC), progressive Familial Intrahepatic Cholestasis (PFIC), or Alagille Syndrome (AS).
93. The method of embodiment 55, wherein the ocular disease is dry eye, meibomian gland dysfunction, keratoconjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer.
94. The method of embodiment 55, wherein the lysosomal storage disorder is neuronal ceroid lipofuscinosis, alzheimer's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), parkinson's disease, multiple System Atrophy (MSA), progressive Supranuclear Palsy (PSP), corticobasal degeneration (CBD), dementia with lewy bodies (DLB), autophagy pathway disorders, tai-saxophone disease, fabry disease, niemann-pick disease, gaucher's disease, hunter's syndrome, alpha-mannosidosis, aspartyl glucosaminuria, cholesterol ester storage disease, chronic aminohexosidase a deficiency, cystine disease, darner's disease, farber disease, fucosidosis, galactosialidosis, or barton disease.
95. The method of embodiment 55, wherein the kidney disease is renal ischemia reperfusion injury.
96. The method of embodiment 55, wherein the impotence is caused by nerve injury, arterial injury, smooth muscle injury, or fibrous tissue injury; diabetes mellitus; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or a neurological disease.
97. A method for treating or preventing hyperlipidemia, hyperlipidaemia, hyperlipoproteinaemia, hypercholesteraemia, hypertriglyceridaemia or dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
98. The method of embodiment 97, wherein the hypercholesterolemia is homozygous familial hypercholesterolemia.
99. A method for treating a subject having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, or preventing a subject from having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, comprising administering to the subject in need thereof an effective amount of a compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
100. A method for treating a subject having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject or preventing a subject from having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
101. A method for treating a subject having or preventing a subject having or having a aberrant decrease or deficiency in lipoprotein lipase concentration or activity in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
102. The method of embodiment 101, wherein the reduced level or activity of the lipoprotein lipase or the lack thereof is a result of a mutation in a gene encoding the lipoprotein lipase.
103. A method for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with alzheimer's disease, or familial mixed hyperlipidemia comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
104. A method for reducing abnormally high concentrations of triglycerides, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) (Lp (a)), the ratio of apolipoprotein B, HDL/(vldl+ldl), apolipoprotein C-II or apolipoprotein C-III in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
105. A method for increasing abnormally low concentrations of High Density Lipoprotein (HDL) -associated protein, HDL-cholesterol, apolipoprotein a-I, or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
106. The method of embodiment 105, wherein the HDL-related protein is an apolipoprotein A-I (apo A-I), an apolipoprotein A-II (apo A-II), an apolipoprotein A-IV (apo A-IV), or an apolipoprotein E (apo E).
107. A method for promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
108. A method for increasing abnormally low glucose metabolism or lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
109. The method of embodiment 108, wherein the method for increasing abnormally low glucose metabolism increases insulin sensitivity or oxygen consumption in the subject, or decreases blood insulin, blood glucose, or glycosylated hemoglobin in the plasma or serum of the subject.
110. The method of embodiment 108, wherein the method for increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the plasma or serum of the subject, or inhibits saponified or non-saponified fatty acid synthesis.
111. A method for treating or preventing a symptom of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
112. The method of embodiment 111, wherein the arthritis is adjuvant arthritis or type II collagen-induced arthritis.
113. The method of embodiment 111, wherein the symptom is nephritis, renal failure or reduced renal function.
114. A method for reducing the fat content of livestock meat comprising administering to livestock an effective amount of a compound of any of embodiments 1-50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
115. A method for reducing the cholesterol level of an avian egg comprising administering to an avian an effective amount of a compound of any one of embodiments 1 to 50, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound.
116. A method for treating a subject suffering from or at risk of Acute Kidney Injury (AKI), comprising administering to the subject an effective amount of a compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
117. The method of embodiment 116, wherein the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound is administered intravenously, optionally wherein the method comprises intravenous administration once daily, optionally for three days.
118. The method of embodiment 116, wherein the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound is administered orally.
119. The method of any one of embodiments 116 to 118, wherein AKI is sepsis-associated AKI.
120. The method of any one of embodiments 116-118, wherein AKI is ischemia/reperfusion AKI.
121. The method of any one of embodiments 116 to 118, wherein AKI is from acute interstitial nephritis.
122. The method of any one of embodiments 116 to 118, wherein AKI is from glomerular kidney disease.
123. The method of any one of embodiments 116 to 118, wherein AKI is from acute vasculitis kidney disease.
124. The method of any one of embodiments 116 to 118, wherein AKI is from ischemia.
125. The method of any one of embodiments 116 to 118, wherein AKI is from a toxic injury.
126. The method of any one of embodiments 116 to 118, wherein AKI is from prerenal azotemia.
127. The method of any one of embodiments 116 to 118, wherein AKI is from acute postrenal destructive kidney disease.
128. The method of any one of embodiments 116 to 118, wherein AKI is from diabetes.
129. The method of any one of embodiments 116 to 118, wherein AKI is from potential renal insufficiency.
130. The method of any one of embodiments 116 to 118, wherein AKI is from nephritis syndrome.
131. The method of any one of embodiments 116 to 118, wherein AKI is from an atherosclerotic disease.
132. The method of any one of embodiments 116 to 118, wherein AKI is from hypotension.
133. The method of any one of embodiments 116 to 118, wherein AKI is from hypoxia.
134. The method of any one of embodiments 116 to 118, wherein AKI is from myoglobin urine-hematuria.
135. The method of any one of embodiments 116 to 118, wherein AKI is from a liver disease.
136. The method of any one of embodiments 116 to 118, wherein AKI is secondary to a viral infection, optionally wherein the viral infection is covd-19.
137. The method of embodiment 136, wherein the subject has a viral infection, optionally wherein the viral infection is covd-19.
138.116 to 119, wherein the subject has sepsis.
139. The method of embodiment 137, wherein the sepsis is associated with a gram-negative bacterial infection.
140. The method of embodiment 138 or embodiment 139, wherein the subject has an intraperitoneal infection.
141. The method of embodiment 138 or embodiment 139, wherein the subject has urine sepsis.
142. The method of any one of embodiments 116 to 141, wherein the subject is an elderly human.
143. The method of any one of embodiments 116 to 142, wherein the subject is a surgical patient.
144. The method of embodiment 143, wherein the surgical patient has undergone a cardiovascular procedure, optionally it is a Coronary Artery Bypass Graft (CABG) procedure and/or a heart valve procedure.
145. The method of any one of embodiments 116 to 141, wherein the subject is pregnant.
146. The method of any one of embodiments 116 to 145, wherein the subject has been exposed to a nephrotoxic agent.
147. The method of embodiment 146, wherein the nephrotoxic agent comprises cisplatin, gentamicin, pioneermycin, cyclosporine, amphotericin, carbon tetrachloride, trichloroethylene, dichloroacetylene, or a combination thereof.
148. The method of any one of embodiments 116 to 147, wherein the subject has AKI.
149. The method of embodiment 148, wherein the effective amount is effective to reduce the severity of AKI.
150. The method of any one of embodiments 116 to 147, wherein the subject is at risk of AKI.
151. The method of any one of embodiments 116 to 147, wherein the subject is at risk of AKI following cardiovascular surgery, optionally the cardiovascular surgery is Coronary Artery Bypass Graft (CABG) surgery and/or heart valve surgery.
152. The method of embodiment 150 or embodiment 151, wherein the effective amount is effective to reduce the likelihood of the subject developing AKI in the future.
153. The method of any one of embodiments 150 to 152, wherein the effective amount is effective to delay the onset of AKI.
154. The method of any one of embodiments 150 to 152, wherein the effective amount is effective to prevent AKI.
155. The method of any of embodiments 150 to 152, wherein if the subject develops AKI, the effective amount is effective to reduce the severity of AKI.
156. The method of any one of embodiments 116 to 155, wherein the subject has a SOFA score of 1 to 4 prior to administration of the compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or the pharmaceutical composition.
157. The method of embodiment 156, wherein the subject has a SOFA score of 2 to 4 prior to administration.
158. The method of embodiment 156, wherein the subject has a SOFA score of 1 prior to administration.
159. The method of embodiment 156, wherein the subject has a SOFA score of 2 prior to administration.
160. The method of embodiment 156, wherein the subject has a SOFA score of 3 prior to administration.
161. The method of embodiment 156, wherein the subject has a SOFA score of 4 prior to administration.
162. The method of any one of embodiments 116 to 161, wherein the subject has an endotoxin activity level of ≡0.6 prior to administration.
163. The method of any one of embodiments 116 to 162, wherein the effective amount is effective to reduce the level of endotoxin activity in the subject.
7.2. Detailed description of the invention, group 2
Various aspects of the disclosure are described in the numbered embodiments set forth in the numbered paragraphs below, wherein references to previously numbered embodiments refer to previously numbered embodiments in this section 7.2.
1. A compound of formula (C):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is phenyl, naphthyl, pyridinyl, thienyl, furyl, quinolinyl or benzothienyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
R 2 is C 2-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl or C substituted by phenyl, naphthyl or pyridyl 1-6 Alkyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
a is oxygen, sulfur or NR 9 Wherein R is 9 Is hydrogen or C 1-8 An alkyl group;
x is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy or hydroxy substituted and having 0 or 1 double bond;
y is C (=O), C (=N-OR 10 )、CH(OR 11 ) Ch=ch, c≡c or C (=ch 2 ) Wherein R is 10 And R is 11 Each hydrogen or C 1-8 An alkyl group;
R 3 、R 4 and R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl; optionally, wherein R 3 、R 4 And R is 5 At least one of which is other than hydrogen;
b is CH or nitrogen;
z is oxygen or sulfur;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
2. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 1 Is phenyl, which may have a moiety selected from C 1-8 Alkyl, C having 1-3 halogen atoms 1-8 Alkyl, C 1-8 Alkoxy, C having 1-3 halogen atoms 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl and pyridyl substituents.
3. The compound of embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 2 Is C 2-8 An alkyl group.
4. A compound of any one of embodiments 1 through 3 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 1 To position 2, and (i) R 4 Attached at position 4 and- -X- -Y- -attached at position 5, or (ii) R 4 To position 5 and-X- -Y- -to position 4.
5. A compound of any one of embodiments 1 through 4 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein a is oxygen or sulfur.
6. A compound of any one of embodiments 1 through 5 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is C 1-8 An alkylene chain.
7. A compound of any one of embodiments 1 through 6 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Y is C (=o).
8. The compound of any one of embodiments 1 through 7 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 、R 4 And R is 5 Each is hydrogen, C 1-8 Alkyl or C with halogen 1-8 An alkyl group.
9. A compound of any one of embodiments 1 through 8 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein B is CH.
10. A compound of any one of embodiments 1 through 9 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein Z is oxygen.
11. The compound of any one of embodiments 1 to 10 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 6 And R is 7 Each hydrogen or C 1-4 An alkyl group.
12. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein:
R 1 is phenyl or naphthyl, each of which may have a group selected from C 1-8 Alkyl, C with halogen 1-8 Alkyl, C 1-8 Alkoxy, C with halogen 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 One or more substituents of acyl, benzoyl, hydroxy, nitro, amino, phenyl and pyridyl;
R 2 is C 2-8 An alkyl group;
a is oxygen or sulfur;
x is C 1-8 Alkylene chains, which may have C 1-8 Alkyl substituents and may contain double bonds;
y is C (=o), ch=ch, or C (=ch 2 )；
R 3 、R 4 And R is 5 Each is hydrogen, C 1-8 Alkyl, C with halogen 1-8 Alkyl, C 1-8 Alkoxy, C with halogen 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl;
b is CH;
z is oxygen or sulfur; and
R 6 and R is 7 Each hydrogen or C 1-8 An alkyl group.
13. A compound of embodiment 12 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is C 1-8 An alkylene chain.
14. Embodiment 12 chemical conversionA compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 1 Is connected to bit 2.
15. The compound of any one of embodiments 12 to 14 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R, except hydrogen 3 、R 4 And R is 5 Located in an ortho position relative to Z.
16. A compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, wherein R 1 Is covered by CF 3 A substituted phenyl group.
17. The compound of embodiment 1 or embodiment 16 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 2 Is isopropyl.
18. A compound of any one of embodiments 1 and 16 through 17 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a is sulfur.
19. The compound of any one of embodiments 1 and 16 through 18 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is CH 2 CH 2 。
20. A compound of any one of embodiments 1 and 16 through 19 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Y is C (=o).
21. A compound of any one of embodiments 1 and 16 through 19 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein Y is CH (OH).
22. The compound of any one of embodiments 1 and 16 through 21 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 3 Is CH 3 And R is 4 And R is 5 Each hydrogen.
23. A compound of any one of embodiments 1 and 16 through 22 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein B is CH.
24. A compound of any one of embodiments 1 and 16 through 23 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Z is oxygen.
25. The compound of any one of embodiments 1 and 16 through 24 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 6 And R is 7 Each hydrogen.
26. A compound of formula (D):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 and R is 2 Each independently is hydrogen, halogen, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, optionally substituted C 6-10 Aryl, with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkyl moieties, heterocyclic groups or having C 1-8 A heterocycloalkyl group of an alkyl group;
R 3 、R 4 and R is 5 Each occurrence is independently hydrogen or C 1-8 An alkyl group;
a is an oxygen atom, a sulfur atom or NR 3 ；
X 1 、X 2 And Z are each independently C (=o), C (=o) NH, C (=n-OR 4 )、CH(OR 5 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c≡c, or a bond; and
y is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
/>
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
27. A compound of embodiment 26 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X 1 Is C (=o), CH (OH), or a bond.
28. The compound of embodiment 26 or embodiment 27 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein X 2 Is C (=o), CH (OH), or a bond.
29. A compound of formula (E):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 And R is 12 Each independently is hydrogen, halogen, nitro, hydroxy, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl group, C with 1 to 3 halogens 1-8 Haloalkoxy groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, or optionally substituted phenyl, naphthyl, benzyl, phenethyl, pyridyl, thienylA furyl, quinolinyl or benzothienyl group, the substituent being a halogen atom, a nitro group, a hydroxyl group, an amino group, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl group, C with 3-7 membered cycloalkyl substituent 1-8 An alkyl group, phenyl or pyridyl;
X 1 and Z 1 Each independently is C (=o), C (=o) NH, C (=n-OR 14 )、CH(OR 15 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c=c or bond, wherein R 14 And R is 15 Each hydrogen or C 1-8 An alkyl group;
Y 1 is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
30. The compound of embodiment 29 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of said compound wherein X 1 Is C (=o), CH (OH), or a bond.
31. The compound of embodiment 29 or embodiment 30 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Z 1 Is C (=o), CH (OH), or a bond.
32A compound of any one of embodiments 29 through 31 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X 1 -Y 1 -Z 1 Bonded to the 3-or 4-position of the benzene ring.
33. The compound of any one of embodiments 29 to 32 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein X 1 Is a bond and Z 1 Is (c=o).
34. The compound of any one of embodiments 29 to 33 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein X 1 -Y 1 -Z 1 Bonded to the 4-position of the five-membered ring.
35. A compound of any one of embodiments 29 through 34 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 11 Is a phenyl or naphthyl group, optionally having a substituent selected from the group consisting of chlorine, fluorine, hydroxyl, an alkyl group having 1 to 5 carbon atoms, and which is bonded to the 2-position of the five-membered ring.
36. The compound of any one of embodiments 29 to 35 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 12 Is an alkyl group having 3 to 6 carbon atoms bonded to the 5-position of the 5-membered ring.
37. A compound of formula (F):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is O, S or NR 7 Wherein R7 is hydrogen or C 1-8 An alkyl group;
B 1 is CW or N, wherein W is hydrogen or a bond; b (B) 2 O, S or NR 8 Wherein R is 8 Is hydrogen or C 1-8 An alkyl group;
X 1 and X 2 O, S, NH each,NHC(＝O)、C(＝O)、C(＝N-OR 9 )、CH(OR 10 ) C= C, C ≡c or bond, wherein R 9 And R is 10 Each hydrogen or C 1-8 An alkyl group;
y is C 1-8 Alkylene which is unsubstituted or C 1-8 Alkyl or C with 1-3 halogens 1-8 Haloalkyl substitution;
z is NH, O or S;
R 1 is aryl (the aryl group being unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl, or halogen substitution), or a heterocyclic group having a five to eight membered ring containing 1 to 3 heteroatoms (wherein each heteroatom is independently nitrogen, oxygen, or sulfur and the other atoms are carbon), optionally wherein the benzene ring is fused to the heterocyclic ring;
R 2 is C 2-8 Alkyl, C with 1-3 halogens 1-8 Haloalkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, aryl (which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl or halogen substituted) substituted C 1-4 Alkyl, or C substituted with a heterocyclic group having a five-to eight-membered ring containing 1 to 3 heteroatoms each of which is independently nitrogen, oxygen or sulfur 1-4 An alkyl group;
R 3 is halogen, trifluoromethyl, C 1-8 Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl;
R 4 and R is 5 Each is hydrogen, C 1-8 Alkyl or C with 1-3 halogens 1-8 A haloalkyl group;
z and R 3 Each being attached to a benzene ring, and X 2 Not attached to the benzene ring;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
38. The compound of embodiment 37 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X 1 Is C (=o), CH (OH), or a bond.
39. The compound of embodiment 37 or embodiment 38 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein X 2 Is C (=o), CH (OH), or a bond.
40. A compound of formula (G):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 and R is 4 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 2 is hydrogen;
R 3 is C 1-8 Alkyl, or R 3 And R is R 2 Bonding forms=o or=c (R 7 )(R 8 ) Wherein R is 7 And R is 8 Are identical or different and are each hydrogen or C 1-8 An alkyl group;
R 5 and R is 6 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl, C 1-8 A haloalkyl group;
x and Y are the same or different and each represents CH or N;
z is oxygen or sulfur;
a is a 5-membered heterocyclic group which is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or substituted C 1-8 Alkyl substitution, the substituent being C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-to 7-membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 An aralkyl group of an alkylene moiety, or a 5-or 6-membered heterocyclyl group;
b is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution, in the case where the alkylene group has 2 to 6 carbon atoms, the alkylene group optionally has a double bond;
q is 0, 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
41. A compound of embodiment 40 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein a is pyrazole.
42. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein- (CH) 2 ) q -is attached to pyrazole at pyrazole 1 position
43. A compound of embodiment 41 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein- (CH) 2 ) q -is attached to pyrazole at pyrazole 3 position.
44. A compound of embodiment 42 or 43 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein-B-is attached to the pyrazole at position 4 or 5.
45. A compound of embodiment 40 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein a is thiophene, furan or pyrrole.
46. The compound of embodiment 45 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of said compound wherein- (CH) 2 ) q -attached to the 5-membered heterocyclic group at the 2-position of the 5-membered heterocyclic group.
47. A compound of embodiment 40 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein a is thiophene.
48. The compound of embodiment 47 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein- (CH) 2 ) q -linking thiophene at the thiophene 2-position.
49. A compound of any one of embodiments 40 to 48 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein q is 0.
50. A compound of any one of embodiments 40 through 49 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X and Y are each CH.
51. The compound of any one of embodiments 40 to 50 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 2 And R is R 3 Combine to represent =o.
52. The compound of any one of embodiments 40 to 51, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein B represents an alkylene chain having 2 to 4 carbon atoms, optionally having a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
53. A compound of any one of embodiments 40 to 52 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein B is an ethylene chain.
54. The compound of any one of embodiments 40 to 53 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 And R is 4 Are identical or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
55. The compound of any one of embodiments 40 to 54 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 5 And R is 6 Are identical or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms.
56. The compound of any one of embodiments 40 to 55, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein the substituent optionally attached to the heterocyclic group of a is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and halogen atom substituents.
57. A compound of formula (H):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 and R is 13 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 12 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 14 and R is 15 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 1 CH or N;
Z 1 is oxygen or sulfur;
when bond a is present, W 1 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 1 OH;
q is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
/>
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
58. A compound of embodiment 57 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X 1 Is CH.
59. A compound of embodiment 57 or 58 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 11 -phenyl or R 11 -pyridyl is attached to pyrazole at position 1.
60. A compound of embodiment 57 or 58 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 11 -phenyl or R 11 -pyridyl is attached to pyrazole at the 3-position.
61. The compound of any one of embodiments 57 to 60 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein- (CH) 2 ) q -to pyrazole at the 4-or 5-position.
62. The compound of any one of embodiments 57 through 61 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 11 And R is 13 Are identical or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
63. Embodiment 5A compound of any one of claims 7 to 61, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 11 And R is 13 Are identical or different and each represents an alkyl group having from 1 to 8 carbon atoms or an alkyl group having from 1 to 8 carbon atoms and halogen atom substituents.
64. A compound of any one of embodiments 57 through 63 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 14 And R is 15 Are identical or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms.
65. The compound of any one of embodiments 57 through 64 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 12 Represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
66. The compound of any one of embodiments 57 through 64 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 12 Represents an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms and a halogen atom substituent.
67. A compound of any one of embodiments 57 through 66 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein q is 2.
68. The compound of any one of embodiments 57 through 67 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein bond a is absent and W 1 Is OH.
69. The compound of any one of embodiments 57 through 67 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and W 1 Is oxygen.
70. A compound of formula (J):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 and R is 23 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 22 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 24 and R is 25 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 2 CH or N;
Z 2 is oxygen or sulfur;
when bond a is present, W 2 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 2 OH;
r is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independent and independentIs alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
71. A compound of embodiment 70 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X 2 Is CH.
72. A compound of embodiment 70 or 71 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 21 -phenyl or R 21 The pyridinyl group is attached to the thiophene in the 2-position.
73. The compound of any one of embodiments 70 to 72 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 21 And R is 23 Are identical or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
74. The compound of any one of embodiments 70 to 72 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 21 And R is 23 Are identical or different and each represents an alkyl group having from 1 to 8 carbon atoms or an alkyl group having from 1 to 8 carbon atoms and halogen atom substituents.
75. The compound of any one of embodiments 70 to 74 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 24 And R is 25 Are identical or different and each represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms.
76. The compound of any one of embodiments 70 to 75 or a pharmaceutically acceptable salt of the compoundSalts, solvates, esters, amides or prodrugs thereof, wherein R 22 Represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and halogen atom substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen atom substituents.
77. The compound of any one of embodiments 70 to 75 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 22 Represents an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms and halogen atom substituents.
78. A compound of any one of embodiments 70 through 77 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein r is 2.
79. The compound of any one of embodiments 70 to 78 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein bond a is absent and W 2 Is OH.
80. The compound of any one of embodiments 70 to 78 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and W 2 Is oxygen.
81. A compound of formula (K):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is CH or nitrogen;
when bond a is present, B is oxygen or C (R 8 )(R 9 ) Wherein R is 8 And R is 9 Each independently is hydrogen or C 1-8 An alkyl group; when bond a is absent, B is OH;
W 1 is a bond, C (=O) or (C (R) 10 )(R 11 )) m Wherein R is 10 And R is 11 Each independently is hydrogen or C 1-8 Alkyl groupAnd m is 1, 2 or 3;
x and Y are different from each other and are each an oxygen atom, a sulfur atom, a nitrogen atom or CR 12 Wherein R is 12 Is hydrogen or C 1-8 An alkyl group;
Z 1 is a bond, oxygen, sulfur or C (R) 13 )(R 14 ) Wherein R is 13 And R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
R 1 、R 2 and R is 3 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 4 And R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 A haloalkyl group;
r is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
82. A compound of embodiment 81 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein a is CH.
83. A compound of embodiment 81 or 82 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein W 1 Is a key.
84. A compound of embodiment 81 or 82 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein W 1 Is methylene or C (=o).
85. The compound of any one of embodiments 81 to 84 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein X and Y are different from each other and are each an oxygen atom, a sulfur atom or a nitrogen atom.
86. A compound of embodiment 85 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, X is a sulfur atom and Y is a nitrogen atom.
87. The compound of any one of embodiments 81 to 86 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Z 1 Is an oxygen atom or a sulfur atom.
88. The compound of any one of embodiments 81 to 87 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 1 、R 2 And R is 3 Independently a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom.
89. The compound of any one of embodiments 81 to 88 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 4 And R is 5 Each independently is a hydrogen atom or a methyl group.
90. The compound of any one of embodiments 81 to 89 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R 6 And R is 7 Each independently is a hydrogen atomOr an alkyl group having 1 to 8 carbon atoms.
91. A compound of any one of embodiments 81 to 90 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein n is an integer from 2 to 4.
92. A compound of embodiment 91 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein n is 2.
93. A compound of any one of embodiments 81 to 92 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein bond a is absent and B is OH.
94. A compound of any one of embodiments 81 to 92 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein bond a is present and B is oxygen.
95. A compound of formula (L):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, B is oxygen; when bond a is absent, B is OH;
W 2 is a bond, C (=O) or CH 2 ；
Z 2 Is oxygen or sulfur;
R 21 、R 22 and R is 23 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 24 and R is 25 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
Each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
96. A compound of embodiment 95 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein W 2 Is a key.
97. The compound of any one of embodiments 95 or 96 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 21 、R 22 And R is 23 Independently a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom.
98. The compound of any one of embodiments 95 to 97 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 24 And R is 25 Each independently is a hydrogen atom or a methyl group.
99. A compound of any one of embodiments 95 to 98 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein bond a is absent and B is OH.
100. A compound of any one of embodiments 95 to 98 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein bond a is present and B is oxygen.
101. A compound of formula (M):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is nitrogen or CH;
x is nitrogen or CH;
y is oxygen or sulfur;
z is a bond, oxygen, sulfur or NR 5 Wherein R is 5 Is hydrogen or C 1-8 An alkyl group;
R 1 and R is 2 Each independently is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl radical of alkylene, or C with 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 3 and R is 4 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
a is a 5-membered heterocyclic ring which is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
b is a bond or C 1-8 Alkylene group, C 1-8 Alkylene is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 1-8 Substituted by alkoxy or halogen substituents, optionally wherein C 1-8 Alkylene has a double bond or a triple bond;
r is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
102. A compound of embodiment 101 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein W 1 And W is 2 Each represents CH.
103. A compound of embodiment 101 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein W 1 Represents CH and W 2 Representing nitrogen atoms
104. A compound according to any one of embodiments 101 to 103, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein X represents a nitrogen atom.
105. A compound according to any one of embodiments 101 to 103 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein X represents a nitrogen atom and Y represents an oxygen atom.
106. A compound according to any one of embodiments 101 to 103 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein X represents CH and Y represents an oxygen atom.
107. A compound according to any one of embodiments 101 to 106 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein Z represents an oxygen atom or a sulfur atom.
108. The compound of any one of embodiments 101 to 107 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein R 1 And R is 2 Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen substituent.
109. The compound of any one of embodiments 101 to 108 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 And R is 4 Each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
110. The compound or pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of any one of embodiments 101 to 109 wherein a represents pyrazole, thiophene, or furan that can have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, a 3-to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and 3-to 7-membered cycloalkyl substituents, an alkyl group having 1 to 8 carbon atoms and halogen substituents, an alkoxy group having 1 to 8 carbon atoms and halogen substituents, an aryl group having 6 to 10 carbon atoms, a 5-or 6-membered heterocyclic group, an aryl portion having 6 to 10 carbon atoms and an alkylene portion of 1 to 8 carbon atoms, and an aralkyl group having 1 to 8 carbon atoms and an alkyl group having 1 to 8 carbon atoms and 5-membered heterocyclic substituents.
111. A compound of any one of embodiments 101 through 109 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a represents pyrazole, thiophene, or furan, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and halogen substituents, or an alkoxy group having 1 to 8 carbon atoms and halogen substituents.
112. A compound of any one of embodiments 101 through 109 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a represents pyrazole, which may have a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen substituent, and an alkoxy group having 1 to 8 carbon atoms and a halogen substituent.
113. A compound of any one of embodiments 101 to 112 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein B represents an alkylene chain having 2 to 4 carbon atoms.
114. A compound of any one of embodiments 101 through 113 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein n is 0.
115. A compound of formula (N):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 3 is nitrogen or CH;
Z 1 is oxygen or sulfur;
R 11 and R is 12 Each independently is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy radicalRadical, C 1-8 Haloalkyl or C 1-8 Haloalkoxy groups;
R 13 and R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
A 1 is a five-membered heterocyclic ring which is pyrazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution;
m is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
116. A compound of embodiment 115 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein W 3 Represents CH.
117. A compound of embodiment 115 or 116 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein a 1 Represents a pyrazole which may have a substituent selected from a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and a halogen substituent, or an alkoxy group having 1 to 8 carbon atoms and a halogen substituent.
118. A compound of any one of embodiments 115 through 117 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein m is 2 or 3.
119. A compound of formula (O):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or nitrogen;
x is NR 5 Or CR (CR) 6 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C 3-7 Cycloalkyl, quilt C 3-7 Cycloalkyl-substituted C 1-8 Alkyl, C substituted by phenyl 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl, and R 6 And R is 7 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 8 R 9 ) r Wherein R is 8 And R is 9 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4; or alternatively
X and Y combine to form CR 10 ＝CR 11 Or ethynylene group, wherein R 10 And R is 11 Each independently is hydrogen or C 1-8 An alkyl group;
when bond a is present, G is O, S or CR 12 R 13 Wherein R is 12 And R is 13 Each independently is hydrogen or C 1-8 An alkyl group; when bond a is absent, G is OH;
a is a five membered heterocycle which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocycle is unsubstituted or C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl or five-membered or six-membered heterocyclic groups;
b is C 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 Alkynylene chain wherein the chain is unsubstituted or C 1-8 Alkyl, C 3-7 Cycloalkyl, C 1-8 Alkoxy or halogen substitution;
R 1 and R is 2 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl, or five-or six-membered heterocyclic groups;
R 3 and R is 4 Each independently is hydrogen or C 1-8 An alkyl group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
120. A compound of embodiment 119 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein W 1 And W is 2 Each is CH.
121. A compound of embodiment 119 or 120 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is CR 6 R 7 。
122. A compound of embodiment 119 or 120 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is CH 2 。
123. A compound of embodiment 119 or 120 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is NR 5 。
124. A compound of embodiment 119 or 120 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is NH.
125. A compound of embodiment 119 or 120 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein X is NR 3 And R is 5 Is C 1-8 An alkyl group.
126. The compound of any one of embodiments 119 to 125 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein Y is CH 2 。
127. A compound of any one of embodiments 119 through 126 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein Z is carboxy.
128. The compound of any one of embodiments 119 to 127 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein a is thiazole, which can be selected from C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, C substituted by halogen 1-8 Alkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl, and substituents of five-or six-membered heterocyclic groups.
129. A compound of any one of embodiments 119 to 128 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein B is an ethylene chain.
130. The compound of any one of embodiments 119 to 129 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 And R is 2 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl or C substituted by halogen 1-8 An alkoxy group.
131. The compound of any one of embodiments 119 to 129 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 And R is 2 Each independently is hydrogen, C 1-8 Alkyl, halogen or C substituted by halogen 1-8 An alkyl group.
132. The compound of any one of embodiments 119 to 131 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 And R is 4 Each hydrogen.
133. A compound of any one of embodiments 119 through 132 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein m is 0.
134. A compound of embodiments 119 through 133 wherein bond a is absent and G is OH, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound.
135. A compound of embodiments 119 through 133 wherein bond a is present and G is oxygen, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound.
136. A compound of formula (P):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, G a Is O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G a Is OH;
A a is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Halogenated compoundsAlkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B a is C 1-8 Alkylene or C 2-8 Alkenylene chains;
R 1a and R is 2a Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
137. A compound of embodiment 136 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a a Is thiazole, which may be selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, C substituted by halogen 1-8 Alkoxy, hydroxy, nitro and C 2-8 The substituent of the acyl group is substituted.
138. A compound of embodiment 136 or 137 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein B a Is an ethylene chain.
139. The compound of any one of embodiments 136 to 138 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1a And R is 2a Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, or C substituted by halogen 1-8 An alkoxy group.
140. The compound of any one of embodiments 136 to 139 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein bond a is absent and G a Is OH.
141. The compound of any one of embodiments 136 through 139 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and G a Is oxygen.
142. A compound of formula (Q):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, G b O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G b OH;
A b is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B b is C 1-8 Alkylene or C 2-8 Alkenylene chains;
R 1b and R is 2b Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R 3b is hydrogen or C 1-8 An alkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
143. A compound of embodiment 142 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein a b Is a thiazole selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, C substituted by halogen 1-8 Alkoxy, hydroxy, nitro and C 2-8 The substituent of the acyl group is substituted.
144. A compound of embodiment 142 or 143 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein B b Is an ethylene chain.
145. The compound of any one of embodiments 142 to 144 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1b And R is 2b Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C substituted by halogen 1-8 Alkyl, or C substituted by halogen 1-8 An alkoxy group.
146. A compound of any one of embodiments 142 through 145 or a pharmaceutical of such a compoundA salt, solvate, ester, amide or prodrug of any of the above, wherein bond a is absent and G b Is OH.
147. The compound of any one of embodiments 142 to 145 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and G b Is oxygen.
148. A compound of formula (R):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or N;
x is NR 3 Or CR (CR) 4 R 5 Wherein R is 3 Is C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, C substituted by phenyl groups 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
R 4 and R is 5 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 6 R 7 ) r Wherein R is 6 And R is 7 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4;
a is a 5 or 6 membered heterocyclic group (which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine) or a phenyl group, wherein the 5 or 6 membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl, 3-7 membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-7 membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5 or 6 membered heterocyclic group containing C 6-10 Aryl group and C 1-8 Aralkyl radicals of alkyl radicalsGroups, or C substituted by 5-or 6-membered heterocyclic groups 1-8 Alkyl group substitution;
b is a bond or C 1-8 Alkylene group, C 1-8 Alkylene being unsubstituted or C 1-8 Alkyl, 3-7 membered cycloalkyl group, C 1-8 Alkoxy or halogen substituted, and when the number of carbons of the alkylene chain is 2 or more, it may have a double bond or a triple bond;
d is N or CH;
e is O or S;
R 1 and R is 2 Each independently H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, nitro, C 2-8 Acyl, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
149. A compound of formula (S):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
A 1 is a 5-or 6-membered heterocyclic group (which is thiazole, oxazole, pyridine or pyrimidine) or a phenyl group, wherein the 5-or 6-membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl or C 1-8 Haloalkyl substitution;
B 1 is C 2-4 An alkylene group;
R 11 and R is 12 Each independently H, C 1-8 Alkyl, halogen or C 1-8 A haloalkyl group;
R 13 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 13 The attached N is attached to the 6 th position of the benzisoxazole;
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
150. A compound of formula (T):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
B 2 is C 2-4 An alkylene group;
R 20 is C 1-8 An alkyl group;
R 21 and R is 22 Each independently H, C 1-8 Alkyl, halogen or C 1-8 A haloalkyl group;
R 23 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 23 The attached N is attached to the 6 th position of the benzisoxazole;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
151. A compound of formula (U):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 2 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 3 、R 4 、R 5 and R is 6 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
x is oxygen, sulfur or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl having C 6-10 Aryl moiety and C 1-8 Aralkyl group of alkylene moiety, C 2-8 Acyl or C 2-8 Alkenyl groups;
y is oxygen, sulfur, NR 8 Or a bond, wherein R 8 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
p is 0 or 1;
when bond a is present, A is oxygen CH 2 、N-NH 2 OR N-OR 9 Wherein R is 9 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, a is OH;
in the case of p=1, B is a benzene ring with or without substituents halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, or having C 6-10 An aryl moiety and an aralkyl group of a C1-C8 alkylene moiety of 1-8 carbon atoms, and, in the case of p=0, B is a fused ring which is indole, benzofuran, benzisoxazole or 1, 2-benzisothiazole, wherein the fused ring is with or without a substituent which is
Halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C with C1-C8 alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy groups, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
y is bonded with the benzene ring of B;
(C(R 3 )(R 4 )) m a fused ring to B is bonded at its 3 position;
m is an integer from 1 to 4;
n is 0, 1,2, 3, 4 or 5;
in the case of n=0, Y is a bond;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
152. A compound of embodiment 151 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of a compound wherein bond a is absent and a is OH.
153. A compound of embodiment 151 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and a is oxygen.
154. A compound of formula (V):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 12 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 13 、R 14 、R 15 and R is 16 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 1 is oxygen, sulfur and NR 18 Or a bond, wherein R 18 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
when bond a is present, A 1 Is oxygen CH 2 、N-NH 2 OR N-OR 19 Wherein R is 19 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, A 1 OH;
Q 1 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
r is 1, 2, 3 or 4;
s is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
155. Description of the embodiments154 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound, wherein bond a is absent and A 1 Is OH.
156. A compound of embodiment 154 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound wherein a bond a is present and a 1 Is oxygen.
157. A compound of formula (W):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 22 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 23 、R 24 、R 25 and R is 26 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 2 is oxygen, sulfur and NR 28 Or a bond, whereinR 28 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
Q 2 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
t is 1, 2, 3 or 4;
u is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
158. A compound of formula (X):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
159. A compound of formula (Y):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
/>
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
160. A compound of formula (Z):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
161. The compound of any one of embodiments 158 to 160 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 Is CH 3 。
162. The compound of any one of embodiments 158 to 161 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein Q 1 CH.
163. The compound of any one of embodiments 158 to 161 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein Q 1 Is N.
164. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is halogen, -C 1 -С 4 -alkyl group 、 -С 1 -С 4 -haloalkyl, -C 1 -С 4 -haloalkoxy, -S (C) 1 -С 4 -alkyl) or furyl, wherein the furyl group may optionally be-c 1 -С 4 -alkyl substitution.
165. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is halogen, -CH 3 、-C 1 -haloalkyl, -C 1 -haloalkoxy, -SCH 3 Or furyl, wherein furyl may optionally be-CH 3 And (3) substitution.
166. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is halogen, -CH 3 、-C 1 -haloalkyl, -C 1 -haloalkoxy ， or-SCH 3 。
167. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is chloro, unsubstituted furyl, -CH 3 、-CF 3 、-OCF 3 、-OCHF 2 or-SCH 3 。
168. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 is-CF 3 or-OCF 3 。
169. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 is-CF 3 。
170. The compound of any one of embodiments 158 to 169 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 Is hydrogen or halogen.
171. The compound of any one of embodiments 158 to 170 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 Is hydrogen or fluorine.
172. The compound of any one of embodiments 158 to 171 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein each R 20 Independently hydrogen or halogen.
173. The compound of any one of embodiments 158 to 171 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 20 Is hydrogen or fluorine.
174. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 Is hydrogen or fluorine, R 2 For C 1 -С 4 -haloalkyl or C 1 -С 4 -haloalkoxy, R 20 Is hydrogen and x is an integer having a value of 1.
175. The compound of any one of embodiments 158 to 163 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 Is hydrogen, R 2 Is trifluoromethyl or trifluoromethoxy, R 20 Is hydrogen and x is an integer having a value of 1.
176. A compound of formula (AA):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
l is (CH) 2 ) 5 Which is unsubstituted or substituted by one methyl group;
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl),5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, C.ident.C-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 0 or 1;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
R 3 is C 1-4 Haloalkyl, NO 2 CN, halogen or C (O) O (C) 1-4 An alkyl group);
R 20 is hydrogen, halogen or C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
Each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
177. A compound of embodiment 176 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound having the formula
178. A compound of embodiment 176 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound having the formula
179. The compound of any one of embodiments 176 to 178 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 Is halomethyl, CN or halogen.
180. The compound of any one of embodiments 176 to 178 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 3 Is CF (CF) 3 Cl or CN.
181. The compound of any one of embodiments 176 to 180 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is hydrogen, halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkyl, S (C) 1 -C 4 -alkyl) or furyl, wherein the furyl may optionally be C 1 -C 4 -alkyl substitution; and x is 0 or 1.
182. The compound of any one of embodiments 176 to 180 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 Is H, halogen, CN, CH 3 A halomethyl, halomethoxy, methoxy or furyl group, wherein the furyl group may optionally be CH 3 Substitution; and R is 20 Methyl or halogen.
183. The compound of any one of embodiments 176 to 180 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 2 H, F, cl, CN, CF of a shape of H, F, cl, CN, CF 3 、OCF 3 Or furyl; and is combined withAnd x is 0.
184. The compound of any one of embodiments 176 to 183 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R 1 Is hydrogen.
185. The compound of any one of embodiments 176 to 184 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound, wherein R 1 Is hydrogen or fluorine.
186. The compound of any one of embodiments 1 to 185 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein R X Is CH 2 OH, COH or COOCH 2 CONR 4 R 5 。
187. A compound of embodiment 186 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein R X Is CH 2 OH。
188. A compound of any one of embodiments 1 to 187 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of such a compound wherein n is 0 when dependent on any one of embodiments 1 to 151.
189. A compound of any one of embodiments 1 to 187, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound, wherein n is 1 when dependent on any one of embodiments 1 to 151.
190. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
191. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
192. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
193. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
194. The compound of embodiment 158 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound Or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
195. A compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
196. A compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
197. A compound selected from the compounds shown in table 1 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
198. A compound selected from the compounds shown in table 2 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
199. A compound selected from the compounds shown in table 3 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
200. A compound selected from the compounds shown in table 4 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
201. A compound selected from the compounds shown in table 5 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
202. A compound selected from the compounds shown in table 6 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
203. A compound selected from the compounds shown in table 7 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
204. A compound selected from the compounds shown in table 8 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
205. A compound selected from the compounds shown in table 9 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
206. A compound selected from the compounds shown in table 10 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof
207. A compound selected from the compounds shown in table 11 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
208. A compound of any one of embodiments 1 through 207 or a pharmaceutically acceptable salt of the compound.
209. A pharmaceutically acceptable salt of the compound of any one of embodiments 1 to 207, which is an alkali metal salt, optionally a sodium or potassium salt.
210. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound, and a pharmaceutically acceptable carrier or vehicle.
211. The pharmaceutical composition of embodiment 210, further comprising a second therapeutically active agent.
212. A pharmaceutical composition of embodiment 211, wherein the second therapeutically active agent is a lipid lowering agent, a statin, a cholesterol absorption inhibitor, an anti-PCSK 9 antibody, siRNA PCSK9, an anti-fibrotic agent, a thyroid hormone, a selective thyroid receptor- β agonist, an inhibitor of apoptosis signal-regulating kinase 1 (ASK 1), an inhibitor of Acetyl Coa Carboxylase (ACC), an integrin antagonist, or a non-steroidal Farnesoid X Receptor (FXR) agonist.
213. The pharmaceutical composition of embodiment 212, wherein the lipid-lowering drug is gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, etoxytheophylline, pirfibrate, gemfibrofibrate or baclofibrate Ma Beite; the statin is atorvastatin, simvastatin, pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, dalvastatin, dihydrocompactin or cerivastatin, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof; the cholesterol absorption inhibitor is ezetimibe; the anti-PCSK 9 antibody is ebo You Shan anti-aliskirumab, bococizumab, 1D05-IgG2, RG7652, LY3015014 or LGT-209; siRNA PCSK9 is inclisiran; the anti-fibrotic agent is a nitrozolamide, a tizoxanide, or a tizoxanide glucuronide, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof; the selective thyroid receptor-beta agonist is VK2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT, ZYT1, MB-0781 or irinotecan; ASK1 inhibitor is ste Long Se; the ACC inhibitor is first ocostat; integrin antagonists are α5β1 inhibitors or ubiquitin inhibitors; or the FXR agonist is cilofexor.
214. A method for treating or preventing liver disorders, dyslipidemia, a kidney disease, a glucose metabolic disorder, a lipid metabolic disorder, a carbohydrate metabolic disorder, a cardiovascular disease, a vascular disease, a metabolic syndrome, a complication associated with a metabolic syndrome, a PPAR-related disorder, sepsis, a thrombotic disorder, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, a cerebrovascular disease, a disorder associated with neovascularization, hypertension, cancer, inflammation, an inflammatory disease, a neurodegenerative disease, an autoimmune disease, a neoplastic disease, muscle atrophy, cholestasis, mitochondrial dysfunction, an ocular disease, a lysosomal storage disease, kidney disease, or impotence, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
215. The method of embodiment 214, wherein the liver disorder involves pathological destruction, inflammation, degeneration, apoptosis, or proliferation of hepatocytes.
216. The method of embodiment 214, wherein the liver disorder is liver fibrosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
217. The method of embodiment 214, wherein the dyslipidemia is hyperlipidemia or abnormally low concentrations of high density lipoprotein cholesterol (HDL-C) in the plasma or serum of the subject.
218. The method of embodiment 217, wherein the hyperlipidemia is hypercholesterolemia, familial hypercholesterolemia, hypertriglyceridemia, or familial mixed hyperlipidemia.
219. The method of embodiment 217, wherein the hyperlipidemia is characterized by abnormally reduced or absent levels or activity of lipoprotein lipase in the plasma or serum of the subject, or abnormally high concentrations of ketone bodies, lipoprotein (a) cholesterol (Lp (a) -C), low-density lipoprotein (LDL), very low-density lipoprotein cholesterol (VLDL-C), or non-esterified fatty acids in the plasma or serum of the subject.
220. The method of embodiment 219, wherein the reduced or absent lipoprotein lipase level or activity is the result of a mutation in a gene encoding a lipoprotein lipase.
221. The method of embodiment 214, wherein the dyslipidemia is characterized by an abnormally high concentration of LDL, apolipoprotein (a) or VLDL in the plasma or serum of the subject, or an abnormally low concentration of High Density Lipoprotein (HDL) or lipoprotein lipase in the plasma or serum of the subject.
222. The method of embodiment 221, wherein the abnormally low concentration of lipoprotein lipase is associated with: mutations in lipoprotein lipase, hypoalphalipoproteinemia, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, lipoprotein abnormalities associated with Alzheimer's disease, or familial mixed hyperlipidemia.
223. The method of embodiment 214, wherein the kidney disease is glomerular disease, tubular interstitial disease, acute or rapidly progressive renal failure, chronic renal failure, kidney stones or tumors.
224. The method of embodiment 223, wherein: glomerular diseases are acute glomerulonephritis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal proliferative glomerulonephritis, glomerular lesions associated with systemic diseases, goodpasture's syndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease or chronic inflammatory diseases; the tubular disease is acute tubular necrosis, acute renal failure, polycystic kidney disease, medullary sponge kidney, medullary cystic disease, nephrogenic diabetes or tubular acidosis; the renal tubule interstitial disease is nephropyelitis, drug or toxin induced renal tubule interstitial nephritis, hypercalcemic nephropathy or hypokalemic nephropathy; or the tumor is a renal cell carcinoma or a wilms' tumor.
225. The method of embodiment 224, wherein the glomerulopathy associated with the systemic disease is systemic lupus erythematosus.
226. The method of embodiment 214, wherein the kidney disease is hypertension, renal sclerosis, microangiopathy hemolytic anemia, atherosclerotic kidney disease, diffuse cortical necrosis, or renal infarction.
227. The method of embodiment 226, wherein the hypertension is primary hypertension, hyperpiersis, malignant hypertension, secondary hypertension, or white coat hypertension.
228. The method of embodiment 214, wherein the glucose metabolism disorder is impaired glucose tolerance; insulin resistance; insulin resistance-associated breast, colon or prostate cancer; diabetes mellitus; pancreatitis; hypertension; polycystic ovarian disease; or abnormally high concentrations of blood insulin or glucose in the plasma or serum of the subject.
229. The method of embodiment 228, wherein the diabetes is non-insulin dependent diabetes mellitus (NIDDM), insulin Dependent Diabetes Mellitus (IDDM), gestational Diabetes Mellitus (GDM), or juvenile onset adult-onset diabetes (MODY).
230. The method of embodiment 214, wherein the vascular disease or cardiovascular disease is peripheral vascular disease, coronary heart disease, stroke, restenosis, arteriosclerosis, ischemia, endothelial dysfunction, ischemia reperfusion injury, myocardial infarction, or cerebral infarction.
231. The method of embodiment 214, wherein the PPAR-related disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, breast cancer, colon cancer or prostate cancer.
232. The method of embodiment 214, wherein the PPAR-related disorder is a vascular disease, a muscle disease, a demyelinating disease, a muscle structure disorder, a neuron activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a mitochondrial dysfunction, a β -oxidation disease, or a metabolic disease.
233. The method of embodiment 232, wherein: muscle disease is muscular dystrophy; demyelinating diseases are multiple sclerosis, summer-Mary-Chart disease, pet Li Zawu S-Mzhibach disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy or Guillain-Barre syndrome; muscle structural disorders are bezame myopathy, central nuclear heart disease, congenital fiber imbalance, distal Muscular Dystrophy (MD), duchenne and beck MD, emery-derifer MD, facial scapular MD, homogeneous body myopathy, limb band MD, muscle sodium channel disorder, tonic cartilage dystrophy, tonic muscular dystrophy, myotube myopathy, line-like body disorders, ocular pharynx MD or stress urinary incontinence; the neuronal activation disorder is amyotrophic lateral sclerosis, mary-Chart disease, guillain-Barre syndrome, lanbert-Eton syndrome, multiple sclerosis, myasthenia gravis, nerve injury, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve paralysis, or toxic muscular disorder; muscle fatigue disorders are chronic fatigue syndrome, diabetes (type I or type II), glycogen storage disease, fibromyalgia, friedel's ataxia, intermittent claudication, lipid deposition myopathy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like attacks) syndrome, mucopolysaccharidosis, pompe disease or thyrotoxic myopathy; muscle mass disorders are cachexia, cartilage degeneration, cerebral palsy, fascial syndrome, critical myopathy, inclusion body myositis, muscle atrophy (disuse), sarcopenia, steroid myopathy or systemic lupus erythematosus; mitochondrial diseases are alper's disease, chronic progressive extraocular muscle paralysis (CPEO), kanns-sal syndrome (KSS), leber Hereditary Optic Neuropathy (LHON), MELAS, myoclonus epilepsy and broken red fiber disease (MERRF), neurogenic muscle weakness (NARP), ataxia, retinitis pigmentosa, pearson syndrome, mitochondrial dysfunction or loss of mitochondrial function; beta oxidation disease is systemic carnitine transporter, carnitine Palmitoyl Transferase (CPT) II deficiency, very long chain acyl-coa dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium chain acyl-coa dehydrogenase (MCAD) deficiency, short chain acyl-coa dehydrogenase (SCAD) deficiency or riboflavin-reactive beta-oxidation disorder (RR-MADD); or metabolic diseases are hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypercholesterolemia, LDL hypercholesterolemia, HLD non-cholesterol, VLDL hyperproteinemia, dyslipidemia, apolipoprotein a-I hypoproteinemia, atherosclerosis, arteriosclerotic diseases, cardiovascular diseases, cerebrovascular diseases, peripheral circulation diseases, metabolic syndrome, syndrome X, obesity, diabetes mellitus type I, diabetes type II, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, cardiac insufficiency, myocardial infarction, cardiomyopathy, hypertension, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), thrombosis, alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, hair morbidity, inflammation, arthritis, asthma, allergic bowel syndrome, ulcerative colitis, or pancreatitis.
234. The method of embodiment 233, wherein the muscular dystrophy is duchenne muscular dystrophy, becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facial shoulder humeral muscular dystrophy, tonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, or emery-debifs muscular dystrophy.
235. The method of embodiment 214, wherein the PPAR related disorder is abnormally low concentration of HDL, abnormally low concentration of apolipoprotein A-I (apo A-I), abnormally high concentration of VLDL-C, abnormally high concentration of low density lipoprotein cholesterol (LDL-C), abnormally high concentration of triglycerides, abnormally high concentration of apolipoprotein B (apo B), abnormally high concentration of apolipoprotein C-III (apo C-III), or abnormally reduced proportion of post-heparin hepatic lipase: lipoprotein lipase activity in the plasma or serum of the subject.
236. The method of embodiment 214, wherein the PPAR-related disorder is abnormally high levels of HDL or abnormally low levels of apo a-I in the lymph or brain fluid of the subject.
237. The method of embodiment 214, wherein the obesity is abdominal obesity.
238. The method of embodiment 214, wherein the cerebrovascular disease is cerebral ischemia.
239. The method of embodiment 214, wherein the disorder associated with neovascularization is retinopathy or diabetes.
240. The method of embodiment 214, wherein the cancer is human sarcoma or human carcinoma.
241. The method of the embodiment 214 is carried out, wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, oral cancer, nasal cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary gland cancer, cyst gland cancer, medullary carcinoma, bronchi cancer, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma medulloblastoma, craniopharyngeal medulloma, ependymoma, pineal tumor, angioblastoma, auditory neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute non-lymphoblastic leukemia, acute undifferentiated leukemia, chronic myelogenous leukemia, hairy cell leukemia, lymphoblastic leukemia, granulocytic leukemia, lymphoblastic leukemia, myelogenous leukemia, polycythemia vera, multiple myeloma, lymphoma, hodgkin's disease, non-hodgkin's lymphoma, megaloblastic Fahrenheit or heavy chain disease.
242. The method of embodiment 241, wherein the leukemia is acute or chronic lymphocytic leukemia, myelogenous leukemia, lymphocytic leukemia or myelogenous leukemia.
243. The method of embodiment 242, wherein the myelogenous leukemia is acute and is myeloblasts, promyelocytes, myelomonocytes, monocytes or leukemia cells.
244. The method of embodiment 242, wherein the lymphoma is hodgkin's lymphoma or non-hodgkin's lymphoma.
245. The method of embodiment 214, wherein the inflammatory disease is multiple sclerosis, chronic inflammatory disorders of the joints, arthritis, respiratory distress syndrome, inflammatory bowel disease, inflammatory lung disorder, inflammatory disorders of the gums, tuberculosis, leprosy, inflammatory diseases of the kidneys, inflammatory disorders of the skin, inflammatory diseases of the central nervous system, systemic Lupus Erythematosus (SLE) or inflammatory diseases of the heart.
246. The method of embodiment 245, wherein: arthritis is rheumatoid arthritis or osteoarthritis; inflammatory bowel disease is ileitis, ulcerative colitis or crohn's disease; inflammatory pulmonary disorders are asthma or chronic obstructive airways diseases; inflammatory disorders of the eye are corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathogenic ophthalmia, or endophthalmitis; inflammatory disorders of the gums are periodontitis or gingivitis; inflammatory disorders of the kidney are glomerulonephritis or kidney disease; inflammatory disorders of the skin are acne, sclerodermatitis, psoriasis, eczema, photoaging or wrinkles; inflammatory diseases of the central nervous system are AIDS-related neurodegenerative diseases, stroke, neurotrauma, alzheimer's disease, encephalomyelitis, or viral or autoimmune encephalitis; or the inflammatory disease of the heart is cardiomyopathy.
247. The method of embodiment 214, wherein the neurodegenerative disease is alzheimer's disease or huntington's disease.
248. The method of embodiment 214, wherein the autoimmune disease is immune complex vasculitis, systemic lupus, or erythema.
249. The method of embodiment 214, wherein the neoplastic disease is carcinogenesis.
250. The method of embodiment 214, wherein cholestasis is an intrahepatic cholestasis disease or an extrahepatic cholestasis disease.
251. The method of embodiment 250, wherein the intrahepatic cholestasis disease is primary cholangitis (PBC), primary Sclerosing Cholangitis (PSC), progressive Familial Intrahepatic Cholestasis (PFIC), or Alagille Syndrome (AS).
252. The method of embodiment 214, wherein the ocular disease is dry eye, meibomian gland dysfunction, keratoconjunctival epithelial disorder, corneal epithelial disorder, or corneal ulcer.
253. The method of embodiment 214, wherein the lysosomal storage disorder is neuronal ceroid lipofuscinosis, alzheimer's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), parkinson's disease, multiple System Atrophy (MSA), progressive Supranuclear Palsy (PSP), corticobasal degeneration (CBD), dementia with lewy bodies (DLB), autophagy pathway disorders, tai-saxophone disease, fabry disease, niemann-pick disease, gaucher's disease, hunter's syndrome, alpha-mannosidosis, aspartyl glucosaminuria, cholesterol ester storage disease, chronic aminohexosidase a deficiency, cystine disease, darner's disease, farber disease, fucosidosis, galactosialidosis, or barton disease.
254. The method of embodiment 214, wherein the kidney disease is renal ischemia reperfusion injury.
255. The method of embodiment 214, wherein the impotence is caused by nerve injury, arterial injury, smooth muscle injury, or fibrous tissue injury; diabetes mellitus; kidney disease; alcoholism; multiple sclerosis; atherosclerosis; vascular disease; or a neurological disease.
256. A method for treating or preventing hyperlipidemia, hyperlipidaemia, hyperlipoproteinaemia, hypercholesteraemia, hypertriglyceridaemia or dyslipidemia comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
257. The method of embodiment 256, wherein the hypercholesterolemia is homozygous familial hypercholesterolemia.
258. A method for treating a subject having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, or preventing a subject from having an abnormally high concentration of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of the subject, comprising administering to the subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
259. A method for treating a subject having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject or preventing a subject from having an abnormally low concentration of High Density Lipoprotein (HDL) in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
260. A method for treating a subject having or preventing a subject having or having a aberrant decrease or deficiency in lipoprotein lipase concentration or activity in the plasma or serum of the subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
261. The method of embodiment 260, wherein the reduced level or activity of lipoprotein lipase or the absence of is the result of a mutation in a gene encoding a lipoprotein lipase.
262. A method for treating or preventing hypoalphalipoproteinemia, a lipoprotein abnormality associated with diabetes, a lipoprotein abnormality associated with obesity, a lipoprotein abnormality associated with alzheimer's disease, or familial mixed hyperlipidemia comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
263. A method for reducing abnormally high concentrations of triglycerides, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) (Lp (a)), the ratio of apolipoprotein B, HDL/(vldl+ldl), apolipoprotein C-II or apolipoprotein C-III in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
264. A method for increasing abnormally low concentrations of High Density Lipoprotein (HDL) -associated protein, HDL-cholesterol, apolipoprotein a-I, or apolipoprotein E in the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
265. The method of embodiment 264, wherein the HDL-related protein is an apolipoprotein A-I (apo A-I), an apolipoprotein A-II (apo A-II), an apolipoprotein A-IV (apo A-IV), or an apolipoprotein E (apo E).
266. A method for promoting the clearance of triglycerides from the plasma or serum of a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
267. A method for increasing abnormally low glucose metabolism or lipid metabolism in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
268. The method of embodiment 267, wherein the method for increasing abnormally low glucose metabolism increases insulin sensitivity or oxygen consumption in the subject, or decreases blood insulin, blood glucose, or glycosylated hemoglobin in the plasma or serum of the subject.
269. The method of embodiment 267, wherein the method for increasing abnormally low lipid metabolism reduces the concentration of LDL or free triglycerides in the plasma or serum of the subject, or inhibits saponified or non-saponified fatty acid synthesis.
270. A method for treating or preventing a symptom of a disease selected from inflammation, systemic lupus erythematosus, lupus nephritis, or arthritis, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of the compound.
271. The method of embodiment 270, wherein the arthritis is adjuvant arthritis or type II collagen-induced arthritis.
272. The method of embodiment 270, wherein the symptom is nephritis, renal failure or reduced renal function.
273. A method for reducing the fat content of livestock meat comprising administering to livestock an effective amount of a compound of any of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
274. A method for reducing the cholesterol content of an avian egg comprising administering to the avian an effective amount of a compound of any one of embodiments 1 to 207, or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug of such a compound.
275. A method for treating a subject having or at risk of Acute Kidney Injury (AKI) comprising administering to the subject (i) an effective amount of a compound of any one of embodiments 1 to 207 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or (ii) the pharmaceutical composition of embodiment 210 or embodiment 211.
276. The method of embodiment 275, wherein (i) the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or (ii) the pharmaceutical composition is administered intravenously, optionally wherein the method comprises intravenous administration once daily, optionally for three days.
277. The method of embodiment 275, wherein the (i) compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or (ii) pharmaceutical composition is administered orally.
278. The method of any one of embodiments 275 to 277, wherein AKI is sepsis-related AKI.
279. The method of any one of embodiments 275 to 277, wherein AKI is ischemia/reperfusion AKI.
280. The method of any one of embodiments 275 to 277, wherein AKI is from acute interstitial nephritis.
281. The method of any one of embodiments 275 to 277, wherein AKI is from glomerular kidney disease.
282. The method of any one of embodiments 275 to 277, wherein AKI is from acute vascular inflammatory kidney disease.
283. The method of any one of embodiments 275 to 277, wherein AKI is from ischemia.
284. The method of any one of embodiments 275 to 277, wherein AKI is from a toxic injury.
285. The method of any one of embodiments 275 to 277, wherein AKI is from prerenal azotemia.
286. The method of any one of embodiments 275 to 277, wherein AKI is from acute postrenal destructive kidney disease.
287. The method of any one of embodiments 275 to 277, wherein AKI is from diabetes.
288. The method of any one of embodiments 275 to 277, wherein AKI is from potential renal insufficiency.
289. The method of any one of embodiments 275 to 277, wherein AKI is from nephritis syndrome.
290. The method of any one of embodiments 275 to 277, wherein AKI is from an atherosclerotic disease.
291. The method of any one of embodiments 275 to 277, wherein AKI is from hypotension.
292. The method of any one of embodiments 275 to 277, wherein AKI is from hypoxia.
293. The method of any one of embodiments 275 to 277, wherein AKI is from myoglobin urine-hematuria.
294. The method of any one of embodiments 275 to 277, wherein AKI is from a liver disease.
295. The method of any one of embodiments 275 to 277, wherein AKI is secondary to a viral infection, optionally wherein the viral infection is covd-19.
296. The method of embodiment 295, wherein the subject has a viral infection, optionally wherein the viral infection is covd-19.
297. The method of claims 275 to 278, wherein the subject has sepsis.
298. The method of embodiment 296, wherein the sepsis is associated with a gram-negative bacterial infection.
299. The method of embodiment 297 or embodiment 298, wherein the subject has an intraperitoneal infection.
300. The method of embodiment 297 or embodiment 298, wherein the subject has urine sepsis.
301. The method of any one of embodiments 275 to 300, wherein the subject is an elderly human.
302. The method of any one of embodiments 275 to 301, wherein the subject is a surgical patient.
303. The method of embodiment 302, wherein the surgical patient has undergone cardiovascular surgery, optionally it is Coronary Artery Bypass Graft (CABG) surgery and/or heart valve surgery.
304. The method of any one of embodiments 275 to 300, wherein the subject is pregnant.
305. The method of any one of embodiments 275 to 304, wherein the subject has been exposed to a nephrotoxic agent.
306. The method of embodiment 305, wherein the nephrotoxic agent comprises cisplatin, gentamicin, pioneermycin, cyclosporine, amphotericin, carbon tetrachloride, trichloroethylene, dichloroacetylene, or a combination thereof.
307. The method of any one of embodiments 275 to 306, wherein the subject has AKI.
308. The method of embodiment 307, wherein the effective amount is effective to reduce the severity of AKI.
309. The method of any one of embodiments 275 to 306, wherein the subject is at risk of AKI.
310. The method of any one of embodiments 275 to 306, wherein the subject is at risk of AKI after cardiovascular surgery, optionally the cardiovascular surgery is Coronary Artery Bypass Graft (CABG) surgery and/or heart valve surgery.
311. The method of embodiment 309 or embodiment 310, wherein the effective amount is effective to reduce the likelihood of the subject developing AKI in the future.
312. The method of any of embodiments 309-311, wherein the effective amount is effective to delay the onset of AKI.
313. The method of any one of embodiments 309-311, wherein the effective amount is effective to prevent AKI.
314. The method of any of embodiments 309-311, wherein if the subject develops AKI, the effective amount is effective to reduce the severity of AKI.
315. The method of any one of embodiments 275 to 314, wherein the subject has a SOFA score of 1 to 4 prior to administration of the compound or pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound or the pharmaceutical composition.
316. The method of embodiment 315, wherein the subject has a SOFA score of 2 to 4 prior to administration.
317. The method of embodiment 315, wherein the subject has a SOFA score of 1 prior to administration.
318. The method of embodiment 315, wherein the subject has a SOFA score of 2 prior to administration.
319. The method of embodiment 315, wherein the subject has a SOFA score of 3 prior to administration.
320. The method of embodiment 315, wherein the subject has a SOFA score of 4 prior to administration.
321. The method of any one of embodiments 275 to 320, wherein the subject has an endotoxin activity level of ≡0.6 prior to administration.
322. The method of any one of embodiments 275 to 321, wherein the effective amount is effective to reduce the level of endotoxin activity in the subject.
8. Incorporated by reference
All publications, patents, patent applications, and other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, and patent application or other document were individually indicated to be incorporated by reference. If there is any inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, it is intended that the teachings of the present specification shall control.

Claims (47)

1. A compound of formula (C):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is phenyl, naphthyl, pyridinyl, thienyl, furyl, quinolinyl or benzothienyl, any of which is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
R 2 Is C 2-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl or C substituted by phenyl, naphthyl or pyridyl 1-6 Alkyl, any of which is unsubstituted or C-substituted, said phenyl, naphthyl or pyridinyl 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl substituents;
a is oxygen, sulfur or NR 9 Wherein R is 9 Is hydrogen or C 1-8 An alkyl group;
x is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy or hydroxy substituted and having 0 or 1 double bond;
y is C (=O), C (=N-OR 10 )、CH(OR 11 ) Ch=ch, c≡c or C (=ch 2 ) Wherein R is 10 And R is 11 Each hydrogen or C 1-8 An alkyl group;
R 3 、R 4 and R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, halogen, C 2-7 Acyl, benzoyl, hydroxy, nitro, amino, phenyl or pyridyl; optionally, wherein R 3 、R 4 And R is 5 At least one of which is other than hydrogen;
b is CH or nitrogen;
z is oxygen or sulfur;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
2. A compound of formula (D):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 and R is 2 Each independently is hydrogen, halogen, nitro, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, optionally substituted C 6-10 Aryl, with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkyl moieties, heterocyclic groups or having C 1-8 A heterocycloalkyl group of an alkyl group;
R 3 、R 4 and R is 5 Each occurrence is independently hydrogen or C 1-8 An alkyl group;
a is an oxygen atom, a sulfur atom or NR 3 ；
X 1 、X 2 And Z are each independently C (=o), C (=o) NH, C (=n-OR 4 )、CH(OR 5 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c≡c, or a bond; and
y is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
3. A compound of formula (E):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 and R is 12 Each independently is hydrogen, halogen, nitro, hydroxy, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl group, C with 1 to 3 halogens 1-8 Haloalkoxy groups, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl, C with 3-7 membered cycloalkyl substituent 1-8 An alkyl group, or a phenyl group, a naphthyl group, a benzyl group, a phenethyl group, a pyridyl group, a thienyl group, a furyl group, a quinolyl group or a benzothienyl group which may be substituted, the substituent being a halogen atom, a nitro group,Hydroxy, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C with 1 to 3 halogens 1-8 Haloalkyl, C with 1 to 3 halogens 1-8 Haloalkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-7 membered cycloalkyl group, C with 3-7 membered cycloalkyl substituent 1-8 An alkyl group, phenyl or pyridyl;
X 1 and Z 1 Each independently is C (=o), C (=o) NH, C (=n-OR 14 )、CH(OR 15 )、NH(C＝O)、NHSO 2 、SO 2 NH, ch=ch, c=c or bond, wherein R 14 And R is 15 Each hydrogen or C 1-8 An alkyl group;
Y 1 is C 1-8 An alkylene group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
4. A compound of formula (F):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is O, S or NR 7 Wherein R is 7 Is hydrogen or C 1-8 An alkyl group;
B 1 is CW or N, wherein W is hydrogen or a bond; b (B) 2 O, S or NR 8 Wherein R is 8 Is hydrogen or C 1-8 An alkyl group;
X 1 and X 2 Each O, S, NH, NHC (=o), C (=n-OR 9 )、CH(OR 10 ) C= C, C ≡c or bond, wherein R 9 And R is 10 Each hydrogen or C 1-8 An alkyl group;
y is C 1-8 Alkylene which is unsubstituted or C 1-8 Alkyl or C with 1-3 halogens 1-8 Haloalkyl substitution;
z is NH, O or S;
R 1 is aryl, which is unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl or halogen substitution, or R 1 Is a heterocyclic group having a five to eight membered ring containing 1 to 3 heteroatoms, wherein each of the heteroatoms is independently nitrogen, oxygen or sulfur and the other atoms are carbon, optionally wherein a benzene ring is fused to the heterocyclic ring;
R 2 is C 2-8 Alkyl, C with 1-3 halogens 1-8 Haloalkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C substituted by aryl 1-4 Alkyl, said aryl being unsubstituted or C 1-8 Alkyl, C 1-8 Alkoxy, C with 1-3 halogens 1-8 Haloalkyl, hydroxy, nitro, amino, phenyl, pyridyl or halogen substituted, or C substituted by a heterocyclic group having a five to eight membered ring containing 1 to 3 heteroatoms 1-4 Alkyl, each of said heteroatoms being independently nitrogen, oxygen or sulfur;
R 3 is halogen, trifluoromethyl, C 1-8 Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl;
R 4 and R is 5 Each is hydrogen, C 1-8 Alkyl groupOr C having 1-3 halogens 1-8 A haloalkyl group;
z and R 3 Each being attached to a benzene ring, and X 2 Not attached to the benzene ring;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
5. A compound of formula (G):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 and R is 4 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 2 is hydrogen;
R 3 is C 1-8 Alkyl, or R 3 And R is R 2 Bonding forms=o or=c (R 7 )(R 8 ) Wherein R is 7 And R is 8 Is the same asOr differently, each of which is hydrogen or C 1-8 An alkyl group;
R 5 and R is 6 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl, C 1-8 A haloalkyl group;
x and Y are the same or different and each represents CH or N;
z is oxygen or sulfur;
a is a 5-membered heterocyclic group which is pyrazole, thiophene, furan or pyrrole, wherein the heterocyclic group is unsubstituted or substituted C 1-8 Alkyl substitution, the substituent is C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-to 7-membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 An aralkyl group of an alkylene moiety, or a 5-or 6-membered heterocyclyl group;
b is C 1-8 Alkylene chain, which is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution, in the case of alkylene groups having 2 to 6 carbon atoms, said alkylene groups optionally having double bonds;
q is 0, 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
6. A compound of formula (H):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 and R is 13 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 12 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 14 and R is 15 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 1 CH or N;
Z 1 is oxygen or sulfur;
when bond a is present, W 1 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 1 OH;
q is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
7. A compound of formula (J):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 and R is 23 Are identical or different and are each hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 22 is hydrogen, C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-to 7-membered cycloalkyl group substituents 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, orC having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 24 and R is 25 Are identical or different and are each a hydrogen atom, C 1-8 Alkyl or C 1-8 A haloalkyl group;
X 2 CH or N;
Z 2 Is oxygen or sulfur;
when bond a is present, W 2 Is oxygen or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When there is no bond a, W 2 OH;
r is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
8. A compound of formula (K):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
a is CH or nitrogen;
when bond a is present, B is oxygen or C (R 8 )(R 9 ) Wherein R is 8 And R is 9 Each of which is a single pieceIndependently hydrogen or C 1-8 An alkyl group; when bond a is absent, B is OH;
W 1 is a bond, C (=O) or (C (R) 10 )(R 11 )) m Wherein R is 10 And R is 11 Each independently is hydrogen or C 1-8 An alkyl group and m is 1, 2 or 3;
x and Y are different from each other and are each an oxygen atom, a sulfur atom, a nitrogen atom or CR 12 Wherein R is 12 Is hydrogen or C 1-8 An alkyl group;
Z 1 is a bond, oxygen, sulfur or C (R) 13 )(R 14 ) Wherein R is 13 And R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
R 1 、R 2 and R is 3 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 4 And R is 5 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R 6 and R is 7 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 1-8 A haloalkyl group;
r is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
9. A compound of formula (L):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, B is oxygen; when bond a is absent, B is OH;
W 2 is a bond, C (=O) or CH 2 ；
Z 2 Is oxygen or sulfur;
R 21 、R 22 and R is 23 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 A haloalkyl group; c (C) 1-8 Haloalkoxy groups; hydroxy, nitro, C 2-8 Acyl group, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
R 24 and R is 25 Each independently is hydrogen, C 1-8 Alkyl, C 1-8 A haloalkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、/>
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
10. A compound of formula (M):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is nitrogen or CH;
x is nitrogen or CH;
y is oxygen or sulfur;
z is a bond, oxygen, sulfur or NR 5 Wherein R is 5 Is hydrogen or C 1-8 An alkyl group;
R 1 and R is 2 Each independently is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl radical of alkylene, or C with 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 3 and R is 4 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
a is a 5-membered heterocyclic ring which is pyrazole, thiophene, furan, isoxazole, isothiazole or pyrrole, wherein the 5-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, 3-to 7-membered cycloalkyl group, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5-or 6-membered heterocyclic group, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
b is a bond or C 1-8 Alkylene group, the C 1-8 Alkylene is unsubstituted or C 1-8 Alkyl, 3-to 7-membered cycloalkyl, C 1-8 Alkoxy or halogen substituents, optionally wherein said C 1-8 Alkylene has a double bond or a triple bond;
r is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
11. A compound of formula (N):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 3 is nitrogen or CH;
Z 1 is oxygen or sulfur;
R 11 and R is 12 Each of which is a single pieceIndependently hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Haloalkoxy groups;
R 13 and R is 14 Each independently is hydrogen or C 1-8 An alkyl group;
A 1 is a five-membered heterocyclic ring which is pyrazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or substituted by halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl or C 1-8 Haloalkoxy substitution;
m is 2, 3 or 4;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
12. A compound of formula (O):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or nitrogen;
x is NR 5 Or CR (CR) 6 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 5 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C 3-7 Cycloalkyl, quilt C 3-7 Cycloalkyl-substituted C 1-8 Alkyl, C substituted by phenyl 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl, and R 6 And R is 7 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 8 R 9 ) r Wherein R is 8 And R is 9 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4; or alternatively
X and Y combine to form CR 10 ＝CR 11 Or ethynylene group, wherein R 10 And R is 11 Each independently is hydrogen or C 1-8 An alkyl group;
when bond a is present, G is O, S or CR 12 R 13 Wherein R is 12 And R is 13 Each independently is hydrogen or C 1-8 An alkyl group; when bond a is absent, G is OH;
a is a five membered heterocycle which is thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, wherein the heterocycle is unsubstituted or C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl or five-membered or six-membered heterocyclic groups;
b is C 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 Alkynylene chain wherein the chain is unsubstituted or C 1-8 Alkyl, C 3-7 Cycloalkyl, C 1-8 Alkoxy or halogen substitution;
R 1 and R is 2 Each independently is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro, C 2-8 Acyl, C 6-10 Aryl, or five-or six-membered heterocyclic groups;
R 3 and R is 4 Each independently is hydrogen or C 1-8 An alkyl group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
13. A compound of formula (P):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, G a Is O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G a Is OH;
A a is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B a is C 1-8 Alkylene or C 2-8 Alkenylene chains;
R 1a and R is 2a Each independently is hydrogen、C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、/>
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
14. A compound of formula (Q):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
when bond a is present, G b O, S or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the When bond a is not present, G b OH;
A b is a five-membered heterocyclic ring which is thiazole, oxazole or thiophene, wherein the five-membered heterocyclic ring is unsubstituted or C-substituted 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 Acyl substitution;
B b is C 1-8 Alkylene or C 2-8 Alkenylene chain；
R 1b And R is 2b Each independently is hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, hydroxy, nitro or C 2-8 An acyl group;
R 3b Is hydrogen or C 1-8 An alkyl group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
15. A compound of formula (R):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
W 1 and W is 2 Each independently is CH or N;
x is NR 3 Or CR (CR) 4 R 5 Wherein R is 3 Is C 1-8 Alkyl, C 1-8 Haloalkyl, quilt C 1-8 Alkoxy substituted C 1-8 Alkyl, C substituted by 3-7 membered cycloalkyl 1-8 Alkyl, C substituted by phenyl groups 1-8 Alkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
R 4 and R is 5 Each independently is hydrogen or C 1-8 An alkyl group;
y is (CR) 6 R 7 ) r Wherein R is 6 And R is 7 Each independently is hydrogen or C 1-8 Alkyl, and r is 1, 2, 3 or 4;
a is a 5 or 6 membered heterocyclic group or a phenyl group, said 5 or 6 membered heterocyclic group being thiazole, oxazole, imidazole, pyrazole, thiophene, furan, pyrrole, pyridine or pyrimidine, wherein said 5 or 6 membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl, 3-7 membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C substituted by 3-7 membered cycloalkyl groups 1-8 Alkyl group, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, C 6-10 Aryl, 5 or 6 membered heterocyclic group containing C 6-10 Aryl group and C 1-8 Aralkyl groups of alkyl groups, or C substituted by 5-or 6-membered heterocyclic groups 1-8 Alkyl group substitution;
b is a bond or C 1-8 Alkylene group, the C 1-8 Alkylene is unsubstituted or C 1-8 Alkyl, 3-7 membered cycloalkyl group, C 1-8 Alkoxy or halogen substituted, and when the number of carbons of the alkylene chain is 2 or more, it may have a double bond or a triple bond;
d is N or CH;
e is O or S;
R 1 and R is 2 Each independently H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, halogen, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, nitro, C 2-8 Acyl, C 6-10 Aryl or a 5-or 6-membered heterocyclic group;
m is 0, 1, 2 or 3;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
16. A compound of formula (S):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
A 1 is a 5-or 6-membered heterocyclic group or a phenyl group, said 5-or 6-membered heterocyclic group being thiazole, oxazole, pyridine or pyrimidine, wherein said 5-or 6-membered heterocyclic group or phenyl group is unsubstituted or C-substituted 1-8 Alkyl or C 1-8 Haloalkyl substitution;
B 1 is C 2-4 An alkylene group;
R 11 and R is 12 Each independently H, C 1-8 Alkyl, halogen or C 1-8 A haloalkyl group;
R 13 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 13 The attached N is attached to the 6 th position of the benzisoxazole;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
17. A compound of formula (T):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
B 2 is C 2-4 An alkylene group;
R 20 is C 1-8 An alkyl group;
R 21 and R is 22 Each independently H, C 1-8 Alkyl, halogen or C 1-8 A haloalkyl group;
R 23 is C 1-8 Alkyl or C 1-8 Haloalkyl, optionally wherein R 23 The attached N is attached to the 6 th position of the benzisoxazole;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 Attached carbon atomsThe children together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; and
n is 0, 1, 2, 3 or 4.
18. A compound of formula (U):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 Is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C 2 -C 8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 2 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 3 、R 4 、R 5 and R is 6 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
x is oxygen, sulfur or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl having C 6-10 Aryl moiety and C 1-8 Aralkyl group of alkylene moiety, C 2-8 Acyl or C 2-8 Alkenyl groups;
y is oxygen, sulfur, NR 8 Or a bond, wherein R 8 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
p is 0 or 1;
when bond a is present, A is oxygen CH 2 、N-NH 2 OR N-OR 9 Wherein R is 9 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, a is OH;
in the case of p=1, B is a benzene ring with or without substituents halogen, hydroxy, nitro, amino, C 1-8 Alkyl, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, or having C 6-10 An aryl moiety and an aralkyl group of a C1-C8 alkylene moiety of 1-8 carbon atoms, and, in the case of p=0, B is a fused ring which is indole, benzofuran, benzisoxazole or 1, 2-benzisothiazole, wherein the fused ring is with or without substituents which are
Halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl, C with C1-C8 alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy groups, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
y is bonded with the benzene ring of B;
(C(R 3 )(R 4 )) m a fused ring to B is bonded at its 3 position;
m is an integer from 1 to 4;
n is 0, 1, 2, 3, 4 or 5;
in the case of n=0, Y is a bond;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
19. A compound of formula (V):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 11 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 12 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl, C with 3-to 7-membered cycloalkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 13 、R 14 、R 15 and R is 16 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 1 is oxygen, sulfur and NR 18 Or a bond, wherein R 18 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
when bond a is present, A 1 Is oxygen CH 2 、N-NH 2 OR N-OR 19 Wherein R is 19 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl, C 2-8 Alkenyl or having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety; when bond a is absent, A 1 OH;
Q 1 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
r is 1, 2, 3 or 4;
s is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
20. A compound of formula (W):
Or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 21 is hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-8 Alkyl, C 3-7 Cycloalkyl, C2-C8 alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl groups, 5-or 6-membered heterocyclic groups, having C 6-10 Aryl moiety and C 1-8 Aralkyl groups of alkylene moieties, or C having 5-or 6-membered heterocyclic substituents 1-8 An alkyl group;
R 22 is hydrogen, C 1-8 Alkyl, C 2-8 Alkenyl having 3-to 7-membered ringsC of alkyl substituents 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl group, C 2-8 Acyl, C 6-10 Aryl, or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
R 23 、R 24 、R 25 and R is 26 Each independently is hydrogen, C 1-8 Alkyl or C 1-8 A haloalkyl group;
Y 2 is oxygen, sulfur and NR 28 Or a bond, wherein R 28 Is hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Acyl or C 2-8 Alkenyl groups;
Q 2 is hydrogen, halogen, hydroxy, nitro, amino, C 1-8 Alkyl group, C 3-7 Cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C with 3-7 membered cycloalkyl substituent 1-8 Alkyl, C 1-8 Haloalkyl having C 1-8 C of alkoxy substituents 1-8 Alkyl, C 1-8 Haloalkoxy, C 2-8 Acyl, C 6-10 Aryl or with C 6-10 Aryl moiety and C 1-8 Aralkyl groups of the alkylene moiety;
t is 1, 2, 3 or 4;
u is 1, 2, 3, 4 or 5;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle;
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
21. A compound of formula (X):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein aryl and heteroaryl are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
22. A compound of formula (Y):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein the aryl and heteroaryl groups are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
23. A compound of formula (Z):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
Q 1 CH or N;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group)、SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein the aryl and heteroaryl groups are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 1 or 2;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
each R 20 Independently hydrogen, halogen, C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R 3 is CH 3 Or CD (compact disc) 3 ；
R X Is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
24. A compound of formula (AA):
or a pharmaceutically acceptable salt, solvate, ester, amide, or prodrug thereof, wherein:
l is (CH) 2 ) 5 Which is unsubstituted or substituted by one methyl group;
R 1 is hydrogen, halogen or C 1-4 Alkyl, C 1-4 Haloalkyl, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Cycloalkyl;
R 2 is hydrogen, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, S (C) 1-4 Alkyl group, SO 2 (C 1-4 -alkyl), 5-or 6-membered heterocycle, aryl, 5-membered heteroaryl, c≡c-R 2A 、O(CH 2 ) m R 2B 、NH(C 1-4 Alkyl), N (C) 1-4 Alkyl group 2 Or C (O) (C 1-4 Alkyl), wherein the aryl and heteroaryl groups are unsubstituted or substituted with halogen, OH, CN, C 1-4 Alkyl, formyl, acetyl, acetoxy or carboxyl substituted, and wherein m is 1, 2 or 3;
x is 0 or 1;
R 2A and R is 2B Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl;
R 3 is C 1-4 Haloalkyl, NO 2 CN, halogen or C (O) O (C) 1-4 An alkyl group);
R 20 is hydrogen, halogen or C 1-4 Alkyl, CN or C 1-4 An alkoxy group;
R X is CH 2 OH、COH、COOCH 2 CONR X4 R X5 、SO 3 H、
Each R X4 And R is X5 Independently alkyl, aryl or heteroaryl; alternatively, R X4 And R is X5 And R is R X4 And R is X5 The attached carbon atoms together form a heterocycle; and
each R X6 And R is X7 H, C independently 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl groups.
25. The compound of claim 1, having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
26. The compound of claim 1, having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
27. The compound of claim 1, having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
28. The compound of claim 1, having the structure:or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
29. A compound having a structureOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
30. A compound which isOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
31. A compound having a structureOr a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof.
32. The compound or pharmaceutically acceptable salt of the compound of any one of claims 1 to 31.
33. A pharmaceutical composition comprising a compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of said compound, and a pharmaceutically acceptable carrier or vehicle.
34. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prophylaxis of liver disorders, dyslipidemia, kidney disease, impaired glucose metabolism, lipid metabolism disorders, carbohydrate metabolism disorders, cardiovascular disease, vascular disease, metabolic syndrome, complications associated with metabolic syndrome, PPAR-related disorders, sepsis, thrombotic disorders, obesity, diabetic nephropathy, diabetic retinopathy, atherosclerosis, pancreatitis, cerebrovascular disease, disorders associated with neovascularization, hypertension, cancer, inflammation, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, tumour diseases, muscle atrophy, cholestasis, mitochondrial dysfunction, ocular diseases, lysosomal storage diseases, kidney disease or impotence.
35. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prophylaxis of hyperlipidemia, hyperlipaemia, hyperlipoproteinaemia, hypercholesteraemia, hypertriglyceridaemia or dyslipidemia.
36. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prophylaxis of abnormally high concentrations of high Low Density Lipoprotein (LDL), apolipoprotein B (apo B), lipoprotein (a) (Lp (a)), apolipoprotein (a) or Very Low Density Lipoprotein (VLDL) in the plasma or serum of a subject.
37. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prevention of abnormally low concentrations of High Density Lipoprotein (HDL) in the plasma or serum of a subject.
38. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prevention of an abnormal decrease or lack of lipoprotein lipase concentration or activity in the plasma or serum of a subject.
39. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prevention of hypoalphalipoproteinemia, diabetic-related lipoprotein abnormalities, obesity-related lipoprotein abnormalities, alzheimer's disease-related lipoprotein abnormalities or familial mixed hyperlipidemia.
40. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in reducing abnormally high concentrations of triglycerides, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) (Lp (a)), the ratio of apolipoprotein B, HDL/(vldl+ldl), apolipoprotein C-II or apolipoprotein C-III in the plasma or serum of a subject.
41. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in elevating abnormally low concentrations of High Density Lipoprotein (HDL) -associated protein, HDL-cholesterol, apolipoprotein a-I or apolipoprotein E in the plasma or serum of a subject.
42. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in promoting the clearance of triglycerides from the plasma or serum of a subject.
43. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in increasing abnormally low glucose metabolism or lipid metabolism in a subject.
44. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in the treatment or prophylaxis of inflammatory, systemic lupus erythematosus, lupus nephritis or the symptoms of arthritis.
45. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in reducing the fat content of livestock meat.
46. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in reducing the cholesterol content of an avian egg.
47. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug thereof, for use in a method of treating a subject suffering from or at risk of Acute Kidney Injury (AKI), comprising administering to the subject (i) an effective amount of the compound or a pharmaceutically acceptable salt, solvate, ester, amide or prodrug of the compound.
CN202280033302.1A 2021-03-08 2022-03-08 Compounds useful for treating liver diseases Pending CN117500791A (en)

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