Aromatic compound and medical application thereof

Abstract

The present disclosure relates to aromatic compounds and medical uses thereof, in particular to compounds of general formula (I): wherein R1, R2, R3, R4, R5, R6 and R7 may be selected from different substituents; n is 0, 1 or 2; and X is hydroxymethyl or a carboxylic acid or a derivative thereof, such as a carboxylate, such as a carboxylic ester, glyceride, anhydride, phospholipid, carboxamide, phospholipid, or a prodrug thereof; or pharmaceutically acceptable salts, solvates, solvates of the salts, or prodrugs thereof. The present disclosure also relates to pharmaceutical and lipid compositions comprising at least one compound according to the present disclosure, and to the use of such compounds as a medicament or for treatment, in particular for the treatment of diseases associated with metabolic and liver diseases, such as non-alcoholic fatty liver diseases and cholestasis diseases. (I)

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: October 10, 2019; application number: 201980067283.2 (international application number: PCT / IB2019 / 001139); invention title: Aromatic compounds and their pharmaceutical uses).

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application 62 / 744,461, filed October 11, 2018, the contents of which are incorporated herein by reference. Technical Field

[0004] This invention relates to substituted aromatic compounds, methods for their preparation, pharmaceutical compositions comprising the aromatic compounds, and their use in treating various diseases and conditions in subjects with such needs. Background Technology

[0005] The growing global prevalence of obesity and its comorbidities (e.g., type 2 diabetes and hyperlipidemia) places a tremendous burden on public health (mortality and morbidity) and on the available public health resources needed to treat these diseases.

[0006] Current medications for treating hyperlipidemia (such as statins, omega-3 fatty acids, and fibrates) generally have a neutral effect on glycemic control, while medications for glycemic control (such as insulin and thiazolidinediones (TZDs)) have adverse effects on weight and other harmful side effects (for TZDs), thus limiting their use.

[0007] In addition to hyperlipidemia and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) has also increased significantly. NAFLD has become the most common chronic liver disease in Western populations, which is related to the prevalence of obesity and type 2 diabetes. Non-alcoholic steatohepatitis (NASH) is a form of NAFLD associated with liver inflammation and hepatocyte swelling, and its incidence in the United States is projected to increase by 63% between 2015 and 2030 (Estes, Hepatology, 2018; 67(1):123-133), with NASH expected to become the leading cause of liver transplantation by 2020. Since liver fibrosis (rather than inflammation) is associated with mortality and morbidity in NASH patients, drugs that can prevent its development / induce fibrosis regression are also a focus of biomedical research.

[0008] Therefore, developing novel compounds that simultaneously target hyperlipidemia and glycemic control without the adverse side effects typically associated with insulin sensitizing drugs (such as weight gain) is an ideal goal. Such compounds would be even more attractive if they could additionally prevent the progression of liver fibrosis / reverse liver fibrosis and reduce hepatic steatosis. The novel treatment methods, compounds, and pharmaceutical compositions of the present invention meet these needs. Summary of the Invention

[0009] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, solvates of these salts or prodrugs thereof, pharmaceutical compositions of these compounds, methods of their preparation, and the use of these compounds or pharmaceutical compositions in the treatment of various diseases and conditions.

[0010] Preferred aspects of the invention relate to compounds of formula (I) described by group (2). Other aspects of the invention relate to compounds of formula (I) described by group (1). Other aspects of the invention relate to compounds of formula (I) described by group (3). Other aspects of the invention relate to compounds of formula (I) described by group (4). Other aspects of the invention also relate to compounds of formula (I) described by group (5).

[0011] Aspects of the present invention relate to pharmaceutically acceptable salts of compounds of formula (I) described by any one of groups (1), (2), (3), (4), or (5). The salt may be selected from sodium, potassium, calcium, and magnesium salts.

[0012] An aspect of the invention relates to pharmaceutical compositions of compounds of formula (I) described by any one of groups (1), (2), (3), (4), or (5). A preferred aspect of the invention relates to pharmaceutically acceptable compositions of compounds of formula (I) described by group (2).

[0013] This invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof, solvates thereof, solvates of such salts, or prodrugs thereof, or pharmaceutical compositions of such compounds for the treatment of diseases related to metabolic and liver diseases. Additionally, this invention relates to pharmaceutical compositions of compounds of formula (I) or salts thereof, which are used for:

[0014] • Treatment of liver inflammation;

[0015] • Increase glucose tolerance and / or decrease postprandial glucose levels;

[0016] • Lower fasting blood glucose levels;

[0017] • Reduce plasma insulin levels, including reducing fasting plasma insulin levels;

[0018] • Treating diabetes, such as type 2 diabetes;

[0019] • Lower plasma triglycerides and / or total cholesterol;

[0020] • Treatment for weight gain;

[0021] • Treatment of metabolic syndrome;

[0022] • To treat conditions of dyslipidemia, such as hypertriglyceridemia and / or hypercholesterolemia;

[0023] • Treatment of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis;

[0024] • In non-alcoholic steatohepatitis, preventive treatment of liver fibrosis or reduction of the development of liver fibrosis or reduction of existing liver fibrosis;

[0025] • Preventive treatment of fatty degeneration or reduction of the progression of fatty degeneration or reduction of hepatic steatosis;

[0026] • Treatment of parenteral nutrition-associated liver disease (PNALD);

[0027] Treatment of sclerosing cholangitis; and

[0028] • Treatment of liver and gallbladder diseases.

[0029] The present invention also relates to a method for treating the conditions listed above, comprising administering to a mammal in need a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof, or a pharmaceutical composition thereof. Attached Figure Description

[0030] Figure 1 Effects of compounds B and A on postprandial blood glucose in ob / ob A MLN mice

[0031] Figure 2 Effects of treatment with compounds B and A for 4 weeks on postprandial blood glucose in ob / ob A MLN mice

[0032] Figure 3 Effects of 4 weeks of treatment with compounds B and A on fasting insulin levels in ob / ob A MLN mice.

[0033] Figure 4 Effects of treatment with compounds B and A for 4 weeks on fasting blood glucose in ob / ob A MLN mice

[0034] Figure 5 Effects of treatment with compounds B and A for 4 weeks on the expression of the liver collagen 1a1 gene in ob / ob A MLN mice.

[0035] Figure 6 Effects of treatment with compounds B and A for 4 weeks on hepatic Slc10a2 gene expression in ob / ob A MLN mice

[0036] Figure 7 Effects of treatment with compounds B and A for 4 weeks on hepatic Slc51b gene expression in ob / ob A MLN mice

[0037] Figure 8 Effects of treatment with compounds B and A for 4 weeks on hepatic ABCC2 gene expression in ob / ob A MLN mice

[0038] Figure 9 Effects of treatment with compounds B and A for 4 weeks on hepatic CYP7A1 gene expression in ob / ob A MLN mice

[0039] Figure 10 Effects of treatment with compounds B and A for 4 weeks on hepatic CD68 gene expression in ob / ob A MLN mice

[0040] Figure 11 Effects of treatment with compounds B and A and pioglitazone for 4 weeks on relative body weight in ob / ob A MLN mice

[0041] Figure 12 Effects of treatment with compounds B and A for 4 weeks on hepatic low-density lipoprotein receptor (LDLr) gene expression in ob / ob A MLN mice.

[0042] Figure 13 Compared to a diet control, the effects of 19 days of oral parenteral nutrition (PN) combined with medium-chain triglycerides (MCTs) or compound A on hepatic steatosis in C57BL / 6 mice.

[0043] Figure 14 The effect of a 19-day oral PN diet combined with MCT, Omegaven®, compound A, or compound B on hepatic steatosis in C57BL / 6 mice compared to a dietary control. Hematoxylin and eosin (H&E) stained mouse hepatocytes magnified 400x: (A) dietary control; and (B) mice fed oral PN with saline administered via orogastric gavage. Arrows indicate lipid accumulation.

[0044] Figure 15The effect of a 19-day oral PN diet combined with MCT, Omegaven®, compound A, or compound B on hepatic steatosis in C57BL / 6 mice compared to a dietary control. Hematoxylin and eosin (H&E) stained mouse hepatocytes magnified 400x: (A) PN-fed mice administered medium-chain triglycerides (MCT) via gavage; and (B) PN-fed mice administered Omegaven® via gavage. ® The arrow indicates lipid accumulation.

[0045] Figure 16 The effects of a 19-day oral PN diet combined with MCT, Omegaven®, compound A, or compound B on hepatic steatosis in C57BL / 6 mice compared to a dietary control. Hematoxylin and eosin (H&E) stained mouse liver sections were magnified 400x: (A) mice treated with PN-fed mice by gavage with 0.3 mmol of compound A; and (B) mice treated with oral PN-fed mice by gavage with 0.6 mmol of compound A. Arrows indicate lipid accumulation.

[0046] Figure 17 The effects of a 19-day oral PN diet combined with MCT, Omegaven®, compound A, or compound B on hepatic steatosis in C57BL / 6 mice compared to a dietary control. Hematoxylin and eosin (H&E) stained mouse liver sections were magnified 400x: (A) PN-fed mice treated with 0.3 mmol of compound B via gavage; and (B) PN-fed mice treated with 0.6 mmol of compound B via gavage. Arrows indicate lipid accumulation.

[0047] Figure 18 Compared to the diet control, the effects of a 19-day oral PN diet in combination with MCT, Omegaven®, compound A, or compound B on: (A) body weight; (B) liver / body weight; (C) spleen / body weight in C57BL / 6 mice.

[0048] Figure 19 Body weight of C57BL / 6 mice within 19 days: (A) diet; (B) combination of PN diet and intravenous administration of saline and MCT via gavage; (C) PN diet and intravenous administration of Intralipid. ® Combined with MCT gavage administration; (D)PN diet with intravenous Omegaven ® (E) Combination of oral administration of PN diet with intravenous administration of normal saline and 0.6 mmol of compound A via gavage; (F) Combination of oral administration of PN diet with intravenous administration of Intralipid ®The combination of oral administration of 0.6 mmol of compound A and (G)PN diet with intravenous administration of Omegaven ® The combination of oral administration of compound A and 0.6 mmol.

[0049] Figure 20 Effects of PN-fed C57BL / 6 mice on intravenous saline, Intralipid® or Omegaven® and MCT or compound A administered by gavage over 19 days: (A) percentage change in body weight; (B) normalized liver quality.

[0050] Figure 21 Effects of PN-fed C57BL / 6 mice on the combination of intravenously administered saline, Intralipid® or Omegaven® and MCT, or compound A administered by gavage over 19 days: (A) normalized kidney mass; (B) normalized spleen mass.

[0051] Figure 22 Compared to a diet control, the effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven® combined with MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Hematoxylin and eosin (H&E) stained mouse liver sections were magnified 400 times: (A) diet control; and (B) PN diet combined with intravenous saline and MCT administered by gavage.

[0052] Figure 23 Compared to a dietary control, the effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven® combined with gavage-administered MCT or compound A on hepatic steatosis in C57BL / 6 mice. Hematoxylin and eosin (H&E) stained mouse liver sections were magnified 400x: (A) PN diet combined with intravenous Intralipid® and gavage-administered MCT; and (B) PN diet combined with intravenous Omegaven® and gavage-administered MCT.

[0053] Figure 24 The effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven®, and gavage administration of MCT or compound A on hepatic steatosis in C57BL / 6 mice compared to a dietary control. Hematoxylin and eosin (H&E) stained mouse liver sections were magnified 400x: (A) PN diet combined with intravenous saline and gavage administration of 0.6 mmol compound A; and (B) PN diet combined with intravenous Intralipid® and gavage administration of 0.6 mmol compound A.

[0054] Figure 25 Compared to a dietary control, the effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven®, and gavage administration of MCT or compound A on hepatic steatosis in C57BL / 6 mice were investigated. Hematoxylin and eosin (H&E) stained mouse liver sections corresponding to the PN diet combined with intravenous Omegaven® and gavage administration of 0.6 mmol of compound A were magnified 400 times.

[0055] Figure 26 The effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven®, and MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice compared to a diet control. Oil Red O stained mouse liver sections were magnified 400x: (A) diet control; and (B) combination of PN diet with intravenous saline and MCT administered by gavage.

[0056] Figure 27 Compared to a diet control, the effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven®, and gavage administration of MCT or compound A on hepatic steatosis in C57BL / 6 mice were compared. Oil Red O stained mouse liver sections were magnified 400x: (A) PN diet combined with intravenous Intralipid® and gavage administration of MCT; and (B) PN diet combined with intravenous Omegaven® and gavage administration of MCT.

[0057] Figure 28 The effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven®, and gavage administration of MCT or compound A on hepatic steatosis in C57BL / 6 mice compared to a diet control. Oil Red O stained mouse liver sections were magnified 400x: (A) PN diet combined with intravenous saline and gavage administration of 0.6 mmol of compound A; and (B) PN diet combined with intravenous Intralipid® and gavage administration of 0.6 mmol of compound A.

[0058] Figure 29 Compared to a dietary control, the effects of oral PN diet combined with intravenous saline, Intralipid® or Omegaven® combined with gavage administration of MCT or compound A on hepatic steatosis in C57BL / 6 mice were investigated. Oil Red O stained mouse liver sections were magnified 400x: PN diet combined with intravenous Omegaven® and gavage administration of 0.6 mmol of compound A.

[0059] Figure 30 Compared to a feed control, oral PN diet and intravenous saline and Intralipid... ® or Omegaven ® Oil Red O histological quantitative analysis of hepatic steatosis in C57BL / 6 mice in combination with MCT or compound A administered by gavage.

[0060] Figure 31 Compounds A, C, and reference compounds (reference 1 and reference 2) showed positive effects on APOE over a 4-week period. Effects of triglyceride levels in 3Leiden mice. Invention Details

[0061] The compounds of the present invention

[0062] This disclosure relates to aromatic compounds of general formula (I):

[0063] (I).

[0064] Group I

[0065] For example, this disclosure relates to compounds of formula (I) described by group (1), wherein:

[0066] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[0067] R2, R3, and R4 may be the same or different, and are independently selected from hydrogen atoms or halogen atoms; and

[0068] R5 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, heteroalkyl with 4-12 atoms, of which 1-4 atoms are heteroatoms, C4-C12 alkenyl with 1-3 double bonds, heteroalkenyl with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, C4-C12 haloalkenyl with 1-3 double bonds, C4-C12 alkynyl with 1-3 triple bonds, C(O)R10 group, OR10 group, S(O)nR10 group or NR9R10 group;

[0069] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0070] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[0071] R9 is a hydrogen atom or a C1-C11 alkyl group;

[0072] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[0073] R11 is a C1-C4 alkyl group;

[0074] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[0075] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0076] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[0077] ·m is 3 or 4; and

[0078] n is 0, 1, or 2;

[0079] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[0080] Group 2

[0081] This disclosure also relates to compounds of formula (I) described by group (2), wherein:

[0082] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[0083] R2 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group;

[0084] R3 and R4 may be the same or different, and can be selected from hydrogen atoms or halogen atoms.

[0085] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group;

[0086] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R2 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0087] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0088] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[0089] R9 is a hydrogen atom or a C1-C11 alkyl group;

[0090] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[0091] R11 is a C1-C4 alkyl group;

[0092] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[0093] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0094] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[0095] ·m is 3 or 4; and

[0096] n is 0, 1, or 2;

[0097] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[0098] Group 3

[0099] This disclosure also relates to compounds of formula (I) described by group (3), wherein:

[0100] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[0101] R2 and R4 may be the same or different, and are independently selected from hydrogen atoms and halogen atoms.

[0102] R3 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, heteroalkyl with 4-12 atoms, of which 1-4 atoms are heteroatoms, C4-C12 alkenyl with 1-3 double bonds, heteroalkenyl with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, C4-C12 haloalkenyl with 1-3 double bonds, C4-C12 alkynyl with 1-3 triple bonds, C(O)R10 group, OR10 group, S(O)nR10 group or NR9R10 group;

[0103] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group;

[0104] • The condition is that if R1 is a haloalkyl, C1-C4 alkyl, SR11 group or NR12R13 group and R5 is a hydrogen atom or OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0105] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0106] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0107] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[0108] R9 is a hydrogen atom or a C1-C11 alkyl group;

[0109] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[0110] R11 is a C1-C4 alkyl group;

[0111] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[0112] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylic acid ester, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0113] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[0114] ·m is 3 or 4; and

[0115] n is 0, 1, or 2;

[0116] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[0117] Group 4

[0118] This disclosure also relates to compounds of formula (I) described by group (4), wherein:

[0119] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[0120] • R2 and R3 may be the same or different, and are independently selected from hydrogen atoms and halogen atoms;

[0121] R4 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group;

[0122] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group;

[0123] • The condition is that if R1 is a haloalkyl, C1-C4 alkyl, OR11 group, SR11 group or NR12R13 group and R5 is a hydrogen atom or OR11 group, then R4 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0124] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0125] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[0126] R9 is a hydrogen atom or a C1-C11 alkyl group;

[0127] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[0128] R11 is a C1-C4 alkyl group;

[0129] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[0130] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0131] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[0132] ·m is 3 or 4; and

[0133] n is 0, 1, or 2;

[0134] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[0135] Group 5

[0136] This disclosure also relates to compounds of formula (I) described by group (5), wherein:

[0137] R1 can be a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, a S(O)nR8 group, an NR8R9 group, or a phenyl group.

[0138] R2 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group;

[0139] R3 is a hydrogen atom or a halogen atom;

[0140] R4 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group;

[0141] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, a S(O)nR8 group, an NR8R9 group, or a phenyl group;

[0142] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0143] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[0144] R9 is a hydrogen atom or a C1-C11 alkyl group;

[0145] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[0146] R11 is a C1-C4 alkyl group;

[0147] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[0148] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic acid ester, glycerol ester; an anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0149] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[0150] ·m is 3 or 4; and

[0151] n is 0, 1, or 2;

[0152] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[0153] In some embodiments, the aromatic compounds of general formula (I) are described in the following embodiments of compounds of group (I), (II), (III), (IV) or (V).

[0154] Group 1

[0155] In some implementations, for compounds of formula (I) described by group (1):

[0156] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl, or a benzyl group; and

[0157] R5 can be a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl group with 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a heteroalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl group with 1-2 double bonds; a C4-C9 alkynyl group with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group.

[0158] in

[0159] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, a heteroalkyl group having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl group having 1-2 double bonds, or a C3-C8 alkynyl group having 1-2 triple bonds.

[0160] Group 2

[0161] In some implementations, for compounds of formula (I) described by group (2):

[0162] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group or an NR9R11 group, a phenyl or benzyl group;

[0163] R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0164] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group with 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, a S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group.

[0165] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R2 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0166] in

[0167] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, a heteroalkyl group having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl group having 1-2 double bonds, or a C3-C8 alkynyl group having 1-2 triple bonds.

[0168] Group 3

[0169] In some implementations, for compounds of formula (I) described by group (3):

[0170] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl or benzyl group;

[0171] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0172] as well as

[0173] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group with 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, a S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group.

[0174] The condition is that if R1 is a haloalkyl, C1-C4 alkyl, SR11, or NR12R13 group and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl, or C4-C6 alkyl; and

[0175] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0176] in

[0177] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, a heteroalkyl group having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl group having 1-2 double bonds, or a C3-C8 alkynyl group having 1-2 triple bonds.

[0178] Group 4

[0179] In some implementations, for compounds of formula (I) described by group (4):

[0180] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl or benzyl group;

[0181] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0182] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group with 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, a S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group.

[0183] • The condition is that if R1 is a C1-C4 haloalkyl, C1-C4 alkyl, OR11 group, SR11 group or NR12R13 group and R5 is a hydrogen atom or OR11 group, then R4 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0184] in

[0185] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, or C3-C8 haloalkyl group having 4-8 atoms, of which 1-2 atoms are heteroatoms; a C3-C8 alkenyl group having 1-2 double bonds; a heteroalkenyl group having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom; a C3-C8 haloalkenyl group having 1-2 double bonds; or a C3-C8 alkynyl group having 1-2 triple bonds.

[0186] Group 5

[0187] In some implementations, for compounds of formula (I) described by group (5):

[0188] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl group, a C(O)R11 group, an OR11 group, a S(O)nR11 group, an NR9R11 group, or a phenyl group;

[0189] ·R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl with 4-9 atoms, of which 1-3 atoms are heteroatoms, C4-C9 alkenyl with 1-2 double bonds, heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, C4-C9 haloalkenyl with 1-2 double bonds, C4-C9 alkynyl with 1-2 triple bonds, C(O)R14 group, OR14 group, S(O)nR14 group or NR9R14 group;

[0190] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0191] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group with 3-4 atoms, one of which is a heteroatom, a C(O)R11 group, an OR11 group, a S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group.

[0192] in

[0193] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, heteroalkyl with 4-8 atoms, of which 1-2 atoms are heteroatoms, C3-C8 alkenyl with 1-2 double bonds, heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, C3-C8 haloalkenyl with 1-2 double bonds, or C3-C8 alkynyl with 1-2 triple bonds.

[0194] In some embodiments, the aromatic compounds of general formula (I) are described in the following embodiments of compounds of group (I), (II), (III), (IV) or (V).

[0195] Group 1

[0196] In some implementations, for compounds of formula (I) described by group (1):

[0197] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, and is a heteroalkyl or OR11 group; and

[0198] R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl with 4-9 atoms, of which 1-3 atoms are heteroatoms, C4-C9 alkenyl with 1-2 double bonds, heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, C4-C9 haloalkenyl with 1-2 double bonds, C4-C9 ynyl with 1-2 triple bonds, C(O)R14 group, OR14 group, S(O)nR14 group or NR9R14 group;

[0199] in

[0200] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

[0201] Group 2

[0202] In some implementations, for compounds of formula (I) described by group (2):

[0203] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or a heteroalkyl having 3-4 atoms, one of which is a heteroatom;

[0204] R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0205] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms, one of which is a heteroatom;

[0206] in

[0207] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

[0208] Group 3

[0209] In some implementations, for compounds of formula (I) described by group (3):

[0210] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, or an OR11 group;

[0211] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0212] • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl group, or an OR11 group;

[0213] The condition is that if R1 is a haloalkyl or C1-C4 alkyl and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl, or C4-C6 alkyl-Y- group; and

[0214] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl or an OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0215] in

[0216] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, heteroalkyl with 4-8 atoms, of which 1-2 atoms are heteroatoms, C3-C8 alkenyl with 1-2 double bonds, heteroalkenyl with 1 double bond and 4-8 atoms, of which 1 atom is a heteroatom, C3-C8 haloalkenyl with 1-2 double bonds, or C3-C8 alkynyl with 1-2 triple bonds.

[0217] Group 4

[0218] In some implementations, for compounds of formula (I) described by group (4):

[0219] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, or an OR11 group;

[0220] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0221] • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl group, or an OR11 group;

[0222] • The condition is that if R1 is a haloalkyl, C1-C4 alkyl or OR11 group and R5 is a hydrogen atom or OR11 group, then R4 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[0223] in

[0224] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, a heteroalkyl group having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl group having 1-2 double bonds, or a C3-C8 alkynyl group having 1-2 triple bonds.

[0225] Group 5

[0226] In some implementations, for compounds of formula (I) described by group (5):

[0227] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, or an OR11 group;

[0228] R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl with 4-9 atoms, of which 1-3 atoms are heteroatoms, C4-C9 alkenyl with 1-2 double bonds, heteroalkenyl with 5-9 atoms (of which 1-2 atoms are heteroatoms) and 1-2 double bonds, C4-C9 haloalkenyl with 1-2 double bonds, C4-C9 alkynyl with 1-2 triple bonds, C(O)R14 group, OR14 group, S(O)nR14 group or NR9R14 group;

[0229] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0230] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl group, or an OR11 group;

[0231] in

[0232] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

[0233] Implementation Plan

[0234] The following implementation schemes involve compounds of formula (I) described by any one of groups (1), (2), (3), (4) or (5).

[0235] "Alkyl" refers to a straight-chain, branched, or cyclic alkyl group. In at least some embodiments, the alkyl group may be selected from methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, sec-butyl, pentyl, n-pentyl, hexyl, n-hexyl, heptyl, n-heptyl, octyl, n-octyl, nonyl, n-nonyl, decyl, and n-decyl.

[0236] "Alkenyl" refers to a straight-chain or branched alkenyl group. In at least some embodiments, the alkenyl group is selected from allyl, 2-butenyl, 3-hexenyl, 4-heptenyl, 5-octenyl, and 6-nonenyl. In some embodiments, the alkenyl group has one double bond. In some embodiments, the alkenyl group has two double bonds. In some embodiments, the alkenyl group has three double bonds. In some embodiments, the alkenyl group has an ω-3 double bond. In some embodiments, the alkenyl group has one double bond at the ω-3 position. In some embodiments, the alkenyl group is a C4-C9 straight-chain alkenyl group having one double bond at the ω-3 position. In some embodiments, the double bond is Z-configured.

[0237] In some embodiments, the alkenyl group has 1-3 double bonds, and each double bond is Z-configured. In some embodiments, the alkenyl group is a C5-C9 straight-chain alkenyl group having one double bond at the ω-3 position and being Z-configured.

[0238] In some embodiments, the alkenyl group is a C5 straight-chain alkenyl group having a double bond at the ω-3 position. In some embodiments, the alkenyl group is a C6 straight-chain alkenyl group having a double bond at the ω-3 position. In some embodiments, the alkenyl group is a C7 straight-chain alkenyl group having a double bond at the ω-3 position. In some embodiments, the alkenyl group is a C8 straight-chain alkenyl group having a double bond at the ω-3 position. In some embodiments, the double bond has a Z configuration.

[0239] "Alynyl" refers to a straight-chain or branched alkynyl group. In some embodiments, the alkynyl group may be selected from a C4-C12 alkynyl group having 1-3 triple bonds. In some embodiments, the alkynyl group has 1 triple bond. In some embodiments, the alkynyl group may be selected from a C5-C10 alkynyl group having 1 triple bond. In some embodiments, the triple bond is at the ω-3 position.

[0240] "Hydroxyalkyl" refers to a hydroxyl derivative of a straight-chain or branched alkyl group. In some embodiments, the hydroxyalkyl group may be selected from C1-C12 hydroxyalkyl, C2-C11 hydroxyalkyl, C1-C6 hydroxyalkyl, or C1-C4 hydroxyalkyl. In some embodiments, the hydroxyalkyl group may be selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, or hydroxybutyl.

[0241] "Heteroalkyl" refers to a straight-chain or branched alkyl group containing one or more heteroatoms selected from S, O, and N, wherein the alkyl chain may optionally contain one or more hydroxyl groups, one or more halogen atoms, and / or carbonyl groups.

[0242] A heteroalkyl group cannot contain a heteroatom at the first position of the chain relative to the aromatic ring. For example, according to this definition, the group of formula -OC6H13 is not a heteroalkyl group.

[0243] Under this definition, hydroxyalkyl groups are not considered heteroalkyl groups. For example, according to this definition, a group with the formula -C6H12OH is not a heteroalkyl group. A group having the formula -C4H8OC2H4OH is considered a heteroalkyl group having 7 atoms, one of which is a heteroatom (oxygen), and further includes a hydroxyl group.

[0244] In some embodiments, the heteroalkyl group has 3-12 atoms. In some embodiments, the heteroalkyl group has 3-9 atoms. In some embodiments, the heteroalkyl group has 4-8 atoms. In some embodiments, the heteroalkyl group has 5 or 6 atoms. In some embodiments, the heteroalkyl group has 1-3 heteroatoms. In some embodiments, the heteroalkyl group has 3-9 atoms, of which 1-3 are heteroatoms.

[0245] In some embodiments, the heteroalkyl group has 4-8 atoms, one of which is a heteroatom. In some embodiments, the heteroatom is located at the second position of the heteroalkyl group. In some embodiments, the heteroatom is located at the third position of the heteroalkyl group. In some embodiments, the heteroatom is located at the fourth position of the heteroalkyl group. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur. In some embodiments, the heteroalkyl group may be selected from -CH2OC4H9, -C2H4OC3H7, -C2H4OC2H3, -C3H6OCH3, -CH2OC5H11, -CH2OC3H7, -C2H4OC3H7, or -C3H6OC2H7.

[0246] The "alkyl-Y-" group is a heteroalkyl group having one heteroatom at the α-position relative to the aromatic ring. Y can be selected from oxygen, sulfur, and NR12 / NR13 groups, wherein R12 and R13 are independently selected from hydrogen groups and C1-C4 groups. For example, in some embodiments, Y can be oxygen. In some embodiments, the C4 alkyl-Y- group has the formula -OC4H9 or -SC4H9. In some embodiments, the C5 alkyl-Y- group has the formula -OC5H11 or -SC5H11. In some embodiments, the C6 alkyl-Y- group has the formula -OC6H13 or -SC6H13.

[0247] "Heteroalkenyl" refers to a straight-chain or branched alkenyl group containing one or more heteroatoms selected from S, O, and N in its main chain, wherein the alkenyl chain may optionally contain hydroxyl, halogen, and / or carbonyl groups. In some embodiments, the heteroatom is sulfur. In some embodiments, the heteroatom is oxygen. In some embodiments, the alkenyl group has two double bonds. In some embodiments, the alkenyl group has three double bonds. In some embodiments, the alkenyl group has an ω-3 double bond. In some embodiments, the alkenyl group has one double bond and it is at the ω-3 position. In some embodiments, the heteroalkenyl group has 3-9 atoms, wherein one atom is a heteroatom and one double bond. In some embodiments, the heteroalkenyl group has 6-9 atoms, wherein one atom is a heteroatom and one double bond, wherein the heteroatom is oxygen, and wherein the double bond is at the ω-3 position. In some embodiments, the double bond is Z-configured.

[0248] The heteroatom cannot be in the first or last position of the heteroalkenyl group. For example, the heteroalkenyl group cannot contain a heteroatom in the first position of the chain relative to the aromatic ring. For example, under this definition, the group of the formula -OCH2CH=CHCH2CH3 is not a heteroalkyl group.

[0249] "Haloalkyl" refers to a straight-chain or branched alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom. For example, the halogen atom may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the halogen atom is F. In some embodiments, the haloalkyl group comprises a -CF3 group.

[0250] In some embodiments, the haloalkyl group may also be a heteroalkyl group. In some embodiments, the haloalkyl group may be a heteroalkyl group having 6-9 atoms, wherein 1-3 atoms are heteroatoms. In some embodiments, the haloalkyl group is a heteroalkyl group having 1 heteroatom. In some embodiments, the heteroatom is an oxygen atom. In some embodiments, the halogen atom is fluorine.

[0251] "Halogenated alkenyl" refers to a straight-chain or branched alkenyl group in which one or more hydrogen atoms have been replaced by halogen atoms. For example, the halogen atom can be selected from fluorine, chlorine, bromine, and iodine.

[0252] In some implementations, the haloalkenyl group can also be a heteroalkenyl group.

[0253] In some embodiments, X is a carboxylic acid. In some embodiments, X is a carboxylic acid derivative. In some embodiments, X may be selected from carboxylic esters, glycerides, acid anhydrides, carboxamides, and phospholipids. In some embodiments, X is a carboxylic acid derivative, such as a carboxylic acid ester. In some embodiments, X is a carboxylic acid ester, such as an acetate group. In some embodiments, X is a glyceride, and in some embodiments, the glyceride may be in the form of triglycerides, 1,2-diglycerides, 1,3-diglycerides, 1-monoglycerides, or 2-monoglycerides. In some embodiments, X is an acid anhydride. In some embodiments, X is a carboxamide, and in some embodiments, the carboxamide may be selected from N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide, and N,N-diethylcarboxamide. In some embodiments, X is a phospholipid.

[0254] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, a carboxamide, or a hydroxymethyl group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is a hydroxymethyl group.

[0255] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 may together form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxylic acid ester, or carboxamide.

[0256] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1, both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1, both R6 and R7 are methyl groups, and X is a carboxylic acid. In some embodiments, n is 1, both R6 and R7 are hydrogen atoms, and X is an acetate group.

[0257] In some implementations, X may be selected from hydroxymethyl, carboxylic acid, carboxylic acid ester and carboxamide.

[0258] Group 1 Implementation Plan

[0259] The following implementation schemes involve compounds of formula (I) described by group (1).

[0260] In some embodiments, R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[0261] In some embodiments, R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms, a C4-C9 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, or an -O-(C3-C8) alkyl group. -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-(C3-C8)alkenyl with 1-2 double bonds, -O-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -O-heteroalkenyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -O-(C3-C8)haloalkenyl with 1-2 double bonds, and -O-(C3-C8)haloalkenyl with 1-2 triple bonds. -O-(C3-C8)alkynyl, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, and -S-heteroalkenyl having 1-2 double bonds. -S-(C3-C8) haloalkenyl, -S-(C3-C8) ynyl with 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, amino with hydrogen atom and C3-C8 alkyl, amino with hydrogen atom and (C1-C6) ketone group, or amino with C1-C9 alkyl and C3-C8 alkyl.

[0262] In some embodiments, R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, having 5-8 atoms, wherein... One of the atoms is a heteroatom and has one double bond -O-heteroalkenyl, one of the atoms is a -O-(C3-C8)haloalkenyl with one or two double bonds, one of the atoms is a -O-(C3-C8)ynyl with one or two triple bonds, one of the atoms is a -S-(C3-C8)alkyl, one of the atoms is a -S-(C3-C8)hydroxyalkyl, one of the atoms is a -S-(C3-C8)alkenyl with one or two double bonds, one of the atoms is a -S-heteroalkenyl with one or two double bonds, one of the atoms is a -S-(C3-C8)haloalkenyl with one or two double bonds, or one of the atoms is a -S-(C3-C8)ynyl with one or two triple bonds.

[0263] In some embodiments, R1 is a C1-C2 alkyl, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, or -O-(C1-C2)alkyl. In some embodiments, R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl having 4-9 atoms, wherein 1-3 atoms are heteroatoms, a C4-C9 alkenyl having 1-2 double bonds, a heteroalkenyl having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms, a -O-(C3-C8)alkyl, a -O-(C3-C8) hydroxyalkyl, a -O-(C3-C8) haloalkyl, a -O-(C3-C8) alkenyl having 1-2 double bonds, a -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, or a -O-heteroalkyl having 5-8 atoms, wherein one is a heteroatom and has... -O-heterenyl with one double bond, -O-(C3-C8)haloalkenyl with one to two double bonds, -O-(C3-C8)ynyl with one to two triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heterenyl with 4 to 8 atoms, of which 1 to 2 are heteroatoms, -S-(C3-C8)alkenyl with one to two double bonds, -S-heterenyl with 5 to 8 atoms, of which one is a heteroatom and has one double bond, -S-(C3-C8)haloalkenyl with one to two double bonds, or -S-(C3-C8)ynyl with one to two triple bonds.

[0264] In some embodiments, R1 is a C1-C2 alkyl, C1-C2 hydroxyalkyl, or -O-(C1-C2)alkyl. In some embodiments, R5 is a C4-C9 alkyl having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, having 1 -O-(C3-C8)alkenyl with 2 double bonds, -O-heterenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond, -O-(C3-C8)haloalkenyl with 1-2 double bonds, -S-(C3-C8)alkyl, -S-heterenyl with 4-8 atoms, one-2 of which are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, or -S-heterenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond.

[0265] In some embodiments, R1 is a C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is O, a -O-heteroalkyl, or an -O-(C5-C8) alkenyl having one double bond. In some embodiments, the double bond is at the ω-3 position. In some embodiments, the double bond is Z-configured.

[0266] In some embodiments, R1 is methyl. In some embodiments, R1 is -OCH3. In some embodiments, R5 is -O-(C3-C8)alkyl and has the formula -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17. In some embodiments, R5 is -S-(C3-C8)alkyl and has the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15, or -SC8H17. In some embodiments, R5 is an -O-(C3-C8)alkenyl group having 1-2 double bonds and may have the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3, or -O(CH2)4CH=CHCH2CH3. In some embodiments, R5 is a -S-(C3-C8) alkenyl group having 1-2 double bonds and may have the formula -SCH2CH=CHCH2CH3, -S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3 or -S(CH2)4CH=CHCH2CH3.

[0267] In some embodiments, R2, R3, and R4 are each hydrogen atoms. In some embodiments, one or more of R2, R3, and R4 are halogen atoms. In some embodiments, one or more of R2, R3, and R4 are fluorine atoms.

[0268] In some embodiments, R1 is methyl or -OCH3; R5 is C4-C8 alkyl, -O-(C4-C8)alkyl, C4-C8 alkenyl with one double bond or -O-(C4-C8)alkenyl with one double bond; R2, R3 and R4 are each hydrogen atoms; n is 0; and X is a carboxylic acid.

[0269] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0270] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, hydroxymethyl, or carboxylic acid ester, such as an acetate group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is hydroxymethyl.

[0271] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxamide, or carboxylic acid esters, such as acetate groups.

[0272] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups, and X is a carboxylic acid.

[0273] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid esters, such as acetate groups.

[0274] In some embodiments, the compounds of formula (I) described by group (1) are described by formula (IA):

[0275] (IA)

[0276] R1 and R5 are each defined as described in any of the embodiments of group (1) above. In some embodiments, Z' is H or a C1-C4 alkyl group.

[0277] In some embodiments, R1 is a C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is O, a -O-heteroalkyl, or an -O-(C5-C8) alkenyl having one double bond. In some embodiments, the double bond is at the ω-3 position. In some embodiments, the double bond has a Z configuration. In some embodiments, Z' is H. In some embodiments, Z' is methyl or ethyl.

[0278] Group 2 Implementation Plan

[0279] The following implementation schemes involve compounds of formula (I) described by group (2).

[0280] In some embodiments, R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or phenyl heteroatom.

[0281] In some embodiments, R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, or having 5-8 atoms. Among them, one is a heteroatom and has one double bond -O-heterenyl, one or two double bonds -O-(C3-C8)haloalkenyl, one or two triple bonds -O-(C3-C8)ynyl, one or two triple bonds -S-(C3-C8)alkyl, one or two hydroxyalkyl, one or two haloalkyl, and one or two atoms of -S-heterenyl, one or two double bonds -S-(C3-C8)alkenyl, and one or two atoms of -S-heterenyl, one or two double bonds -S-(C3-C8)ynyl, and one or two double bonds -S-(C3-C8)alkenyl. Haloalkenyl, -S-(C3-C8)ynyl with 1-2 triple bonds, -C(O)-(C3-C8)alkyl, -C(O)-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -C(O)-(C3-C8)alkenyl with 1-2 double bonds, -S(O)-(C3-C8)alkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S(O)-heteroalkyl with 1-2 double bonds, -S(O)-(C3-C8)alkenyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S(O)2-(C3-C8)alkyl with 4-8 atoms, and its The group may contain 1-2 heteroatoms of -S(O)2-heteroalkyl, 1-2 double bonds of -S(O)2-(C3-C8)alkenyl, 4-8 atoms of -S(O)2-heteroalkyl, 1-2 of which are heteroatoms; an amino group of hydrogen atom and C3-C8 alkyl; an amino group of hydrogen atom and heteroalkyl, wherein the heteroalkyl has 4-8 atoms, 1-2 of which are heteroatoms; an amino group of hydrogen atom and ketone group; an amino group of C1-C9 alkyl and C3-C8 alkyl; an amino group of C1-C9 alkyl and 4-8 atoms of heteroalkyl, 1 of which is a heteroatom, or an amino group of C1-C9 alkyl and 1-2 double bonds of C3-C8 alkenyl.

[0282] In some embodiments, R1 is a C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl, or phenyl. In some embodiments, R1 is selected from methyl, ethyl, isopropyl, -CF3, -(CH2)3OH, and phenyl.

[0283] In some embodiments, R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatoms, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, having 4-8 atoms, wherein 1-2 are heteroatoms, -O-heteroalkyl having 5-8 atoms, wherein one is a heteroatom and has 1 double bond, or having 1-2 double bonds. -O-(C3-C8)haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl, -S(O)2-(C3-C8)alkyl, amino with hydrogen atom and C3-C8 alkyl, amino with hydrogen atom and (C1-C6) ketone group or amino with C1-C9 alkyl and C3-C8 alkyl.

[0284] In some embodiments, R1 is a C1-C3 alkyl or C1-C3 hydroxyalkyl. In some embodiments, R2 is a C4-C9 alkyl having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, -O-(C4-C8)alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and has 1 double bond, having -O-(C4-C8) haloalkenyl with 1-2 double bonds, -S-(C3-C8)alkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C4-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl, -S(O)2-(C3-C8)alkyl, amino group with hydrogen atom and C3-C8 alkyl, amino group with hydrogen atom and (C1-C6) ketone group; amino group with C1-C9 alkyl and C3-C8 alkyl.

[0285] In some embodiments, R1 is a C1-C2 alkyl or C1-C2 hydroxyalkyl. In some embodiments, R2 is a C4-C9 alkyl having 4-9 atoms, wherein 1-3 atoms are heteroatomous heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomous heteroalkenyl, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, having 4-8 atoms, wherein 1-2 are heteroatomous -O-heteroalkyl, having 1 -O-(C4-C8)alkenyl with 2 double bonds, -O-heterenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond, -O-(C4-C8)haloalkenyl with 1-2 double bonds, -S-(C3-C8)alkyl, -S-heteroalkyl with 4-8 atoms, one-2 of which are heteroatoms, -S-(C4-C8)alkenyl with 1-2 double bonds, or -S-heterenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond.

[0286] In some embodiments, R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl, or an -O-(C5-C8) alkenyl having one double bond at the ω-3 position.

[0287] In some embodiments, R1 is a C1-C2 alkyl or C1-C2 hydroxyalkyl and R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl having 4-6 atoms, one of which is a heteroatom, and said heteroatom is an O-type -O-heteroalkyl or an -O-(C5-C8) alkenyl having one double bond.

[0288] In some embodiments, R1 is methyl or ethyl and R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond, an -O-(C4-C6) straight-chain alkyl, an -O-(C4-C6) hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is an O-type -O-heteroalkyl or an -O-(C5-C8) alkenyl having one double bond.

[0289] In some embodiments, R1 is methyl or ethyl and R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl, or an -O-(C5-C8) alkenyl having one double bond.

[0290] In some embodiments, R1 is methyl and R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position. In some embodiments, the double bond is Z-configured.

[0291] In some embodiments, R1 is methyl. In some embodiments, R2 is an -O-(C3-C8)alkyl group having the formula -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17. In some embodiments, R2 is an -S-(C3-C8)alkyl group having the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15, or -SC8H17. In some embodiments, R2 is an -O-(C3-C8)alkenyl group having 1-2 double bonds and may have the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3, or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 is a -S-(C3-C8) alkenyl group having 1-2 double bonds and may have the formula -SCH2CH=CHCH2CH3, -S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3 or -S(CH2)4CH=CHCH2CH3.

[0292] In some embodiments, R3, R4, and R5 are each hydrogen atoms. In some embodiments, R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, or a heteroalkyl group having 3-4 atoms, one of which is a heteroatom. In some embodiments, one or more of R3, R4, and R5 are halogen atoms. In some embodiments, one or more of R2, R3, and R4 are fluorine atoms. In some embodiments, R3 and R5 are each hydrogen atoms and R4 is a fluorine atom.

[0293] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0294] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, hydroxymethyl, or carboxylic acid ester, such as an acetate group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is hydroxymethyl.

[0295] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxamide, or carboxylic acid esters, such as acetate groups.

[0296] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups, and X is a carboxylic acid.

[0297] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid esters, such as acetate groups.

[0298] In some implementation schemes:

[0299] R1 is methyl or ethyl;

[0300] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0301] • R3, R4, and R5 are each hydrogen atoms;

[0302] n is 0 or 1;

[0303] • R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and methyl groups;

[0304] • And X is selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as acetate group.

[0305] In some implementation schemes:

[0306] R1 is a methyl group;

[0307] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0308] • R3, R4, and R5 are each hydrogen atoms;

[0309] ·n is 0;

[0310] And X is a carboxylic acid.

[0311] In some implementation schemes:

[0312] R1 is a methyl group;

[0313] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0314] • R3, R4, and R5 are each hydrogen atoms;

[0315] n is 1;

[0316] R6 and R7 are each hydrogen atoms.

[0317] And X is a carboxylic acid.

[0318] In some embodiments, the compounds of formula (I) described by group (2) are described by formula (IB-1), (IB-2), (IB-3) or (IB-4):

[0319] (IB-1), (IB-2), (IB-3), (IB-4);

[0320] R1, R2, R6 and R7 are each defined freely in any of the implementation schemes of the above group (2);

[0321] Furthermore, in some implementation schemes:

[0322] • X1 is a halogen atom;

[0323] a is 0 or 1;

[0324] Z' is H or a C1-C4 alkyl group;

[0325] R1 is a C1-C4 alkyl group;

[0326] R1 is methyl or ethyl;

[0327] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0328] • R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups;

[0329] Z1 can be -O-, -S(O)n-, or -N(R14)-.

[0330] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl having 1-2 double bonds, a heteroalkenyl having 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl having 1-2 double bonds, or a C3-C8 alkynyl having 1-2 triple bonds;

[0331] R15 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[0332] ·R9 is a hydrogen atom or a C1-C11 alkyl group.

[0333] In some embodiments, R1 is a C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl with one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom and said heteroatom is O, or an -O-(C5-C8) alkenyl with one double bond. In some embodiments, said double bond is at the ω-3 position. In some embodiments, said double bond has a Z configuration. In some embodiments, Z' is H. In some embodiments, Z' is methyl or ethyl. In some embodiments, R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl. In some embodiments, R6 and R7 together may form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0334] In some embodiments, R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatoms, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, having 4-8 atoms, wherein 1-2 are heteroatoms, -O-heteroalkyl having 5-8 atoms, wherein one is a heteroatom and has 1 double bond, or having 1-2 double bonds. -O-(C3-C8)haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl, -S(O)2-(C3-C8)alkyl, amino with hydrogen atom and C3-C8 alkyl, amino with hydrogen atom and (C1-C6) ketone group or amino with C1-C9 alkyl and C3-C8 alkyl.

[0335] Group 3 Implementation Plan

[0336] The following implementation schemes involve compounds of formula (I) described by group (3).

[0337] In some embodiments, R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms, a C4-C9 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, or an -O-(C3-C8) alkyl group. -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-(C3-C8)alkenyl with 1-2 double bonds, -O-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -O-heteroalkenyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -O-(C3-C8)haloalkenyl with 1-2 double bonds, and -O-(C3-C8)haloalkenyl with 1-2 triple bonds. -O-(C3-C8)alkynyl, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, and -S-heteroalkenyl having 1-2 double bonds. -S-(C3-C8) haloalkenyl, -S-(C3-C8) ynyl with 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, amino with hydrogen atom and C3-C8 alkyl, amino with hydrogen atom and (C1-C6) ketone group, or amino with C1-C9 alkyl and C3-C8 alkyl.

[0338] In some implementation schemes,

[0339] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl atom;

[0340] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a heteroalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; or a group with 5-8 atoms, of which 1 is a heteroatom. The following are considered compounds with the following characteristics: -O-heterenyl group having one double bond; -O-(C3-C8)haloalkenyl group having one or two double bonds; -O-(C3-C8)ynyl group having one or two triple bonds; -S-(C3-C8)alkyl group; -S-(C3-C8)hydroxyalkyl group; -S-(C3-C8)haloalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; -S-(C3-C8)alkenyl group having one or two double bonds; -S-heterenyl group having 5-8 atoms, of which one is a heteroatom and has one double bond; -S-(C3-C8)haloalkenyl group having one or two double bonds; or -S-(C3-C8)ynyl group having one or two triple bonds; and

[0341] R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl group having 3-4 atoms, one of which is a heteroatom.

[0342] In some implementation schemes,

[0343] R1 is a heteroalkyl group having 3-4 atoms, one of which is a heteroatom;

[0344] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a heteroalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; or a group with 5-8 atoms, of which 1 is a heteroatom. The following are considered compounds with the following characteristics: -O-heterenyl group having one double bond; -O-(C3-C8)haloalkenyl group having one or two double bonds; -O-(C3-C8)ynyl group having one or two triple bonds; -S-(C3-C8)alkyl group; -S-(C3-C8)hydroxyalkyl group; -S-(C3-C8)haloalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; -S-(C3-C8)alkenyl group having one or two double bonds; -S-heterenyl group having 5-8 atoms, of which one is a heteroatom and has one double bond; -S-(C3-C8)haloalkenyl group having one or two double bonds; or -S-(C3-C8)ynyl group having one or two triple bonds; and

[0345] R5 is a hydrogen atom or an -O-(C1-C4) alkyl group.

[0346] In some implementation schemes,

[0347] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, or a heteroalkyl having 3-4 atoms, one of which is a heteroatom;

[0348] R3 is a heteroalkyl group with 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkenyl group with 1-2 double bonds; a heteroalkenyl group with 5-9 atoms, of which 1-2 atoms are heteroatoms; a -O-heteroalkyl group with 4-8 atoms, of which 1-2 are heteroatoms; a -O-(C3-C8)alkenyl group with 1-2 double bonds; a -O-heteroalkenyl group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; or a -O-(C3-C8)alkenyl group with 1-2 double bonds. 3-C8) haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl with 1-2 double bonds, or -S-(C3-C8)ynyl with 1-2 triple bonds; and

[0349] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom of a heteroaryl group.

[0350] In some implementation schemes,

[0351] R1 is an -O-(C1-C4) alkyl group;

[0352] R3 is a heteroalkyl group with 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkyl group with 1-2 double bonds; a heteroalkeny group with 5-9 atoms, of which 1-2 atoms are heteroatoms; a -O-heteroalkyl group with 4-8 atoms, of which 1-2 are heteroatoms; a -O-(C3-C8)alkeny group with 1-2 double bonds; a -O-heteroalkeny group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; or a -O-(C3-C8)alkeny group with 1-2 double bonds. 3-C8) haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl with 1-2 double bonds, or -S-(C3-C8)ynyl with 1-2 triple bonds; and

[0353] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[0354] In some implementation schemes,

[0355] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[0356] R3 is a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; a -O-(C4-C8)alkenyl group having 1 double bond at the ω-3 position; and a -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and 1 double bond at the ω-3 position.

[0357] R5 is a hydrogen atom, a C1-C2 alkyl group, or an -O-(C1-C4) alkyl group.

[0358] In some implementation schemes,

[0359] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[0360] R3 is an -O-(C4-C8) alkenyl group having one double bond at the ω-3 position;

[0361] Both R2 and R4 are hydrogen atoms;

[0362] R5 is a hydrogen atom, a C1-C2 alkyl group, or an -O-(C1-C4) alkyl group.

[0363] ·n is 0; and

[0364] X is a carboxylic acid.

[0365] In some embodiments, R2 and R4 are each hydrogen atoms. In some embodiments, either R2 or R4, or both R2 and R4, are halogen atoms. In some embodiments, either R2 or R4, or both R2 and R4, are fluorine atoms.

[0366] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0367] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, hydroxymethyl, or carboxylic acid ester, such as an acetate group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is hydroxymethyl.

[0368] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxamide, or carboxylic acid esters, such as acetate groups.

[0369] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups, and X is a carboxylic acid.

[0370] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid esters, such as acetate groups.

[0371] In some embodiments, the compounds of formula (I) described by group (3) are described by formula (IC-1) or (IC-2):

[0372] (IC-1), (IC-2)

[0373] R1, R3 and R5 are each defined freely in any of the implementation schemes of the above group (3).

[0374] In some embodiments, Z' is H or a C1-C4 alkyl group. In some embodiments, Z' is H. In some embodiments, Z' is methyl or ethyl.

[0375] In some embodiments, R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl.

[0376] In some embodiments, R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms, a C4-C9 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, or an -O-(C3-C8) alkyl group. -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-(C3-C8)alkenyl with 1-2 double bonds, -O-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -O-heteroalkenyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -O-(C3-C8)haloalkenyl with 1-2 double bonds, and -O-(C3-C8)haloalkenyl with 1-2 triple bonds. -O-(C3-C8)ynyl, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, and having 1-2 double bonds. -S-(C3-C8) haloalkenyl groups with 1-2 triple bonds, -S-(C3-C8) ynyl groups, -C(O)-(C3-C8) alkyl groups, -S(O)-(C3-C8) alkyl groups, -S(O)2-(C3-C8) alkyl groups, amino groups with hydrogen atoms and C3-C8 alkyl groups, amino groups with hydrogen atoms and (C1-C6) ketone groups, or amino groups with C1-C9 alkyl groups and C3-C8 alkyl groups.

[0377] In some embodiments, R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[0378] Group 4 Implementation Plan

[0379] The following implementation schemes involve compounds of formula (I) described by group (4).

[0380] In some embodiments, R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms, a C4-C9 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, or an -O-(C3-C8) alkyl group. -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-(C3-C8)alkenyl with 1-2 double bonds, -O-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -O-heteroalkenyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -O-(C3-C8)haloalkenyl with 1-2 double bonds, and -O-(C3-C8)haloalkenyl with 1-2 triple bonds. -O-(C3-C8)alkynyl, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, and -S-heteroalkenyl having 1-2 double bonds. -S-(C3-C8) haloalkenyl, -S-(C3-C8) ynyl with 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, amino with hydrogen atom and C3-C8 alkyl, amino with hydrogen atom and (C1-C6) ketone group, or amino with C1-C9 alkyl and C3-C8 alkyl.

[0381] In some implementation schemes,

[0382] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl, -O-(C1-C4)alkyl, or a phenyl;

[0383] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a haloalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; an -O-halekenyl group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; or a group with 1-2 double bonds. -O-(C3-C8) haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl with 1-2 double bonds, -S-(C3-C8)ynyl with 1-2 triple bonds, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl or -S(O)2-(C3-C8)alkyl; and

[0384] R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl group having 3-4 atoms, one of which is a heteroatom.

[0385] In some implementation schemes,

[0386] R1 is a heteroalkyl or phenyl group having 3-4 atoms, one of which is a heteroatom;

[0387] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a haloalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; an -O-halekenyl group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; or a group with 1-2 double bonds. -O-(C3-C8) haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl with 1-2 double bonds, -S-(C3-C8)ynyl with 1-2 triple bonds, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl or -S(O)2-(C3-C8)alkyl; and

[0388] R5 is a hydrogen atom, a halogen atom, or an -O-(C1-C4) alkyl group.

[0389] In some implementation schemes,

[0390] R1 is a phenyl group;

[0391] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group having 1-2 double bonds; a haloalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C4-C8) alkenyl group having 1-2 double bonds; or an -O-harealkenyl group having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond.

[0392] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, one of which is a heteroatom; or an -O-(C1-C4)alkyl group.

[0393] In some implementation schemes,

[0394] R1 is a C1-C4 alkyl, C1-C4 haloalkyl, -O-(C1-C4)alkyl, having 3-4 atoms, one of which is a heteroatom, or a heteroalkyl or phenyl.

[0395] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a haloalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; an -O-halekenyl group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; or a group with 1-2 double bonds. -O-(C3-C8) haloalkenyl, -O-(C3-C8)ynyl with 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl with 1-2 double bonds, -S-heteroalkyl with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl with 1-2 double bonds, -S-(C3-C8)ynyl with 1-2 triple bonds, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl or -S(O)2-(C3-C8)alkyl; and

[0396] R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, or a heteroalkyl having 3-4 atoms, one of which is a heteroatom.

[0397] In some implementation schemes,

[0398] R1 is a C1-C4 alkyl, C1-C4 haloalkyl, or -O-(C1-C4)alkyl;

[0399] R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a haloalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C4-C8) alkenyl group with 1-2 double bonds; or an -O-harealkenyl group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond.

[0400] R5 is a C1-C4 alkyl or a C1-C4 haloalkyl.

[0401] In some implementation schemes,

[0402] R1 is a C1-C4 alkyl or -O-(C1-C4) alkyl;

[0403] R4 is a C4-C9 alkyl, -O-(C3-C8) alkyl, or -C(O)-(C3-C8) alkyl; and

[0404] R5 is a C1-C4 alkyl or a C1-C4 haloalkyl.

[0405] In some implementation schemes,

[0406] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, a heteroalkyl, -O-(C1-C4)alkyl, or a phenyl;

[0407] R4 is a heteroalkyl group with 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkyl group with 1-2 double bonds; a heteroalkeny group with 5-9 atoms, of which 1-2 atoms are heteroatoms; a -O-heteroalkyl group with 4-8 atoms, of which 1-2 are heteroatoms; a -O-(C3-C8)alkeny group with 1-2 double bonds; a -O-heteroalkeny group with 5-8 atoms, of which 1 is a heteroatom and has 1 double bond; a -O-(C3-C8)haloalkeny group with 1-2 double bonds; or a -O-(C3-C8)haloalkeny group with 1-2 triple bonds. -C8) alkyne, -S-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkyne having 1-2 triple bonds, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl or -S(O)2-(C3-C8)alkyl; and

[0408] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom of a heteroaryl group.

[0409] In some implementation schemes,

[0410] R1 is a C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2)alkyl, or phenyl;

[0411] R4 is a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; an -O-(C4-C8)alkenyl group having 1 double bond at the ω-3 position; or an -O-heterenyl group having 5-8 atoms, of which 1 is a heteroatom and 1 double bond at the ω-3 position.

[0412] R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, or an -O-(C1-C2) alkyl group.

[0413] In some implementation schemes,

[0414] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[0415] R4 can be a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms; a -O-(C4-C8)alkenyl group having 1 double bond at the ω-3 position; or a -O-heterenyl group having 5-8 atoms, wherein 1 is a heteroatom and 1 double bond at the ω-3 position.

[0416] R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, or an -O-(C1-C2) alkyl group.

[0417] In some implementation schemes,

[0418] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[0419] R4 is an -O-(C4-C8) alkenyl or -C(O)-(C3-C8) alkyl group having one double bond at the ω-3 position;

[0420] R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, or an -O-(C1-C2) alkyl group;

[0421] R2 and R3 are each hydrogen atoms;

[0422] ·n is 0; and

[0423] X is a carboxylic acid.

[0424] In some embodiments, R2 and R3 are each hydrogen atoms. In some embodiments, either R2 or R4, or both R2 and R4, are halogen atoms. In some embodiments, either R2 or R4, or both R2 and R4, are fluorine atoms.

[0425] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0426] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, hydroxymethyl, or carboxylic acid ester, such as an acetate group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is hydroxymethyl.

[0427] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxamide, or carboxylic acid esters, such as acetate groups.

[0428] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups, and X is a carboxylic acid.

[0429] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid esters, such as acetate groups.

[0430] In some embodiments, the compounds of formula (I) described by group (4) are described by formula (ID-1) or (ID-2):

[0431] (ID-1), (ID-2)

[0432] R1, R4 and R5 are each defined in any of the implementation schemes of the above group (4).

[0433] In some embodiments, Z' is H or a C1-C4 alkyl group. In some embodiments, Z' is H. In some embodiments, Z' is methyl or ethyl.

[0434] In some embodiments, R1 is a C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2)alkyl, or phenyl.

[0435] In some embodiments, R4 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, having 4-8 atoms, of which 1-2 are heteroatoms, -O-(C4-C8) alkenyl having 1-2 double bonds, or -O-heteroalkenyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond.

[0436] In some embodiments, R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group, or an -O-(C1-C2) alkyl group.

[0437] Group 5 Implementation Plan

[0438] The following implementation schemes involve compounds of formula (I) described by group (5).

[0439] In some implementation schemes,

[0440] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl;

[0441] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl having 4-9 atoms, of which 1-3 atoms are heteroatoms, C4-C9 alkenyl having 1-2 double bonds, heteroalkenyl having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8)alkenyl having 1-2 double bonds, -O-heteroalkyl having 4-8 atoms, of which 1-2 are heteroatoms, -O-heteroalkyl having 5-8 atoms, of which 1 is a heteroatom and has 1 double bond, -O-( -O-(C3-C8) haloalkenyl groups, -O-(C3-C8) ynyl groups with 1-2 triple bonds, -S-(C3-C8) alkyl groups, -S-(C3-C8) hydroxyalkyl groups, -S-(C3-C8) haloalkenyl groups, -S-heteroalkyl groups with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl groups with 1-2 double bonds, and -O-(C3-C8) haloalkenyl groups with 5-8 atoms, of which 1 is a heteroatom and has... -S-heterenyl groups with one double bond, -S-(C3-C8)ynyl groups with one or two triple bonds, -C(O)-(C3-C8)alkyl groups, -S(O)-(C3-C8)alkyl groups, -S(O)2-(C3-C8)alkyl groups, amino groups with hydrogen atoms and C3-C8 alkyl groups, amino groups with hydrogen atoms and (C1-C6) ketone groups, and amino groups with C1-C9 alkyl groups and C3-C8 alkyl groups; and

[0442] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[0443] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl having 4-9 atoms, wherein 1-3 atoms are heteroatoms, C4-C9 alkenyl having 1-2 double bonds, heteroalkenyl having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, and -O-heteroalkyl having 5-8 atoms, wherein 1 The following are heteroatom-containing compounds: -O-heteroalkenyl, -O-(C3-C8)haloalkenyl, -O-(C3-C8)ynyl, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-(C3-C8)alkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms; -S-(C3-C8)alkenyl with 1-2 double bonds; -S-heteroalkenyl with 5-8 atoms, of which 1 is a heteroatom and has a double bond; -S-(C3-C8)haloalkenyl with 1-2 double bonds; or -S-(C3-C8)ynyl with 1-2 triple bonds.

[0444] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C9 alkyl groups having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl groups; C4-C9 alkenyl groups having 1-2 double bonds; heteroalkenyl groups having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl groups; -O-(C3-C8)alkyl groups; -O-(C3-C8)hydroxyalkyl groups; -O-(C3-C8) haloalkyl groups having 4-8 atoms, wherein 1-2 are heteroatomic -O-alkyl groups. -heteroalkyl, -O-(C3-C8)alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, one of which is a heteroatom and having 1 double bond, -O-(C3-C8)haloalkenyl having 1-2 double bonds, -S-(C3-C8)alkyl, -S-heteroalkyl having 4-8 atoms, one of which is a heteroatom, -S-(C3-C8)alkenyl having 1-2 double bonds, or -S-heteroalkenyl having 5-8 atoms, one of which is a heteroatom and having 1 double bond.

[0445] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C8 straight-chain alkyl, C6-C8 alkenyl with one double bond, -O-(C4-C6)alkyl, -O-(C4-C6)hydroxyalkyl, -O-(C4-C6)haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is an O-type -O-heteroalkyl or an -O-(C5-C8) alkenyl with one double bond. In some embodiments, the double bond is at the ω-3 position. In some embodiments, the double bond is Z-configured.

[0446] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C8 alkyl or -O-(C3-C8) alkyl and have the formula -C4H9, -C5H11, -C6H13, -C7H15, -C8H17, -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -S-(C3-C8) alkyl and have the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15, or -SC8H17. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -O-(C3-C8) alkenyl groups having 1-2 double bonds and having the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3, or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -S-(C3-C8) alkenyl groups having 1-2 double bonds and having the formula -SCH2CH=CHCH2CH3, -S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3, or -S(CH2)4CH=CHCH2CH3.

[0447] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C8 straight-chain alkyl, -O-(C4-C6) alkyl and -O-heteroalkyl having 4-6 atoms, one of which is a heteroatom, and said heteroatom is O;

[0448] In some embodiments, R1 and R5 may be the same or different, and are independently selected from C1-C4 alkyl groups. In some embodiments, R1 and R5 may be the same or different, and are independently selected from methyl or ethyl groups. In some embodiments, R1 and R5 are the same and are both methyl.

[0449] In some embodiments, R1 and R5 may be the same or different, and are independently selected from -O-(C1-C4) alkyl groups. In some embodiments, both R1 and R5 are -OCH3.

[0450] In some embodiments, R5 is a hydrogen atom. In some embodiments, R1 is a C1-C4 alkyl or -O-(C1-C4)alkyl and R5 is a hydrogen atom. In some embodiments, R1 is methyl or ethyl and R5 is a hydrogen atom. In some embodiments, R1 is -OCH3 or -OCH2CH3 and R5 is a hydrogen atom. In some embodiments, R5 is a halogen atom. In some embodiments, R5 is a fluorine atom.

[0451] In some embodiments, R3 is a hydrogen atom. In other embodiments, R3 is a halogen atom. In some embodiments, R3 is a fluorine atom.

[0452] In some implementation schemes,

[0453] R1 is a methyl group or -OCH3;

[0454] R2 and R4 may be the same or different, and are independently selected from C4-C8 straight-chain alkyl, -O-(C4-C6) alkyl and -O-heteroalkyl having 4-6 atoms, one of which is a heteroatom, and said heteroatom is O;

[0455] R3 is a hydrogen atom;

[0456] • R5 is a hydrogen atom, a methyl group, or -OCH3;

[0457] ·n is 0; and

[0458] X is a carboxylic acid.

[0459] In some implementation schemes,

[0460] R1 is a methyl group or -OCH3;

[0461] R2 and R4 are the same and are selected from C4-C8 straight-chain alkyl and -O-(C4-C6) alkyl;

[0462] R3 represents a hydrogen atom;

[0463] • R5 is a hydrogen atom, a methyl group, or -OCH3;

[0464] ·n is 0; and

[0465] X is a carboxylic acid.

[0466] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0467] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, hydroxymethyl, or carboxylic acid ester, such as an acetate group. In some embodiments, n is 0 and X is a carboxylic acid. In some embodiments, n is 0 and X is a carboxamide having the formula -C(O)NH2. In some embodiments, n is 0 and X is hydroxymethyl.

[0468] In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 2 and R6 and R7 are the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In some embodiments, n is 1 or 2 and X is selected from hydroxymethyl, carboxylic acid, carboxamide, or carboxylic acid esters, such as acetate groups.

[0469] In some embodiments, n is 1 and R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C2 alkyl groups. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms. In some embodiments, n is 1 and both R6 and R7 are methyl groups. In some embodiments, R6 is methyl and R7 is hydrogen. In some embodiments, n is 1 and both R6 and R7 are hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups, and X is a carboxylic acid.

[0470] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid esters, such as acetate groups.

[0471] In some embodiments, the compounds of formula (I) described by group (5) are described by formula (IE-1) or (IE-2):

[0472] (ID-1), (ID-2)

[0473] R1, R2, R4 and R5 are each defined in any of the implementation schemes of the above group (5).

[0474] In some embodiments, Z' is H or a C1-C4 alkyl group. In some embodiments, Z' is H. In some embodiments, Z' is methyl or ethyl.

[0475] In some embodiments, R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[0476] In some embodiments, R2 and R4 may be the same or different, and are independently selected from C4-C8 alkyl or -O-(C3-C8) alkyl and have the formula -C4H9, -C5H11, -C6H13, -C7H15, -C8H17, -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -S-(C3-C8) alkyl and have the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15, or -SC8H17. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -O-(C3-C8) alkenyl groups having 1-2 double bonds and having the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3, or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 and R4 may be the same or different, and are independently selected from -S-(C3-C8) alkenyl groups having 1-2 double bonds and may have the formula -SCH2CH=CHCH2CH3, -S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3, or -S(CH2)4CH=CHCH2CH3.

[0477] In some embodiments, R5 is a hydrogen atom, a methyl group, or -OCH3. In some embodiments, R5 is a fluorine atom.

[0478] Salt

[0479] This disclosure also relates to salts of compounds of formula (I). Such salts can be represented as

[0480]

[0481] Where X is COO- and Z+ can be NH4+; metal ions, such as Li+, Na+, K+, Mg2+ or Ca2+; protonated primary amines, such as tert-butylammonium, (3S,5S,7S)-adamantane-1-ammonium, 1,3-dihydroxy-2-(hydroxymethyl)prop-2-ammonium, protonated aminopyridine (e.g., pyridine-2-ammonium); protonated secondary amines, such as diethylammonium, 2,3,4,5,6-pentahydroxy-N-methylhexane-1-ammonium, N-ethylnaphthyl-1-ammonium, protonated tertiary amines, such as 4-methylmorpholino-4-ammonium, quaternary amines, such as 2-hydroxy-N,N,N-trimethylethyl-1-ammonium, and protonated guanidines, such as amino((4-amino-4-carboxybutyl)amino)methylammonium, or protonated heterocycles, such as 1H-imidazol-3-ammonium. Other examples of suitable salts include salts of diprotonated diamines, such as ethane-1,2-diammonium or piperazine-1,4-diammonium.

[0482] or

[0483]

[0484] Where X = COO-, and Z2+ can be Mg2+ or Ca2+, or a diprotonated diamine, such as ethane-1,2-diammonium or piperazine-1,4-diammonium.

[0485] Examples of pharmaceutically acceptable salts are also described, for example, in Pharmaceutical Salts: Properties, Selection, and Use, Second Revised Edition, P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.).

[0486] Some of the compounds of the present invention may exist in zwitterionic form, and the present invention includes zwitterionic forms of these compounds and mixtures thereof.

[0487] This disclosure also relates to prodrugs of compounds of formula (I). Examples of such prodrugs include pharmaceutically acceptable esters or amides obtained by reacting an alcohol or amine (including amino acids) with a free acid as defined in formula I.

[0488] Compounds of formula (I) can exist in stereoisomeric forms. It should be understood that this invention covers all optical isomers of compounds of formula (I) and mixtures thereof. Therefore, compounds of formula (I) existing as diastereomers, racemates, and enantiomers are included within the scope of this disclosure. This disclosure also relates to at least one lipid compound of formula (I) used as a pharmaceutical.

[0489] It should also be understood that some compounds of formula (I) may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention covers all such solvated forms that are biologically active.

[0490] preparation

[0491] "Pharmaceutical composition" refers to any form of compound according to the invention suitable for use in a medical purpose. The term "pharmaceutical acceptable" means a drug, preparation, inert ingredient, etc., suitable for contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic reactions, etc., and which has a reasonably reasonable benefit / risk ratio.

[0492] "Pharmaceutically acceptable mediators" refer to diluents, adjuvants, excipients, or carriers used in conjunction with a compound. Pharmaceutically acceptable mediators can be solvents or dispersion media, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Other examples of pharmaceutically acceptable mediators include, but are not limited to: water for injection (USP); aqueous mediators, such as, but not limited to, sodium chloride injection, Ringer's injection, dextran injection, dextran and sodium chloride injection, and lactated Ringer's injection; water-miscible mediators, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous mediators, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0493] Microbial activity can be prevented by adding antimicrobial and antifungal agents. Examples of such agents include parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Isotonic agents may be included in the formulation. Examples of isotonic agents in compositions include sugars, sodium chloride, or polyols such as mannitol and sorbitol.

[0494] The compounds of the present invention can be formulated using feasible techniques and methods prior to administration of the pharmaceutical composition. For example, the pharmaceutical composition can be formulated in a manner suitable for administration via local, oral, intravenous (iv), intramuscular (im), intramuscular long-acting (depo-im), subcutaneous (sc), subcutaneous long-acting (depo-sc), sublingual, intranasal, intrathecal, or rectal routes.

[0495] Preferably, the compounds of the present invention can be administered orally or intravenously. The formulation can be conveniently available in unit dosage forms and can be prepared by any method known in the field of pharmaceutical science. In such therapeutically useful compositions, the amount of therapeutic agent is the appropriate dose obtained.

[0496] The compounds and compositions of the present invention can be formulated into conventional oral administration forms, such as tablets, coated tablets, capsules, powders, granules, solutions, dispersants, suspensions, syrups, emulsions, sprays, etc., using conventional excipients, such as solvents, diluents, binders, sweeteners, aromas, pH adjusters, viscosity adjusters, antioxidants (e.g., tocopherol), corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerin, sorbitol, polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose, or fatty substances such as stearin or suitable mixtures thereof. Conventional formulation techniques known in the art can be used.

[0497] Formulations of the present invention suitable for oral administration may be in the form of capsules (e.g., hard or soft-shell gelatin capsules), flat capsules, pills, tablets, lozenges, powders, granules, pellets, sugar-coated pills, such as coated (e.g., enteric-coated) or uncoated, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as pastils or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered in the form of large pills, medicated sugars, or pastes, or directly incorporated into the subject's diet. Furthermore, in some embodiments, these pills may be formulated to (a) provide immediate or rapid drug release (i.e., without a coating); (b) be coated, for example, to provide sustained drug release over time; or (c) be coated with an enteric coating to improve gastrointestinal tolerance. Coating can be achieved using conventional methods, typically with pH or time-varying coatings, allowing the compounds of the present invention to be released near the desired site or at different times to prolong the desired action. Such formulations typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, waxes, and shellac.

[0498] In solid dosage forms for oral administration, the compounds of the present invention may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; humectants, such as glycerin; disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and colorants. For capsules, tablets, and pills, the pharmaceutical compositions may also contain buffers. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0499] Oral compositions include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable media suitable for preparing such compositions are well known in the art. Typical components of carriers used in syrups, elixirs, emulsions, and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, astragalus gum, and sodium alginate. Typical wetting agents include lecithin and polysorbate 80; additionally, typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavoring agents, and coloring agents.

[0500] Pharmaceutical formulations suitable for injection (e.g., via IV) may include sterile aqueous solutions (in the case of water solubility) or dispersants, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersants. Dispersants can be prepared by incorporating a therapeutic agent into a sterile medium comprising a basic dispersion medium and the other desired components described above. For sterile powders used to prepare sterile injectable solutions, preparation methods include vacuum drying and freeze-drying of a pre-sterile filtered solution of the active ingredient to produce a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired components. Extended absorption of the injectable composition can be achieved by including a delayed-absorption agent, such as aluminum monostearate or gelatin, in the composition.

[0501] Injectable compositions must be sterile and must be fluids that are readily injectable. They must remain stable under production and storage conditions and must be preserved to prevent contamination by microorganisms such as bacteria and fungi. Sterile injectable solutions can be prepared by incorporating the desired amount of the therapeutic agent in a suitable solvent into one or a combination of the components listed above (if desired), followed by filtration and sterilization.

[0502] The compounds according to the invention can be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. The compounds of the invention can be prepared into compositions in glycerol, liquid polyethylene glycol, mixtures thereof, and oils. Under normal storage and use conditions, the formulation may contain preservatives to prevent microbial growth.

[0503] Pharmaceutical formulations suitable for administration by inhalation in aerosol form are also provided. These formulations comprise solutions or suspensions of a plurality of solid particles of a desired compound or such compound of any kind described herein. For example, metal salts of the compounds of the present invention, rather than free acid forms of these compounds, are contemplated to have physicochemical properties suitable for the preparation of fine particles of active pharmaceutical ingredient (API) for administration by inhalation. The desired formulation can be placed in a chamber and nebulized. Nebulization can be accomplished by compressed air or ultrasonic energy to form a plurality of droplets or solid particles containing the reagent or salt. The particle size of the droplets or solid particles should be in the range of about 0.5 to about 5 micrometers. Solid particles can be obtained by any suitable method known in the art, for example by micronization of a solid reagent or salt thereof of any kind described herein. The size of the solid particles or droplets will be, for example, about 1 to about 2 micrometers. In this regard, commercial nebulizers can be used to achieve this purpose. Pharmaceutical formulations suitable for administration as aerosols can be in liquid form, which will contain a water-soluble reagent or salt thereof of any kind described herein in a water-containing carrier. A surfactant may be present that reduces the surface tension of the formulation, thereby enabling droplet formation within the desired size range during atomization.

[0504] The compositions of the present invention can also be applied topically to a subject, for example by applying or spreading the composition directly onto the subject's epidermis or epithelial tissue, or by transdermal application via a "patch". Such compositions include, for example, lotions, creams, solutions, gels, emulsions, and solids. These topical compositions may contain an effective amount, typically from about 0.01% to about 10% (w / w), or from about 0.1% to about 5% (w / w), or from about 1% to about 5% (w / w) of the compound of the present invention. Suitable carriers for topical application are typically retained on the skin as a continuous film and resist removal due to sweating or immersion in water. Typically, the carrier is organic in nature and capable of dispersing or dissolving the therapeutic agent therein. The carrier may include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents, etc. The carrier may include vernix. Topical formulations include one or more excipients, such as, but not limited to, protectants, adsorbents, soothing agents, emollients, preservatives, antioxidants, moisturizers, buffers, solubilizers, skin penetrants, and surfactants.

[0505] Suitable protective and absorbent agents include, but are not limited to, dusting powders, zinc stearate, PVC foam, dimethicone, silicone, zinc carbonate, aloe vera gel and other aloe vera products, vitamin E oil, allantoin, glycerin, petrolatum, and zinc oxide. Suitable soothing agents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.

[0506] Suitable emollients include, but are not limited to, animal and vegetable oils, myristicin, alum, and aluminum acetate. Suitable preservatives include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzyl chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercury agents such as phenylmercuric nitrate, phenylmercuric acetate, and thiomercuric sulfate; alcoholic agents such as chlorobutanol, phenethyl alcohol, and benzyl alcohol; antimicrobial esters such as esters of p-hydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid, and polymyxin.

[0507] Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid.

[0508] Suitable humectants include, but are not limited to, glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Buffers suitable for use in this invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactate buffers, and borate buffers.

[0509] Suitable solubilizers include, but are not limited to, quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate.

[0510] Suitable skin penetrants include, but are not limited to, ethanol, isopropanol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate and propylene monooleate); and N-methylpyrrolidone.

[0511] Other compositions for achieving systemic delivery of the subject reagent may include sublingual, buccal, and nasal dosage forms. Such compositions typically contain one or more soluble fillers, such as sucrose, sorbitol, and mannitol; and binders, such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. They may also include flow aids, lubricants, sweeteners, colorants, antioxidants, and flavorings.

[0512] use

[0513] Compounds of formula (I) and their pharmaceutical preparations can be used to treat a variety of diseases and disorders. In particular, compounds of formula (I) can be used to treat diseases and disorders associated with dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, and cholestasis.

[0514] "Treatment" includes any therapeutic application that can benefit humans or non-human mammals. Treatment for both humans and animals is within the scope of this invention. Treatment can be for existing conditions or preventative, i.e., preventative measures.

[0515] Dyslipidemia and metabolic syndrome

[0516] Factors such as high LDL / non-HDL cholesterol, hypertriglyceridemia (HTG), and low HDL cholesterol are characteristic of metabolic syndrome, representing a combination of lipid and non-lipid (e.g., hypertension) risk factors of metabolic origin. Metabolic syndrome is closely associated with a pervasive metabolic disorder called insulin resistance, in which the normal function of insulin is impaired. The condition is characterized by abnormally high blood cholesterol and / or lipid levels, including hypercholesterolemia, hyperlipidemia (hyperlipoproteinemia), HTG, and mixed dyslipidemia. Current medications for treating hyperlipidemia (e.g., statins, omega-3 fatty acids, fibrates) generally have a neutral effect on glycemic control, while medications for glycemic control (e.g., insulin, thiazolidinediones (TZDs)) have adverse effects on weight and other harmful side effects (for TZDs), thus limiting their use.

[0517] Surprisingly, compounds of formula (I) were found to reduce APOE in patients fed a high-fat, high-cholesterol diet. Plasma triglyceride and total cholesterol levels in 3 Leiden mice. Furthermore, surprisingly, in the ob / ob mouse model, the compound of formula (I) also improved glycemic control by reducing postprandial total plasma glucose levels, fasting glucose levels, and fasting plasma insulin levels. Surprisingly, unlike current drugs used to target glycemic control (e.g., insulin, thiazolidinediones), the compound of formula (I) also resulted in weight loss in this model.

[0518] In some embodiments, the compound of formula (I) can be used to lower plasma triglycerides and / or total cholesterol. In some embodiments, the compound of formula (I) can be used to treat conditions of dyslipidemia, such as hypertriglyceridemia and / or hypercholesterolemia. In some embodiments, treatment of conditions of dyslipidemia such as hypertriglyceridemia and / or hypercholesterolemia can be preventative.

[0519] Some embodiments may include the use of a compound of formula (I) for lowering plasma triglycerides and / or total cholesterol. Some embodiments may include the use of a compound of formula (I) for treating conditions of dyslipidemia, such as hypertriglyceridemia and / or hypercholesterolemia. The use may be preventative.

[0520] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for lowering plasma triglycerides and / or total cholesterol. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating dyslipidemia (e.g., hypertriglyceridemia and / or hypercholesterolemia). In some embodiments, the use or treatment may be preventative.

[0521] In some embodiments, the compound of formula (I) can be used to lower plasma insulin levels. In some embodiments, the compound of formula (I) can be used to lower fasting plasma insulin levels. In some embodiments, the compound of formula (I) can be used to increase glucose tolerance and / or lower postprandial glucose levels. In some embodiments, the compound of formula (I) can be used to lower fasting blood glucose levels. In some embodiments, the compound of formula (I) can be used to treat diabetes, such as type 2 diabetes. In some embodiments, the treatment of said diabetes (such as type 2 diabetes) can be preventative.

[0522] Some embodiments may include the use of a compound of formula (I) for lowering plasma insulin levels. Some embodiments may include the use of a compound of formula (I) for lowering fasting plasma insulin levels. Some embodiments may include the use of a compound of formula (I) for increasing tolerability and / or lowering postprandial glucose levels. Some embodiments may include the use of a compound of formula (I) for lowering fasting blood glucose levels. Some embodiments may include the use of a compound of formula (I) for treating diabetes, such as type 2 diabetes. In some embodiments, the use may be preventative.

[0523] In some embodiments, the compound of formula (I) can be used to manufacture a drug that lowers plasma insulin levels. In some embodiments, the compound of formula (I) can be used to manufacture a drug for lowering fasting plasma insulin levels. In some embodiments, the compound of formula (I) can be used to manufacture a drug for increasing glucose tolerance and / or lowering postprandial glucose levels. In some embodiments, the compound of formula (I) can be used to manufacture a drug for lowering fasting blood glucose levels. In some embodiments, the compound of formula (I) can be used as a drug for treating diabetes (e.g., type 2 diabetes). In some embodiments, the use or treatment may be preventative.

[0524] In some embodiments, the compound of formula (I) can be used for weight loss. In some embodiments, the compound of formula (I) can be used for weight loss in overweight individuals. In some embodiments, the compound of formula (I) can be used for weight loss in individuals suffering from metabolic syndrome.

[0525] Some embodiments may include the use of a compound of formula (I) for weight loss. Some embodiments may include the use of a compound of formula (I) for weight loss in overweight individuals. Some embodiments may include the use of a compound of formula (I) for weight loss in individuals suffering from metabolic syndrome.

[0526] In some embodiments, the compound of formula (I) can be used to manufacture a drug for weight loss. In some embodiments, the compound of formula (I) can be used to manufacture a drug for weight loss in overweight individuals. In some embodiments, the compound of formula (I) can be used to manufacture a drug for weight loss in individuals suffering from metabolic syndrome.

[0527] Nonalcoholic fatty liver disease and steatohepatitis

[0528] Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver disorders characterized by the accumulation of lipids in the liver, including isolated hepatic steatosis (historically >5% of hepatocytes) that is not caused by alcohol consumption. Subgroups of NAFLD patients, in addition to hepatic steatosis, a condition known as nonalcoholic steatohepatitis (NASH), also exhibit hepatocellular damage and inflammation. NASH significantly increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

[0529] The main histological components of NASH are steatosis, hepatocyte swelling, and lobular inflammation. Fibrosis is not part of the histological definition of NASH. Hepatocyte swelling is generally defined as an increase in cell size of 1.5–2 times the normal hepatocyte diameter, accompanied by cytoplasmic sparseness, and has been shown to be associated with fibrosis and liver injury. However, the degree of fibrosis (stage) on liver biopsy is predictable prognostically, while the degree of inflammation and necrosis (grading) on ​​liver biopsy is not. Despite the significant role of fibrosis in clinical outcomes, regulatory approval for novel and effective drugs for the treatment of NASH involves the clinical NAFLD activity score (NAS score) without addressing the progression of fibrosis. The NAS score encompasses steatosis, lobular inflammation, and hepatocyte swelling.

[0530] The new findings are that the compound of formula (I) significantly reduced hepatic expression of α-11 collagen 1 in an ob / ob A MLN-diet mouse NASH model. α-11 collagen 1 is a key gene involved in liver fibrosis after 4 weeks of treatment. It was also found that, in this model, the compound of formula (I) reduced hepatic expression of CD68, a marker of hepatic macrophages (and therefore a symbol of inflammation). Furthermore, the compound of formula (I) significantly reduced hepatic steatosis in mice fed a high-carbohydrate, fat-free diet.

[0531] In some embodiments, the compound of formula (I) can be used to treat NAFLD. In some embodiments, the treatment of NAFLD can be preventative. In some embodiments, the compound of formula (I) can be used to treat NASH. In some embodiments, the treatment of NASH can be preventative. In some embodiments, the compound of formula (I) can be used to reduce or prevent the development of liver fibrosis or reduce existing liver fibrosis. In some embodiments, the compound of formula (I) can be used to reduce or prevent the development of liver inflammation in NASH or alleviate existing liver inflammation. In some embodiments, the compound of formula (I) can be used to reduce or prevent hepatic steatosis in NAFLD or NASH or reduce existing hepatic steatosis.

[0532] Some embodiments may include the use of a compound of formula (I) for the treatment of NAFLD. Some embodiments may include the use of a compound of formula (I) for the treatment of NASH. Some embodiments may include the use of a compound of formula (I) for the treatment of the development of liver fibrosis in NASH or to reduce existing liver fibrosis. Some embodiments may include the use of a compound of formula (I) for the treatment of the development of liver inflammation in NASH or to reduce existing liver inflammation. Some embodiments may include the use of a compound of formula (I) for the reduction or preventative treatment of the development of hepatic steatosis in NAFLD or NASH or to reduce existing hepatic steatosis.

[0533] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating NAFLD. In some embodiments, the treatment of NAFLD can be preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating NASH. In some embodiments, the treatment of NASH is preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of liver fibrosis or reducing existing liver fibrosis in NASH. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of liver inflammation in NASH or alleviating existing liver inflammation. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of hepatic steatosis or reducing existing hepatic steatosis in NAFLD or NASH.

[0534] cholestasis

[0535] Cholestasis is a reduction or cessation of bile flow, leading to impaired bile salt homeostasis. Several liver diseases are associated with cholestasis, including hepatobiliary disorders such as primary biliary cholangitis and sclerosing cholangitis, as well as parenteral nutrition-associated liver disease (PNALD). NAFLD and NASH are also associated with impaired bile salt homeostasis.

[0536] Primary biliary cholangitis is characterized by progressive deterioration of the bile ducts, leading to the retention of bile acids in the liver. Sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, resulting in narrowing of the bile ducts that normally allow bile to drain from the gallbladder. These diseases can lead to liver inflammation, fibrosis, and cirrhosis.

[0537] Parenteral nutrition (PN) is a life-saving therapy for patients with intestinal failure who are unable to absorb nutrients through the enteral route. However, long-term PN dependence puts patients at risk of developing PN-associated liver disease (PNALD), characterized by hepatic steatosis, inflammation, and cholestasis, which can progress to fibrosis and cirrhosis. End-stage liver disease requires a liver transplant and can lead to death if left untreated.

[0538] Impaired bile salt homeostasis (one of the causes of cholestasis) has been shown to be associated with increased expression of CYP7A1 (the rate-limiting step mediating bile acid synthesis) and decreased hepatic expression of ABBC2 (which mediates bilirubin excretion via Mrp2). Dysregulation of CYP7A1 and ABBC2 has been shown to occur in PNALD models. Zhan et al., Am J Physiol Gastrointest Liver Physiol., 2016; 310(2): G93-G102; Koelfat et al., Clin Nutr., 2017; 36(5): 1403-1410.

[0539] The new finding is that the compound of formula (I) affected the hepatic expression of genes involved in bile salt homeostasis in an ob / ob AML-N diet mouse model. Specifically, the compound of formula (I) simultaneously reduced CYP7A1 expression and increased ABBC2 expression, which may be advantageous in the treatment or prevention of PNALD and other hepatobiliary disorders involving cholestasis.

[0540] Another new finding is that the compound of formula (I) reduced hepatic steatosis in an oral PN diet mouse model. It was also found that the compound of formula (I) reduced the expression of α-1 type 1 collagen in an ob / ob A MLN-diet mouse model, which may be beneficial for reducing or preventing fibrosis and / or reducing existing fibrosis in PNALD and disorders characterized by liver fibrosis.

[0541] In some embodiments, the compound of formula (I) can be used to treat hepatobiliary disorders. In some embodiments, the treatment of the hepatobiliary disorders is preventative. In some embodiments, the compound of formula (I) can be used to treat sclerosing cholangitis. In some embodiments, the treatment of sclerosing cholangitis can be preventative. In some embodiments, the compound of formula (I) can be used to treat primary biliary cholangitis. In some embodiments, the treatment of primary biliary cholangitis can be preventative. In some embodiments, the compound of formula (I) can be used to improve bile salt homeostasis. In some embodiments, the compound of formula (I) can be used to improve bile salt homeostasis in hepatobiliary disorders such as sclerosing cholangitis or primary biliary cholangitis.

[0542] Some embodiments may include the use of a compound of formula (I) for the treatment of hepatobiliary disorders. Some embodiments may include the use of a compound of formula (I) for the treatment of sclerosing cholangitis. Some embodiments may include the use of a compound of formula (I) for the treatment of biliary cholangitis. Some embodiments may include the use of a compound of formula (I) for the improvement of bile salt homeostasis. Some embodiments may include the use of a compound of formula (I) for the improvement of bile salt homeostasis in hepatobiliary disorders such as sclerosing cholangitis or primary biliary cholangitis.

[0543] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating hepatobiliary diseases. In some embodiments, the treatment of said hepatobiliary disease is preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating sclerosing cholangitis. In some embodiments, the treatment of said sclerosing cholangitis can be preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating primary biliary cholangitis. In some embodiments, the treatment of said primary biliary cholangitis can be preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for improving bile salt homeostasis. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for improving bile salt homeostasis in hepatobiliary diseases such as sclerosing cholangitis or primary biliary cholangitis.

[0544] In some embodiments, the compound of formula (I) can be used to reduce or prevent the development of liver inflammation or reduce existing liver inflammation in hepatobiliary conditions such as sclerosing cholangitis or primary biliary cholangitis. In some embodiments, the compound of formula (I) can be used to reduce or prevent the development of liver fibrosis or reduce existing liver fibrosis in hepatobiliary conditions such as sclerosing cholangitis or primary biliary cholangitis.

[0545] Some embodiments may include the use of compounds of formula (I) for the purpose of reducing or preventing the development of liver inflammation or reducing existing liver inflammation in hepatobiliary conditions (such as sclerosing cholangitis or primary biliary cholangitis). Some embodiments may include the use of compounds of formula (I) for the purpose of reducing or preventing the development of liver fibrosis or reducing existing liver fibrosis in hepatobiliary conditions (such as sclerosing cholangitis or primary biliary cholangitis).

[0546] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of liver inflammation or reducing existing liver inflammation in hepatobiliary conditions such as sclerosing cholangitis or primary biliary cholangitis. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing liver fibrosis or reducing existing liver fibrosis in hepatobiliary conditions such as sclerosing cholangitis or primary biliary cholangitis.

[0547] In some embodiments, the compound of formula (I) can be used to treat PNALD. In some embodiments, the treatment of PNALD can be preventative. In some embodiments, the compound of formula (I) can be used to improve bile salt homeostasis in PNALD. In some embodiments, the compound of formula (I) can be used to reduce or preventatively treat hepatic steatosis or reduce existing hepatic steatosis in PNALD. In some embodiments, the compound of formula (I) can be used to reduce or preventatively treat the development of liver inflammation or reduce existing liver inflammation in PNALD. In some embodiments, the compound of formula (I) can be used to reduce or preventatively treat the development of liver fibrosis or reduce existing liver fibrosis in PNALD.

[0548] Some embodiments may include the use of a compound of formula (I) for the treatment of PNALD. Some embodiments may include the use of a compound of formula (I) for improving bile salt homeostasis in PNALD. Some embodiments may include the use of a compound of formula (I) for reducing or preventing the development of liver inflammation or reducing existing liver inflammation in PNALD. Some embodiments may include the use of a compound of formula (I) for reducing or preventing the development of liver fibrosis or reducing existing liver fibrosis in PNALD.

[0549] In some embodiments, the compound of formula (I) can be used to manufacture a medicament for treating PNALD. In some embodiments, the treatment of PNALD can be preventative. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for improving bile salt homeostasis in PNALD. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of hepatic steatosis or reducing existing hepatic steatosis in PNALD. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of liver inflammation or reducing existing liver inflammation in PNALD. In some embodiments, the compound of formula (I) can be used to manufacture a medicament for reducing or preventing the development of liver fibrosis or reducing existing liver fibrosis in PNALD.

[0550] Dosage and administration

[0551] Suitable daily doses of the disclosed compounds, such as those of formula (I), can range from about 5 mg to about 2 g, for example, from about 25 mg to about 1 g. For example, in some embodiments, the daily dose is from about 10 mg to about 1 g, from about 25 mg to about 750 mg, from about 30 mg to about 600 mg, from about 35 mg to about 500 mg, from about 40 mg to about 300 mg, from about 45 mg to about 250 mg, from about 50 mg to about 200 mg, from about 20 to about 100 mg, or from about 25 to about 75 mg. In at least one embodiment, the daily dose is from about 30 mg to about 70 mg. In at least one embodiment, the daily dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 600 mg. mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg. The compound may be administered, for example, once, twice, or three times daily. In at least one embodiment, the compound of formula (I) is administered in amounts ranging from about 20 mg to about 300 mg per dose. In some embodiments, the compound of formula (I) is administered in amounts ranging from about 25 mg to about 100 mg. In at least one embodiment, the compound of formula (I) is administered once daily.

[0552] In some embodiments, the dosage may be provided as one dose per day or multiple doses per day. For example, the daily dose may be provided as two, three, or four doses per day. In some embodiments, the daily dose may be provided as a single dose per day.

[0553] In some implementations, the dosage is not necessarily administered daily. In some implementations, the dosage may be administered every other day, every three days, every four days, twice a week, or once a week.

[0554] In some embodiments, the compound of formula (I) is administered once daily at a dose of 30 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 40 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 50 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 75 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 100 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 150 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 200 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 250 mg. In some embodiments, the compound of formula (I) is administered once daily at a dose of 300 mg.

[0555] "Active amount of medicine" refers to the amount that will result in the desired pharmacological and / or therapeutic effect, i.e., the amount of the combination product that effectively achieves its intended purpose. Although individual patient needs may vary, the optimal range for determining the effective amount of the combination product remains within the scope of the art. Typically, the dosage regimen for treating a condition with the combination product of the present invention is selected based on a variety of factors including patient type, age, weight, sex, diet, and medical condition.

[0556] Unless otherwise stated, all figures used in the specification and claims to represent quantities of ingredients, reaction conditions, concentrations, properties, etc., should be understood to be modified by the term "about" in all cases. At a minimum, each numerical parameter should be interpreted according to the number of significant figures reported and by applying common rounding techniques. Therefore, unless otherwise indicated, the numerical parameters set forth in this specification and the appended claims are approximate values ​​that may vary depending on the properties sought to be obtained. While the numerical ranges and parameters illustrating a broad range of embodiments are approximate, the values ​​set forth in specific examples are reported as precisely as possible. However, any numerical value inherently contains some error due to variations in experimental, test measurements, statistical analyses, etc.

[0557] This invention is not intended to be limited to the embodiments shown herein, but should be given the broadest scope consistent with the principles and novel features disclosed herein. Those skilled in the art will recognize or be able to identify many equivalents of the specific methods, embodiments, claims, and examples described herein using only conventional experimentation. Such equivalents are considered to be within the scope of this invention. The disclosed invention is further illustrated by the following examples, which should not be construed as limiting the invention.

[0558] Examples of compounds of formula (I)

[0559] This disclosure relates to the following non-limiting examples of compounds of formula (I).

[0560] Group 1

[0561] Example 1.

[0562]

[0563] 2-Methyl-6-(pentoxy)benzoic acid

[0564] Example 2.

[0565]

[0566] 2-Methoxy-6-(pentoxy)benzoic acid

[0567] Example 3.

[0568]

[0569] (Z)-2-(hex-3-en-1-yl)-6-methylbenzoic acid

[0570] Group 2

[0571] Example 1.

[0572]

[0573] 3-Butoxy-2-methylbenzoic acid

[0574] Example 2.

[0575]

[0576] 3-(hexyloxy)-2-methylbenzoic acid

[0577] Example 3.

[0578]

[0579] 3-Hexyl-2-methylbenzoic acid

[0580] Example 4.

[0581]

[0582] 2-Methyl-3-octylbenzoic acid

[0583] Example 5.

[0584]

[0585] (Z)-2-Methyl-3-(oct-5-en-1-yl)benzoic acid

[0586] Example 6.

[0587]

[0588] (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoic acid

[0589] Example 7.

[0590]

[0591] (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoic acid

[0592] Example 8.

[0593]

[0594] (Z)-3-(hex-3-en-1-yl)-2-methylbenzoic acid

[0595] Example 9.

[0596]

[0597] (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (“Compound B”)

[0598] Example 10.

[0599]

[0600] 2-Methyl-3-(pentoxy)benzoic acid (“Compound A”)

[0601] Example 11.

[0602]

[0603] (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzamide (“Compound C”)

[0604] Example 12.

[0605]

[0606] (Z)-(2-Methyl-3-(pent-2-en-1-yloxy)phenyl)methanol

[0607] Example 13.

[0608]

[0609] (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid

[0610] Example 14.

[0611]

[0612] (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid

[0613] Example 15.

[0614]

[0615] (Z)-2-Ethyl-3-(pent-2-en-1-yloxy)benzoic acid

[0616] Example 16.

[0617]

[0618] 2-Methyl-3-octylbenzoic acid

[0619] Example 17.

[0620]

[0621] 3-(2-ethoxyethoxy)-2-methylbenzoic acid

[0622] Example 18.

[0623]

[0624] 2-Methyl-3-(pent-2-yn-1-yloxy)benzoic acid

[0625] Example 19.

[0626]

[0627] 3-((5-hydroxypentyl)oxy)-2-methylbenzoic acid

[0628] Example 20.

[0629]

[0630] 2-Methyl-3-((5,5,5-trifluoropentyl)oxy)benzoic acid

[0631] Example 21.

[0632]

[0633] 3-(pentoxy)-2-(trifluoromethyl)benzoic acid

[0634] Example 22.

[0635]

[0636] 6-(pentoxy)-[1,1'-biphenyl]-2-carboxylic acid

[0637] Example 23.

[0638]

[0639] 2-Isopropyl-3-(pentoxy)benzoic acid

[0640] Example 24.

[0641]

[0642] 2-(3-hydroxypropyl)-3-(pentoxy)benzoic acid

[0643] Example 25.

[0644]

[0645] 5-Fluoro-2-methyl-3-(pentoxy)benzoic acid

[0646] Example 26.

[0647]

[0648] 2-Methyl-3-(pentathio)benzoic acid

[0649] Example 27.

[0650]

[0651] 2-Methyl-3-(pentylsulfinyl)benzoic acid

[0652] Example 28.

[0653]

[0654] 2-Methyl-3-(benzenesulfonyl)benzoic acid

[0655] Example 29.

[0656]

[0657] 2-Methyl-3-(pentanamino)benzoic acid

[0658] Example 30.

[0659]

[0660] 3-(dipentanamino)-2-methylbenzoic acid

[0661] Example 31.

[0662]

[0663] 2-Methyl-3-(methyl(pentyl)amino)benzoic acid

[0664] Example 32.

[0665]

[0666] 2-Methyl-3-pentamidobenzoic acid

[0667] Example 33.

[0668]

[0669] (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzylacetate

[0670] Example 34.

[0671]

[0672] 6-Fluoro-2-methoxy-3-(pentoxy)benzoic acid

[0673] Example 35.

[0674]

[0675] 2-Methyl-2-(2-methyl-3-(pentoxy)phenyl)propionic acid

[0676] Example 36.

[0677]

[0678] 2-(hydroxymethyl)-3-(pentoxy)benzoic acid

[0679] Example 37.

[0680]

[0681] Sodium 2-methyl-3-(pentoxy)benzoate

[0682] Example 38.

[0683]

[0684] Potassium 2-methyl-3-(pentoxy)benzoate

[0685] Example 39.

[0686]

[0687] Magnesium 2-methyl-3-(pentoxy)benzoate

[0688] Example 40.

[0689]

[0690] Calcium 2-methyl-3-(pentoxy)benzoate

[0691] Group 3

[0692] Example 1.

[0693]

[0694] (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoic acid

[0695] Example 2.

[0696]

[0697] (Z)-2,6-Dimethoxy-4-(pent-2-en-1-yloxy)benzoic acid

[0698] Example 3.

[0699]

[0700] (Z)-2,6-Dimethyl-4-(pent-2-en-1-yloxy)benzoic acid

[0701] Group 4

[0702] Example 1.

[0703]

[0704] 5-Hexanoyl-2-methylbenzoic acid

[0705] Example 2.

[0706]

[0707] (Z)-2-methyl-5-(pent-2-en-1-yloxy)benzoic acid

[0708] Example 3.

[0709]

[0710] 4-(pentoxy)-[1,1'-biphenyl]-2-carboxylic acid

[0711] Example 4.

[0712]

[0713] 2,6-Dimethyl-3-(pentoxy)benzoic acid

[0714] Example 5.

[0715]

[0716] (Z)-2,6-Dimethoxy-3-(pent-2-en-1-yloxy)benzoic acid

[0717] Group 5

[0718] Example 1.

[0719]

[0720] 2-Methyl-3,5-bis(pentoxy)benzoic acid

[0721] Example 2.

[0722]

[0723] 2,6-Dimethyl-3,5-bis(pentoxy)benzoic acid

[0724] Example 3.

[0725]

[0726] 2,6-Dimethoxy-3,5-Dipentylbenzoic acid

[0727] General synthetic methods of the compounds described in this article

[0728] Generally, all compounds of this invention can be prepared by conventional methods, using readily available and / or conventionally prepared starting materials, reagents, and conventional synthetic methods. Key synthetic steps may include cross-coupling reactions, ether-forming reactions (e.g., Mitsunobu-type reactions), Friedel-Craft reactions, aromatic nucleophilic substitution reactions, and functional group tautomerization (FGI) reactions. It should also be understood that in some reactions, it may be necessary / required to protect any sensitive groups in the compound. Suitable protecting groups and methods for protecting and deprotecting different substituents are well known to those skilled in the art. Conventional protecting groups can be used according to standard practice. Pharmaceutically acceptable salts can be synthesized from parent compounds containing acid moieties by conventional chemical methods. Salts can be prepared in situ or in a separate step.

[0729] Compounds of general formula (I) can be prepared by the following general method:

[0730] Method I:

[0731]

[0732] The compounds of formulas (II) and (III) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The leaving group (LG) present in the compounds of formula (II) may, for example, be a methanesulfonate, a toluenesulfonate, or a suitable halogen, such as bromine or chlorine. R is an optionally substituted group selected from alkyl, alkenyl, and alkynyl groups. Ar is a benzene ring containing four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X each contain any of the foregoing embodiments of formula (I) and each optionally contains a protecting group. Those skilled in the art will be able to select a suitable protecting group based on the desired results.

[0733] Using method I, in the presence of a base, such as a metal hydride, such as NaH; a metal hydroxide, such as NaOH; a metal alkoxide, such as NaOEt; a metal carbanion, such as n-butyllithium; or a metal carbonate, such as K₂CO₃, in a suitable solvent or solvent system, an alcohol of formula (III) can undergo a substitution reaction with a compound of formula (II). A suitable solvent system may include a two-phase mixture optionally in the presence of additional heat and the use of a phase-transfer catalyst. Method I may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of method I may include the use of a catalyst and / or heating to provide a compound of formula (IV).

[0734] In some embodiments, the compounds of formula (III) can be described by any of formulas (IIIA)-(IIIE):

[0735] (III-A), (III-B), (III-C), (III-D), (III-E);

[0736] The substituents R1, R2, R3, R4, R5, R6, R7 and X each include any one of the aforementioned embodiments of formula (I).

[0737] In some embodiments, the compound of formula (IV) may comprise any one of formulas (IV-A)-(IV-E):

[0738] (IV-A), (IV-B), (IV-C), (IV-D), (IV-E);

[0739] Substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and R is an optional substituted group selected from alkyl, alkenyl and alkynyl groups.

[0740] Method II:

[0741]

[0742] The compounds of formulas (II) and (V) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The leaving group (LG) present in the compounds of formula (II) may, for example, be a methanesulfonate, a toluenesulfonate, or a suitable halogen, such as bromine or chlorine. R is an optionally substituted group selected from alkyl, alkenyl, and alkynyl groups. Ar is a benzene ring comprising four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally comprises a protecting group.

[0743] Using method II, in the presence of a base such as a metal hydride, such as NaH, a metal hydroxide, such as NaOH, a metal carbonate, such as K₂CO₃, or an organic base, such as Et₃N, in a suitable solvent or solvent system, the thiol of formula (V) can undergo a substitution reaction with a compound of formula (II) to form a compound of formula (VI) (step 1). Suitable solvent systems may include a two-phase mixture optionally in the presence of additional heat and the use of a phase-transfer catalyst. Method II may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of method II may include the use of a catalyst and / or heating to provide a compound of formula (VII).

[0744] The corresponding sulfoxides and sulfones of compound (VI) can be prepared by oxidizing sulfides with a suitable oxidizing agent (step 2). Examples of oxidizing agents are m-chloroperbenzoic acid (MCPBA), hydrogen peroxide (H2O2), and oxone (potassium peroxymonosulfonate). With the use of 1 equivalent or less of the oxidizing agent, the major product is usually sulfoxide (n=1). With the use of an excess of the oxidizing agent, the major product is usually sulfone (n=2).

[0745] In some embodiments, the compound of formula (V) can be described by any of formulas (VA)-(VE):

[0746] (VA), (VB), (VC), (VD), (VE);

[0747] Substituents R1, R2, R3, R4, R5, R6, R7 and X each contain a group of any one of the aforementioned embodiments according to formula (I).

[0748] In some embodiments, the compound of formula (VI) may comprise any one of formulas (VI-A)-(VI-E):

[0749] (VI-A) (VI-B), (VI-C), (VI-D), (VI-E);

[0750] Substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and R is an optional substituted group selected from alkyl, alkenyl and alkynyl groups.

[0751] In some embodiments, the compounds of formula (VII) can be described by any one of formulas (VII-A)-(VII-E):

[0752] (VII-A), (VII-B), (VII-C), (VII-D), (VII-E);

[0753] The substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and R is an optional substituted group selected from alkyl, alkenyl and alkynyl groups, and n is 1 or 2.

[0754] Method III:

[0755]

[0756] The compounds of formulas (VIII) and (IX) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. R is an optionally substituted group selected from alkyl, alkenyl, or alkynyl groups, and aromatic groups, such as aryl groups. Ar is a benzene ring comprising four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally comprises a protecting group.

[0757] Using method III, the alcohol of formula (IX) can be reacted with a compound of formula (VIII) under classical or non-classical Mitsunobu conditions using methods familiar to those skilled in the art. Method III may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of method III may include using a catalyst and / or heating to provide a compound of formula (X).

[0758] In some embodiments, the compounds of formula (IX) can be described by the compounds of formulas (III), (III-A), (III-B), (III-C), (III-D), or (III-E) described above.

[0759] In some embodiments, the compound of formula (X) can be described by the compounds of formulas (IV), (IV-A), (IV-B), (IV-C), (IV-D), or (IV-E) described above.

[0760] Method IV:

[0761]

[0762] The compounds of formula (XI) and (XII) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The leaving group (LG) present in the compound of formula (XI) may be, for example, a hydride, a trifluoromethanesulfonate, a toluenesulfonate, or a suitable halogen, such as bromine or iodine. The leaving group (E) present in the compound of formula (XII) is based on an element of boron, copper, magnesium, silicon, tin, or zinc. R is an optionally substituted group selected from alkyl, alkenyl, alkynyl, and aromatic groups, such as aryl. Ar is a benzene ring comprising four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally comprises a protecting group.

[0763] Method IV represents various cross-coupling reactions in which segments (XI) and (XII) are linked together by means of a metal catalyst, such as a palladium, copper, iron, cobalt, or nickel-based complex, to form carbon-carbon bonds between the segments. These cross-coupling reactions can be carried out using methods familiar to those skilled in the art under classical or non-classical Heck, Kumada, Negishi, Sonogashira, Stille, or Suzuki conditions. Those skilled in the art will be able to select appropriate leaving groups (LG' and E), catalysts, and reaction conditions according to the desired results. Method IV may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of Method IV may include the use of a catalyst and / or heating to provide a compound of formula (XIII).

[0764] In some embodiments, the compound of formula (XII) can be described by any of formulas (XII-A)-(XII-E):

[0765] (XII-A), (XII-B), (XII-C), (XII-D), (XII-E);

[0766] Substituents R1, R2, R3, R4, R5, R6, R7 and X each contain a group of any one of the aforementioned embodiments according to formula (I).

[0767] In some embodiments, compounds of formula (XIII) can be described by any of formulas (XIII-A)-(XIII-E):

[0768] (XII-A), (XII-B), (XII-C), (XII-D), (XII-E);

[0769] Substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and R is an optional substituted group selected from alkyl, alkenyl, alkynyl and aromatic groups.

[0770] Method V:

[0771]

[0772] The compounds of formulas (XIV) and (XV) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The LG- group present in the compound of formula (XIV) may, for example, be a halogen, such as chlorine, or a thioalkyl (SR'). The group (E) present in the compound of formula (XV) may be a Sn(alkyl)3 group or a BR2 group (i.e., a boric acid or cyclic or acyclic borate ester group). R is allyl, alkenyl, or aryl. Ar is a benzene ring containing four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally contains a protecting group.

[0773] Method V represents a cross-coupling reaction in which fragments (XIV) and (XV) are linked together by means of a metal catalyst, such as a palladium- or copper-based complex. These cross-coupling reactions can be carried out using methods familiar to those skilled in the art, under classical or non-classical Stille or Liebeskind-Srogl coupling conditions. Those skilled in the art will be able to select appropriate leaving groups (LG and E), catalysts, and reaction conditions based on the desired results. Method V may also include optional steps of adding and removing protecting groups. For example, removing a protecting group may include converting an ester group to a carboxylic acid. Some embodiments of Method V may include using a catalyst and / or heating to provide a compound of formula (XVI).

[0774] In the presence of CO, under classical or non-classical Stille-Carbonylative cross-coupling conditions, when a compound of formula (XV) reacts with a compound of formula R-LG, a compound of formula (XVI) can also be formed, wherein the LG- group can, for example, be a trifluoromethanesulfonate or a halogen, such as bromine, chlorine or iodine.

[0775] In some embodiments, compounds of formula (XV) can be described by compounds of formulas (XII), (XII-A), (XII-B), (XII-C), (XII-D), or (XII-E) as described above.

[0776] In some embodiments, compounds of formula (XVI) can be described by any of formulas (XVI-A)-(XVI-E):

[0777] (XVI-A) (XVI-B), (XVI-C), (XVI-D) (XII-E);

[0778] Substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and R is an optional substituted group selected from alkyl, alkenyl, alkynyl and aromatic groups.

[0779] Method VI:

[0780]

[0781] The compounds of formulas (XVII) and (XVIII) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The R and R'- groups present in the compounds of formula (XVII) may be the same or different, for example, they may be optionally substituted groups selected from alkyl, alkenyl, alkynyl, aryl, -COR'' groups, or H atoms, provided that R and R' cannot both be H atoms. The R'' group may be the same as R and R', except for the H atom or the -COR group. The leaving group (E) present in the compounds of formula (XVIII) may be, for example, an O-trifluoromethanesulfonate (OTf), a suitable halogen, such as chlorine, bromine, or iodine, or boric acid. Ar is a benzene ring containing four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally contains a protecting group.

[0782] Method VI represents a cross-coupling reaction in which two segments (XVII) and (XVIII) are linked together by means of a metal catalyst, such as a palladium- or copper-based complex. These cross-coupling reactions can be carried out using methods familiar to those skilled in the art, under classical or non-classical Buchwald–Hartwig amination or Chan-Lam coupling conditions. Those skilled in the art will be able to select appropriate leaving groups (LG), catalysts, and reaction conditions based on the desired results. Method VI may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of Method VI may include using a catalyst and / or heating to provide a compound of formula (XIX).

[0783] In some embodiments, compounds of formula (XVIII) can be described by compounds of formulas (XV), (XV-A), (XV-B), (XV-C), (XV-D), or (XV-E) as described above.

[0784] In some embodiments, compounds of formula (XIX) can be described by any of formulas (XIX-A)-(XIX-E):

[0785] (XIX-A), (XIX-B), (XIX-C), (XIX-D), (XIX-E);

[0786] Substituents R1, R2, R3, R4, R5, R6, R7, and X each comprise any one of the foregoing embodiments of formula (I); and the R and R'- groups present in the compound of formula (XVII) may be the same or different, and may, for example, be optional substituted groups selected from: alkyl, alkenyl, alkynyl, aryl, -COR'' group, or H atom, provided that R and R' cannot both be H atoms. The R'' group may be the same as R and R', except for the H atom or the -COR group.

[0787] Method VII:

[0788]

[0789] The compounds of formulas (XX) and (XXI) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The R-group present in the compound of formula (XX) may be, for example, an optionally substituted group selected from alkyl, alkenyl, alkynyl, and aryl. X' is O or S. The leaving group (E) present in the compound of formula (XXI) may be, for example, an O-trifluoromethanesulfonate (OTf) or a suitable halogen, such as chlorine, bromine, iodine, or boric acid. Ar is a benzene ring comprising four substituents selected from R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally comprises a protecting group.

[0790] Method VII represents a cross-coupling reaction in which two segments (XX) and (XXI) are linked together by means of a metal catalyst, such as a palladium- or copper-based complex. These cross-coupling reactions can be carried out using methods familiar to those skilled in the art, under classical or non-classical Buchwald–Hartwig reactions, Ullman condensations, or Chan-Lam coupling conditions. Those skilled in the art will be able to select appropriate leaving groups (E), catalysts, and reaction conditions based on the desired results. Method VII may also include optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group to a carboxylic acid. Some embodiments of Method VII may include using a catalyst and / or heating to provide a compound of formula (XXII).

[0791] In some embodiments, compounds of formula (XXI) can be described by compounds of formulas (XV), (XV-A), (XV-B), (XV-C), (XV-D), or (XV-E) as described above.

[0792] In some embodiments, compounds of formula (XXII) can be described by any of formulas (XXII-A)-(XXII-E):

[0793] (XXII-A), (XXII-B), (XXII-C), (XXII) (XXII-E);

[0794] Wherein substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); n is 0, 1 or 2; and R is an optional substituted group selected from alkyl, alkenyl and alkynyl groups.

[0795] Method VIII

[0796]

[0797] The compounds of formulas (XXIII) and (XXIV) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The LG- group present in the compounds of formula (XXIII) may, for example, be a halogen, such as chlorine, or an RCOO- group. R is allyl, alkenyl, or aryl. Ar is a benzene ring comprising four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally comprises a protecting group.

[0798] Method VIII represents an electrophilic aromatic substitution reaction in which segments (XXIII) and (XXIV) are linked together by a Lewis acid, such as a complex based on aluminum, iron, zinc, boron, or titanium. These reactions can be carried out using methods familiar to those skilled in the art under classical or non-classical Friedel-Crafts acylation coupling conditions. Those skilled in the art will be able to select appropriate leaving groups (LG), catalysts, and reaction conditions based on the desired results. Method VIII may also include optional steps of adding and removing protecting groups. For example, removing a protecting group may include converting an ester group to a carboxylic acid. Some embodiments of Method VIII may include using a catalyst and / or heating to provide a compound of formula (XXV).

[0799] In some embodiments, compounds of formula (XXIV) can be described by any of formulas (XXIV-A)-(XXIV-E):

[0800] (XXIV-A) (XXIV-B) (XXIV-C), (XXIV-D), (XXIV-E);

[0801] In some embodiments, compounds of formula (XXV) can be described by compounds of formulas (XVI), (XVI-A), (XVI-B), (XVI-C), (XVI-D), or (XVI-E) as described above.

[0802] Method IX

[0803]

[0804] The compounds of formulas (XXVI) and (XXVII) are commercially available, or are known in the literature, or are prepared by standard methods known in the art. The LG- group present in the compounds of formula (XXIII) may, for example, be a halogen, such as chlorine. R is allyl, alkenyl, or aryl. Ar is a benzene ring containing four substituents selected from the following: R1, R2, R3, R4, and R5. Substituents R1, R2, R3, R4, R5, R6, R7, and X comprise any of the foregoing embodiments of formula (I), and each optionally contains a protecting group.

[0805] Method IX represents an electrophilic aromatic substitution reaction in which segments (XXIII) and (XXIV) are linked together by means of a Lewis acid, such as a complex based on aluminum, iron, zinc, boron, or titanium. These reactions can be carried out using methods familiar to those skilled in the art under classical or non-classical Friedel Crafts alkylation coupling conditions. Those skilled in the art will be able to select appropriate leaving groups (LG), catalysts, and reaction conditions based on the desired results. Method IX may also include optional steps of adding and removing protecting groups. For example, removing a protecting group may include converting an ester group to a carboxylic acid. Some embodiments of Method IX may include using a catalyst and / or heating to provide a compound of formula (XXVIII).

[0806] In some embodiments, compounds of formula (XXVII) can be described by compounds of formulas (XXIV), (XXIV-A), (XXIV-B), (XXIV-C), (XXIV-D), or (XXIV-E) as described above.

[0807] In some embodiments, compounds of formula (XXVIII) can be described by compounds of formulas (XVI), (XVI-A), (XVI-B), (XVI-C), (XVI-D), or (XVI-E) as described above.

[0808] The Examples section below provides general schemes for synthesizing compounds of Formula I and specific, but not limiting, examples.

[0809] Synthesis Examples

[0810] This disclosure can be further described through the following non-limiting embodiments, wherein standard techniques known to those skilled in the art and techniques similar to those described in these embodiments may be used where appropriate. It should be understood that those skilled in the art will envision other embodiments consistent with the disclosure provided herein.

[0811] Unless otherwise specified, reactions are carried out at room temperature, typically in the range of 18–25 °C, using HPLC-grade solvents under anhydrous conditions. Evaporation is performed by rotary evaporation in vacuum. Column chromatography is performed on silica gel using a rapid program. Nuclear magnetic resonance (NMR) shift values ​​are recorded on a Bruker Avance DPX 200 or 300 or an AVII 400 instrument, exhibiting the following peak multiplicity: s, singlet; d, doublet; dd, twint; t, triplet; q, quartet; p, quintet; m, multiplet; br, broad peak. Mass spectra are recorded using a GL956A mass spectrometer (electrospray, 3000 V) switching between positive and negative ionization modes. Reported yields are illustrative and do not necessarily represent the maximum achievable yield.

[0812] Example 1: Preparation of 3-butoxy-2-methylbenzoic acid:

[0813]

[0814] Step 1:

[0815] Potassium carbonate (3.32 g, 24.00 mmol) and 1-iodobutane (2.05 ml, 18.01 mmol) were added to a solution of 3-hydroxy-2-methylbenzoic acid (0.913 g, 6 mmol) in DMF (30 ml), and the mixture was stirred overnight. Water (300 ml) was added, and the mixture was extracted with diethyl ether (200 ml). The organic phase was washed with brine (200 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum to give butyl 3-butoxy-2-methylbenzoate (1.55 g, 5.86 mmol, 98% yield) as a solid. MS (electrospray ionization): 287.0 [M+Na]⁺.

[0816] Step 2:

[0817] LiOH was added to a solution of butyl 3-butoxy-2-methylbenzoate (1.6 g, 6.0 mmol) in THF (10 ml). A solution of H₂O (1.0 g, 23.8 mmol) in H₂O (5 ml) was prepared, and the mixture was heated at 70 °C overnight. TLC showed no reaction. EtOH (5 ml) was added, and the mixture was heated at 70 °C for 3 nights, cooled to room temperature, and acidified to pH 1-2 with 1M HCl. The mixture was extracted with EtOAc (100 ml), the organic phase was washed with brine (100 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc w / 5% HCOOH 90 / 10) yielded 3-butoxy-2-methylbenzoic acid (0.81 g, 3.85 mmol, 63.6% yield) as a solid. ¹H NMR (300 MHz, CDCI₃) δ 7.61 (dd, ¹H), 7.33–7.16 (m, ¹H), 7.05 (d, ¹H), 4.01 (t, 2H), 2.55 (s, 3H), 1.94–1.74 (m, 2H), 1.67–1.45 (m, 2H), 1.02 (t, 3H). MS (electrospray): 207.0 [MH]⁻.

[0818] Example 2: Preparation of 3-(hexyloxy)-2-methylbenzoic acid:

[0819]

[0820] Step 1:

[0821] K₂CO₃ (2.49 g, 18.02 mmol) was added to a solution of 3-hydroxy-2-methylbenzoic acid (0.913 g, 6.00 mmol) in DMF (10 ml), and the mixture was stirred for 5 minutes. 1-Iodohexane (3.6 ml, 24.39 mmol) was added, and the mixture was stirred overnight. Et₂O (100 ml) was added, and the resulting mixture was washed with brine (2 x 25 ml). The phases were separated, and the organic layer was concentrated under vacuum to give hexyl 3-(hexyloxy)-2-methylbenzoate (1.92 g, 5.99 mmol, 100% yield).

[0822] Step 2:

[0823] LiOH in water (10 ml) was added to a solution of 1.92 g (5.99 mmol) of hexyl 3-(hexyloxy)-2-methylbenzoate in THF (20 ml). H₂O (2.1 g, 50.0 mmol) was added, and the mixture was stirred at room temperature for two nights, then stirred at 50 °C for one night. The reaction was incomplete. The mixture was concentrated under vacuum, dissolved in dioxane (20.00 ml) and water (20.00 ml), and refluxed for 3 hours. The mixture was cooled, acidified with 6M HCl (15 ml), and extracted with Et₂O (2 x 50 ml). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (silica gel, heptane:EtOAc-0:100, 10:90) was used to obtain 3-(hexyloxy)-2-methylbenzoic acid (0.33 g, 1.41 mmol, 23.6% yield). ¹H NMR (300 MHz, CDCI₃) δ 7.68 -7.56 (m, ¹H), 7.31 - 7.17 (m, ¹H), 7.10 - 7.01 (m, ¹H), 4.00 (t, 2H), 2.56 (s, 3H), 1.92 - 1.78 (m, 2H), 1.60 - 1.47 (m, 2H), 1.44 - 1.30 (m, 4H), 1.00 - 0.86 (m, 3H). MS (electrospray): 235.1 [MH]-.

[0824] Example 3: Preparation of 2-methyl-3-octylbenzoic acid:

[0825]

[0826] Step 1:

[0827] Under a nitrogen atmosphere and at room temperature, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (5.3 g, 21 mmol), AcOK (6.17 g, 62.9 mmol), and Pd(dppf)Cl2([1,1′-bis(diphenylphosphine)ferrocene]palladium(II)) (0.613 g, 0.838 mmol) were added to a solution of methyl 3-bromo-2-methylbenzoate (4.8 g, 21 mmol) in DMSO (250 ml). The mixture was heated overnight at 120 °C. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc (300 ml), filtered through a diatomaceous earth pad, and washed with water (2 x 200 ml). The aqueous phase was extracted with EtOAc (150 ml). The combined organic phases were washed with brine (150 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 98 / 2–95 / 5) yielded methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)benzoate (2.3 g, 8.3 mmol, 40% yield), in an oily form. ¹H NMR (400 MHz, CDCI₃) δ 7.88–7.75 (m, 2H), 7.19 (t, 1H), 3.86 (s, 3H), 2.72 (s, 3H), 1.34 (s, 12H).

[0828] Step 2:

[0829] Under a nitrogen atmosphere, LiOtBu (0.311 g, 3.89 mmol), Cul (0.056 g, 0.292 mmol), and 1-iodooctane (0.526 ml, 2.92 mmol) were added to a solution of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabortyl-2-yl)benzoate (0.537 g, 1.943 mmol) in DMF (25 ml). The mixture was stirred overnight at 60 °C and cooled to room temperature. The mixture was diluted with Et2O (150 ml) and filtered through a silica pad, which was washed with EtOAc (150 ml). The filtrate was concentrated and subjected to rapid chromatography (heptane / EtOAc 99 / 1, 98 / 2) to give methyl 2-methyl-3-octylbenzoate (320 mg, 1.22 mmol, 62.8% yield), in an oily form. ¹H NMR (400 MHz, CDCI₃) δ 7.58–7.47 (m, 1H), 7.22–7.12 (m, 1H), 7.10–7.01 (m, 1H), 3.80 (s, 3H), 2.62–2.53 (m, 2H), 2.40 (s, 3H), 1.53–1.42 (m, 2H), 1.32–1.14 (m, 10H), 0.80 (t, 3H).

[0830] Step 3:

[0831] Under a nitrogen atmosphere, a solution of LiOHxH2O (384 mg, 9.15 mmol) in water (5 ml) was added to a solution of methyl 2-methyl-3-octylbenzoate (300 mg, 1.143 mmol) in ethanol (10 ml), and the mixture was heated at 70 °C for 2 hours. The mixture was cooled to room temperature, acidified to pH 1–2 with 1 M HCl (aq), extracted with EtOAc (2 x 50 ml), washed with brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc / HCOOH 90 / 10 / 0.1–88 / 12 / 0.1) yielded 2-methyl-3-octylbenzoic acid (200 mg, 0.767 mmol, 67.1% yield) as a solid. ¹H NMR (400 MHz, CDCI₃) δ 7.82 (d, ¹H), 7.35 (d, ¹H), 7.21 (t, ¹H), 2.73–2.65 (m, 2H), 2.58 (s, 3H), 1.63–1.53 (m, 2H), 1.43–1.25 (m, ¹⁰H), 0.91 (t, 3H). MS (electrospray): 247.1 [MH]⁻.

[0832] Example 4: Preparation of (Z)-2-methyl-3-(oct-5-en-1-yl)benzoic acid:

[0833]

[0834] Step 1:

[0835] Under a N2 atmosphere at 0 °C, 4-methylbenzene-1-sulfonyl chloride (14.87 g, 78 mmol) was added to a solution of (Z)-oct-5-en-1-ol (5.88 ml, 39.0 mmol) in CH2Cl2 (50 ml), followed by the addition of TEA (7.89 g, 78 mmol). The reaction mixture was stirred at 0 °C for 3 hours, poured onto ice water (100 ml), and extracted with CH2Cl2 (2 x 100 ml). The combined organic phases were concentrated under vacuum. Pyridine (13 ml) and water (10 ml) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. Heptane (200 ml) was added, and the organic layer was washed with water (100 ml), 1M HCl (aq, 100 ml), and brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 90 / 10) yielded (Z)-oct-5-en-1-ol-4-methylbenzenesulfonate (8.6 g, 30.5 mmol, 78% yield) in an oily form. ¹H NMR (300 MHz, CDCI₃) δ 7.74 (d, 2H), 7.30 (d, 2H), 5.40–5.25 (m, 1H), 5.24–5.08 (m, 1H), 3.98 (t, 2H), 2.43 (s, 3H), 2.02–1.76 (m, 4H), 1.70–1.50 (m, 2H), 1.43–1.15 (m, 2H), 0.98–0.75 (m, 3H). MS (electrospray): 305.0 [M+Na]+.

[0836] Step 2:

[0837] Sodium iodide (1.7 g, 11.3 mmol) was added to a solution of (Z)-oct-5-en-1-ol-4-methylbenzenesulfonate (2.0 g, 7.1 mmol) in acetone (25 ml), and the mixture was stirred at ambient temperature for two nights. The mixture was concentrated under reduced pressure. Et2O (100 ml) was added, and the resulting organic phase was washed with water (2 x 100 ml) and brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum to give (Z)-8-iodooct-3-ene (1.1 g, 4.6 mmol, 65.2% yield) as an oil. 1H NMR(400MHz, CDCI3)δ 5.50-5.26(m, 2H), 3.21(t, 2H), 2.13 - 1.97(m, 4H), 1.93 - 1.79(m, 2H), 1.56 - 1.43(m, 2H), 0.98(t, 3H).

[0838] Step 3:

[0839] Under a nitrogen atmosphere, lithium tert-butoxide (0.464 g, 5.79 mmol), cuprous iodide (I) (0.083 g, 0.435 mmol), and (Z)-8-iodooct-3-ene (1.035 g, 4.35 mmol) were added to a solution of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabolic-2-yl) in DMF (40 ml). The mixture was stirred overnight at 60 °C and cooled to room temperature. The mixture was diluted with Et2O (150 ml) and filtered through a silica pad, which was washed with EtOAc (150 ml). The filtrate was concentrated and purified by rapid chromatography (heptane / EtOAc 99 / 1, 98 / 2) to give methyl (Z)-2-methyl-3-(oct-5-en-1-yl)benzoate (0.3 g, 1.2 mmol, 40% yield), as an oil. MS (electrospray ionization): 283.1 [M+Na]+.

[0840] Step 4:

[0841] Under a nitrogen atmosphere, a solution of lithium hydroxide monohydrate (366 mg, 8.73 mmol) in water (5 ml) was added to a solution of (Z)-2-methyl-3-(oct-5-en-1-yl)benzoate (284 mg, 1.09 mmol) in EtOH (10 ml), and the mixture was heated at 50 °C for 3 hours. The mixture was cooled to room temperature, acidified to pH 1–2 with 1 M HCl (aq), extracted with EtOAc (2 x 50 ml), washed with brine (100 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc / HCOOH 80 / 10 / 0.1) followed by preparative HPLC yielded (Z)-2-methyl-3-(oct-5-en-1-yl)benzoic acid (125 mg, 0.498 mmol, 45.6% yield) as an oil. ¹H NMR (400 MHz, CDCI₃) δ 11.83 (s, ¹H), 7.75 (d, ¹H), 7.29–7.22 (m, ¹H), 7.15–7.06 (m, ¹H), 5.39–5.16 (m, 2H), 2.65–2.56 (m, 2H), 2.50 (s, 3H), 2.05–1.92 (m, 4H), 1.57–1.47 (m, 2H), 1.41–1.33 (m, 2H), 0.89 (t, 3H). MS (electrospray): 245.1 [MH]⁻.

[0842] Example 5: Preparation of (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoic acid:

[0843]

[0844] Step 1:

[0845] Under a N2 atmosphere at 0 °C, 4-methylbenzene-1-sulfonyl chloride (19.0 g, 100 mmol) was added to a solution of (Z)-hexane-3-en-1-ol (5.0 g, 50 mmol) in CH2Cl2 (50 ml), followed by the addition of TEA (10.1 g, 100 mmol). The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was poured onto ice water (100 ml) and extracted with CH2Cl2 (2 x 100 ml). The combined organic phases were concentrated under vacuum. Pyridine (13 ml) and water (10 ml) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. Heptane (200 ml) was added, and the organic layer was washed with water (100 ml), 1 M HCl (aq, 100 ml), and brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 90 / 10) yielded (Z)-hex-3-en-1-ol-4-methylbenzenesulfonate (10.8 g, 42.5 mmol, 85% yield) in an oily form. ¹H NMR (400 MHz, CDCI₃) δ 7.75 (d, 2H), 7.31 (d, 2H), 5.50–5.38 (m, 1H), 5.21–5.05 (m, 1H), 3.96 (t, 2H), 2.41 (s, 3H), 2.35 (q, 2H), 2.00–1.88 (m, 2H), 0.89 (t, 3H). MS (electrospray ionization): 277.0 [M+Na]⁺.

[0846] Step 2:

[0847] Under a nitrogen atmosphere, LiOtBu (0.298 g, 3.72 mmol), Cul (0.035 g, 0.186 mmol), and (Z)-hex-3-en-1-ol-4-methylbenzenesulfonate (0.473 g, 1.859 mmol) were added to a solution of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabort-2-yl)benzoate (0.77 g, 2.79 mmol) in DMF (35 ml). The reaction mixture was stirred overnight at 60 °C and cooled to room temperature. The reaction mixture was diluted with Et2O (100 ml) and filtered through a silica pad, which was washed with EtOAc (100 ml). The filtrate was concentrated and purified by rapid chromatography (heptane / EtOAc100 / 1) to give methyl (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoate (0.35 g, 1.409 mmol, 76% yield) as an oil (impure according to 1 H NMR).

[0848] Step 3:

[0849] Under a nitrogen atmosphere, LiOH was added to a solution of (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoate (0.35 g, 1.41 mmol) (impure) in ethanol (20 ml). A solution of H₂O (0.472 g, 11.28 mmol) in water (10 ml) was prepared, and the mixture was stirred overnight at 40 °C. The mixture was cooled to room temperature, acidified to pH ~1-2 with 2M HCl (aq, 3 ml), and extracted with Et₂O (2 x 50 ml). Rapid chromatography (heptane / EtOAc w / 5% HCOOH 95 / 5-90 / 10) yielded 100 mg of impure product, which was purified by preparative HPLC to give (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoic acid (0.10 g, 0.42 mmol, 30% yield) as a solid. ¹H NMR (400 MHz, MeOD) δ 7.40 (d, ¹H), 7.22 (t, ¹H), 7.09 (d, ¹H), 5.65 - 5.44 (m, 2H), 4.04 (t, 2H), 2.66 - 2.52 (m, 2H), 2.42 (s, 3H), 2.23 - 2.08 (m, 2H), 1.03 (t, 3H). MS (electrospray): 233.0 [MH]-.

[0850] Example 6: Preparation of (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoic acid:

[0851]

[0852] Step 1:

[0853] Under a N2 atmosphere at 0 °C, 4-methylbenzene-1-sulfonyl chloride (14.87 g, 78.0 mmol) was added to a solution of (Z)-oct-5-en-1-ol (5.88 ml, 39.0 mmol) in CH2Cl2 (50 ml), followed by the addition of TEA (7.89 g, 78.0 mmol). The reaction mixture was stirred at 0 °C for 3 hours, poured onto ice water (100 ml), and extracted with CH2Cl2 (2 x 100 ml).

[0854] The combined organic phases were concentrated under vacuum. Pyridine (13 ml) and water (10 ml) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. Heptane (200 ml) was added, and the organic layer was washed with water (100 ml), 1M HCl (aqueous solution, 100 ml), and brine (100 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 90 / 10) yielded (Z)-oct-5-en-1-ol-4-methylbenzenesulfonate (8.6 g, 30.5 mmol, 78% yield) as an oil. ¹H NMR (300MHz, CDCI₃) δ 7.74 (d, 2H), 7.30 (d, 2H), 5.40–5.25 (m, 1H), 5.24–5.08 (m, 1H), 3.9 s (t, 2H), 2.43 (s, 3H), 2.02–1.76 (m, 4H), 1.70–1.50 (m, 2H), 1.43–1.15 (m, 2H), 0.98–0.75 (m, 3H). MS (electrospray): 305.0 [M+Na]⁺.

[0855] Step 2:

[0856] Under a nitrogen atmosphere, LiOtBu (0.290 g, 3.62 mmol), Cul (0.069 g, 0.362 mmol), and (Z)-oct-5-en-1-ol-4-methylbenzenesulfonate (0.511 g, 1.811 mmol) were added to a solution of methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzoate (0.75 g, 2.72 mmol) in DMF (30 ml). The reaction mixture was stirred overnight at 60 °C and cooled to room temperature. The mixture was diluted with Et2O (100 ml) and filtered through a silica pad, which was washed with EtOAc (100 ml). The filtrate was concentrated and purified by rapid chromatography (heptane / EtOAc100 / 1) to give methyl (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoate (0.22 g, 0.78 mmol, 44% yield) as an oil. 1H NMR(400 MHz, CDCI3)δ 7.36(d,1H), 7.19 - 7.07(m,1H), 6.94(d,1H), 5.48 - 5.24(m, 2H), 3.95(t, 2H), 3.87(s, 3H), 2.41(s, 3H), 2.14 -1.95(m, 4H), 1.85 - 1.76(m, 2H), 1.59 - 1.48(m, 2H), 0.98 - 0.90(m, 3H).

[0857] Step 3:

[0858] Under a nitrogen atmosphere, LiOH was added to a solution of (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoate (220 mg, 0.796 mmol) in EtOH (25 ml). A solution of H₂O (267 mg, 6.37 mmol) in water (10 ml) was prepared, and the mixture was stirred overnight at 40 °C. The mixture was cooled to room temperature, acidified to pH 1–2 with 3 M HCl (aq, 1 ml), extracted with Et₂O (2 x 20 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc w / 5% HCOOH 95 / 5–90 / 10) yielded 150 mg of product. (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoic acid (60 mg, 0.228 mmol, 28.6% yield) was purified by preparative HPLC to a solid. ¹H NMR (400 MHz, MeOD) δ 7.39(d,¹H), 7.22(t,¹H), 7.09(d,¹H), 3.51 - 5.29(m, 2H), 4.04(t, 2H), 2.43(s, 3H), 2.24 - 2.00(m, 4H), 1.95 - 1.76(m, 2H), 1.68 - 1.52(m, 2H), 1.00(t, 3H). MS (electrospray): 261.1 [MH]-.

[0859] Example 7: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (“Compound B”):

[0860]

[0861] Step 1:

[0862] Under a N2 atmosphere at 0 °C, diisopropyl azodicarbonate (20.5 ml, 105 mmol) was added dropwise to a solution of triphenylphosphine (26.4 g, 101 mmol) in dry THF (600 ml). The resulting suspension was stirred for 30 min, followed by the dropwise addition of a solution of (Z)-pent-2-en-1-ol (7.89 g, 92.0 mmol) and ethyl 3-hydroxy-2-methylbenzoate (16.5 g, 92 mmol) in THF (200 ml). The cooling was removed, and the reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 97 / 3) yielded ethyl (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate (16.5 g, 66.4 mmol, 72.6% yield) as an oil. 1H NMR(400 MHz, CDCl3)δ 7.37(d,1H), 7.15(t,1H), 6.96(d,1H), 5.71 – 5.57(m, 2H), 4.64 – 4.52(m, 2H), 4.33(q, 2H), 2.42(s, 3H), 2.19 – 2.02(m, 2H), 1.37(t, 3H), 1.00(t, 3H).

[0863] Step 2:

[0864] Under a nitrogen atmosphere, a solution of lithium hydroxide monohydrate (22.2 g, 528 mmol) in water (100 ml) was added to a solution of ethyl (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate (16.4 g, 66.0 mmol) in EtOH (200 ml), and the mixture was heated at 50 °C for 1 hour. The mixture was cooled to room temperature, acidified to pH ~1-2 with 3M HCl (aq), extracted with EtOAc (2 x 300 ml), washed with brine (300 ml), dried (Na₂SO₄), filtered, and concentrated under vacuum to give 14.5 g of crude product. The crude product was recrystallized from heptane / EtOAc (approximately 90 / 10) to give (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (12.6 g, 55.9 mmol, 85% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 12.11 (s, ¹H), 7.59 (d, ¹H), 7.20 (t, ¹H), 7.03 (d, ¹H), 5.74 – 5.55 (m, 2H), 4.64 – 4.56 (m, 2H), 2.51 (s, 3H), 2.21 – 2.07 (m, 2H), 1.01 (t, 3H). MS (electrospray): 219.1 [MH]-.

[0865] Example 8: Preparation of 2-methyl-3-(pentoxy)benzoic acid (“Compound A”):

[0866]

[0867] Step 1:

[0868] Under a nitrogen atmosphere at 0 °C, diisopropyl azodicarbonate (10.2 ml, 51.8 mmol) was added dropwise to a solution of triphenylphosphine (13.0 g, 49.5 mmol) in THF (200 ml). The suspension was stirred for 30 minutes, followed by the dropwise addition of 1-pentanol (4.9 ml, 45 mmol) and ethyl 3-hydroxy-2-methylbenzoate (8.1 g, 45 mmol) in THF (50 ml). The cooling was removed, and the reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. Rapid chromatography (heptane / EtOAc-98 / 2) yielded ethyl 3-hydroxy-2-methylbenzoate (8.9 g, 35.6 mmol, 79% yield) as an oil. ¹H NMR (300 MHz, CDCI₃) δ 7.35 (dd, ¹H), 7.20–7.06 (m, ¹H), 6.95–6.91 (m, ¹H), 4.33 (q, 2H), 3.94 (t, 2H), 2.41 (s, 3H), 1.84–1.75 (m, 2H), 1.51–1.28 (m, 7H), 0.92 (t, 3H). MS (electrospray): 273.2 [M+Na]⁺.

[0869] Step 2:

[0870] Under a nitrogen atmosphere, a solution of lithium hydroxide monohydrate (11.9 g, 284 mmol) in water (50 ml) was added to a solution of ethyl 3-hydroxy-2-methylbenzoate (8.9 g, 35.6 mmol) in EtOH (100 ml), and the mixture was stirred overnight at room temperature. The mixture was acidified to pH ~1-2 with 3M HCl (aq), extracted with EtOAc (2 x 300 ml), washed with water (300 ml) and brine (300 ml), dried (Na2SO4), filtered, and concentrated under vacuum to obtain 2-methyl-3-(pentoxy)benzoic acid (7.7 g, 34.0 mmol, 96% yield) as a solid. ¹H NMR (300 MHz, CDCI₃) δ 12.24 (s, ¹H), 7.57 (dd, ¹H), 7.19 (t, ¹H), 7.01 (d, ¹H), 3.96 (t, 2H), 2.51 (s, 3H), 1.88–1.75 (m, 2H), 1.55–1.31 (m, 4H), 0.93 (t, 3H). MS (electrospray): 221.1 [MH]⁻.

[0871] Example 9: Preparation of (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoic acid:

[0872]

[0873] Step 1:

[0874] Under a N2 atmosphere at 0 °C, diisopropyl azodicarbonate (10.4 ml, 53.4 mmol) was added dropwise to a solution of triphenylphosphine (13.4 g, 51.1 mmol) in THF (200 ml). The resulting suspension was stirred for 30 minutes, followed by the dropwise addition of a solution of cis-2-penten-1-ol (4 g, 46 mmol) and ethyl 4-hydroxy-2-methylbenzoate (8.37 g, 46.4 mmol) in THF (50 ml). The cooling was removed, and the yellow reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. Rapid chromatography (heptane / EtOAc 98 / 2-95 / 5) yielded (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoate (9.5 g, 38.3 mmol, 82% yield) as an oil.

[0875] Step 2:

[0876] Under a nitrogen atmosphere, a solution of lithium hydroxide monohydrate (12.8 g, 306 mmol) in water (50 ml) was added to a solution of ethyl (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoate (9.5 g, 38.3 mmol) in ethanol (100 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH ~1-2 with 3M HCl (aq), extracted with EtOAc (2 x 150 ml), washed with water (100 ml) and brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc / HCOOH 90 / 10 / 0.5-85 / 15 / 0.5) yielded (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoic acid (4.9 g, 22 mmol, 57% yield) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 8.09 – 7.99 (m, ¹H), 6.80 – 6.70 (m, 2H), 5.79 – 5.49 (m, 2H), 4.61 (d, 2H), 2.63 (s, 3H), 2.15 (p, 2H), 1.02 (t, 3H). MS (electrospray): 219.1 [MH]-.

[0877] Example 10: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzamide (“Compound C”):

[0878]

[0879] HBTU (4.13 g, 10.90 mmol) was added to a solution of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (2.0 g, 9.1 mmol) in DCM (50 ml), followed by TEA (1.58 ml, 11.35 mmol). The mixture was stirred at room temperature for 20 minutes, and ammonia (28% in water) (3.14 ml, 45.4 mmol) was added. After stirring for 30 minutes, 1M HCl (100 ml) and tert-butyl methyl ether (200 ml) were added. The phases were separated, and the organic phase was washed with saturated NaHCO3 (100 ml) and brine (100 ml), dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (heptane / EtOAc / HCOOH-65 / 35 / 0.5) yielded (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzamide (1.4 g, 6.3 mmol, 69.3% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.16–7.12 (m, 1H), 7.02–6.98 (m, 1H), 6.90–6.86 (m, 1H), 6.04 (s, 1H), 5.74 (s, 1H), 5.68–5.54 (m, 2H), 4.63–4.51 (m, 2H), 2.32 (s, 3H), 2.20–2.02 (m, 2H), 1.00 (t, 3H). MS (electrospray): 220.1 [M+H]+.

[0880] Example 11: Preparation of (Z)-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)methanol:

[0881]

[0882] Under a nitrogen atmosphere, a suspension of lithium aluminum hydride (0.564 ml, 13.66 mmol) in dry THF (25 ml) was cooled to 0 °C, and then a solution of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate (3.08 g, 12.40 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. 40 ml of water was added dropwise, followed by 1 M HCl (80 ml). The cooling bath was removed, and the reaction mixture was stirred for 5 minutes. The reaction mixture was extracted with tert-butyl methyl ether (2 x 200 ml), the organic phase was washed with 1 M HCl (100 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure. Rapid chromatography with heptane-heptane:EtOAc (90:10) elution on silica gel (80 g) yielded (Z)-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)methanol (2.39 g, 11.48 mmol, 92% yield) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, 1H), 6.96 (d, 1H), 6.81 (d, 1H), 5.76–5.49 (m, 2H), 4.68 (d, 2H), 4.65–4.50 (m, 2H), 2.22 (s, 3H), 2.19–1.92 (m, 2H), 1.50 (t, 1H), 1.01 (dd, 3H). MS (electrospray): 229.1 [M+Na]+.

[0883] Example 12: Preparation of (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid:

[0884]

[0885] Step 1:

[0886] Sulfuric acid (1 ml, 167 mmol) was added to a mixture of 2-(3-hydroxy-2-methylphenyl)acetic acid (27.7 g, 167 mmol) in methanol (100 ml). The reaction mixture was refluxed and stirred for 60 hours. The methanol was partially evaporated under reduced pressure. EtOAc (1000 ml) was added to the residue. The mixture was washed with NaHCO3 (300 ml) and brine (300 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure. Dry rapid chromatography was performed on silica gel (500 g) with heptane-heptane:EtOAc (80:20) to give methyl 2-(3-hydroxy-2-methylphenyl)acetic acid (13.15 g, 73.0 mmol, 43.8% yield) as a solid. 1H NMR(300 MHz, CDCl3)δ 6.98(t,1H), 6.76(d,1H), 6.65(d,1H), 5.10(s,1H), 3.68(s, 3H), 3.64(s, 2H), 2.16(s, 3H).

[0887] Step 2:

[0888] Under a nitrogen atmosphere at 0 °C, diisopropyl azodicarbonate (5 ml, 25.4 mmol) was added dropwise to a solution of triphenylphosphine (6.41 g, 24.44 mmol) in dry THF (125 ml). The reaction mixture was stirred at 0 °C for 35 min, and then a solution of methyl 2-(3-hydroxy-2-methylphenyl)acetate (4 g, 22.2 mmol) and cis-4-hepta-1-ol (3 ml, 22.3 mmol) in dry THF (45 ml) was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 17.5 h and concentrated under reduced pressure. Rapid chromatography on silica gel (200 g) with heptane-heptane:EtOAc (98:2) yielded (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetate (4.18 g, 15.12 mmol, 68.1% yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.08 (t, ¹H), 6.76 (dd, 2H), 5.52 – 5.19 (m, 2H), 3.93 (t, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 2.23 (dd, 2H), 2.17 (s, 3H), 2.10 – 1.93 (m, 2H), 1.91 – 1.75 (m, 2H), 0.92 (t, 3H). MS (electrospray): 299.2 [M+Na]⁺.

[0889] Step 3:

[0890] A solution of lithium hydroxide monohydrate (5.04 g, 120 mmol) in water (55 ml) was added to a solution of (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid (4.15 g, 15.02 mmol) in ethanol (55 ml). The reaction mixture was purified with argon and stirred at room temperature for 20 hours. 6 M HCl was added to pH 1. The mixture was extracted with EtOAc (200 ml x 2), dried (MgSO4), filtered, and concentrated under reduced pressure. Rapid chromatography on silica gel (80 g) with heptane-heptane:EtOAc (80:20) yielded (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid (3.69 g, 13.22 mmol, 88% yield) as an oil that solidified upon standing. 1H NMR(300 MHz, CDCl3)δ 7.08(t,1H),6.77(t, 2H), 5.37(dt, 2H), 3.93(t, 2H), 3.66(s, 2H), 2.33 – 2.10(m, 2H), 2.17(s, 3H), 2.10 – 1.94(m, 2H), 1.94 – 1.78(m, 2H), 0.92(t, 3H).

[0891] Example 13: Preparation of (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid:

[0892]

[0893] Step 1:

[0894] Under a nitrogen atmosphere at 0 °C, diisopropyl (E)-azo-1,2-dicarboxylate (5 ml, 25.4 mmol) was added dropwise to a solution of triphenylphosphine (6.40 g, 24.42 mmol) in dry THF (125 ml). The reaction mixture was stirred at 0 °C for 30 min, followed by the dropwise addition of methyl 2-(3-hydroxy-2-methylphenyl)acetate (4 g, 22.2 mmol) and (Z)-pent-2-en-1-ol (2.24 ml, 22.20 mmol) in dry THF (45 ml). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 67.5 h. The reaction mixture was then concentrated under reduced pressure. Methyl (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetate (3.67 g, 14.78 mmol, 66.6% yield) was obtained by rapid chromatographic separation on silica gel (80 g) with heptane-heptane:EtOAc (98:2), as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.08 (t, 1H), 6.79 (t, 2H), 5.72 – 5.41 (m, 2H), 4.56 (d, 2H), 3.66 (s, 3H), 3.63 (s, 2H), 2.23 – 2.03 (m, 5H), 1.00 (t, 3H). MS (electrospray ionization): 271.2 [M+Na]⁺.

[0895] Step 2:

[0896] A solution of lithium hydroxide monohydrate (4.96 g, 118 mmol) in water (55 ml) was added to a solution of (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid (3.67 g, 14.78 mmol) in ethanol (55 ml). The reaction mixture was purged with argon and stirred at room temperature for 20 hours. 6 M HCl was added to pH 1. The mixture was extracted with MTBE (200 ml x 2), dried over (MgSO4), filtered, and concentrated under reduced pressure. Rapid chromatography on silica gel (80 g) with heptane-heptane:EtOAc (80:20) yielded (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid (2.96 g, 12.33 mmol, 83% yield) as a solid. 1H NMR(300 MHz, CDCl3)δ 7.10(t,1H), 6.80(dd, 2H), 5.77 –5.45(m, 2H), 4.56(d, 2H), 3.66(s, 2H), 2.25 – 2.05(m, 5H), 1.01(t, 3H).

[0897] Example 14: Preparation of 2-methyl-3-(pent-2-yn-1-yloxy)benzoic acid:

[0898]

[0899] Step 1:

[0900] Under nitrogen atmosphere at room temperature, a mixture of 3-hydroxy-o-methylbenzoic acid (0.20 g, 1.32 mmol), 1-bromo-2-pentyne (0.49 g, 3.3 mmol), and potassium carbonate (0.64 g, 4.6 mmol) contained in 5 mL of dimethylformamide was stirred overnight. After transferring to a separatory funnel, water (50 mL) was added, and the mixture was extracted twice with 50 mL of diethyl ether. The combined organic phases were washed twice with 25 mL of water and then 25 mL of saturated NaCl (aq.), and then dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the crude product was purified on a silica gel column, eluting with 4% ethyl acetate in n-heptane. Evaporation of the solvent from the purified fraction yielded 0.33 g of penty-2-yn-1-yl-2-methyl-3-(penty-2-yn-1-yloxy)benzoate as an oil (88% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.46 (dd, ¹H), 7.17 (t, ¹H), 7.10 (d, ¹H), 4.86 (t, 2H), 4.67 (t, 2H), 2.44 (s, 3H), 2.21 (m, 4H), 1.13 (t, 3H), 1.11 (t, 3H). 13C NMR (100 MHz, chloroform-d) δ 167.50, 156.59, 131.49, 129.63, 126.07, 123.07, 116.01, 89.80, 89.13, 74.44, 73.64, 57.46, 53.36, 13.80, 13.79, 13.13, 12.70, 12.69. MS (ESI, positive ion mode) m / z 307.1 [M+Na]+.

[0901] Step 2:

[0902] Lithium hydroxide monohydrate (2.02 g, 48 mmol) was added to a solution of pentyl-2-yn-1-ol-2-methyl-3-(pentyl-2-yn-1-yloxy)benzoate (0.32 g, 1.13 mmol) in 40 mL of 1:1 tetrahydrofuran / water, and the mixture was stirred at 60°C for three days. After complete conversion was observed by TLC, the mixture was neutralized to a weakly acidic pH with 100 mL of 0.5 M HCl (aq.). The product was extracted with 2 x 100 mL of ethyl acetate, followed by washing with saturated NaCl (aq.) and drying over MgSO4. The solvent was removed by filtration to give a solid, which was purified by recrystallization from 50 mL of 1:1 methanol / water. The product was filtered off and dried under vacuum to give 0.19 g (77% yield) of the title compound. ¹H NMR (400 MHz, chloroform-d) δ 7.62 (dd, ¹H), 7.24–7.15 (m, 2H), 4.70 (t, 2H), 2.52 (s, 3H), 2.21 (qt, 2H), 1.12 (t, 3H). ¹³C NMR (100 MHz, chloroform-d) δ 173.76, 156.70, 130.70, 130.50, 126.12, 123.94, 116.84, 89.90, 74.39, 57.54, 13.80, 13.28, 12.70. MS (ESI, negative ion mode) m / z 217.1 [MH]⁻.

[0903] Example 15: Preparation of 2-methyl-3-(pentanamino)benzoic acid:

[0904]

[0905] Step 1:

[0906] A mixture of methyl 3-amino-2-methylbenzoate (0.41 g, 2.46 mmol), 1-iodopentane (0.4 ml, 3.1 mmol), and potassium carbonate (0.83 g, 6.01 mmol) in 10 ml of dimethylformamide was stirred at 100 °C for 2 hours, diluted with 100 ml of water, and extracted with 2 x 100 ml of diethyl ether. The combined organic phases were washed twice with 50 ml of water and 50 ml of saturated NaCl (aq.). After drying over MgSO4, the crude product was filtered and the solvent removed under reduced pressure. The crude product was purified on a silica gel column, eluted with 5% ethyl acetate in n-heptane. The purified fractions were combined, and the solvent was evaporated under reduced pressure to give 0.31 g of methyl 2-methyl-3-(pentanamino)benzoate (60% yield) as an oil. ¹H NMR (400 MHz, chloroform-d) δ 7.14–7.08 (m, 2H), 6.72 (dd, 1H), 3.86 (s, 3H), 3.61 (br s, 1H), 3.13 (t, 2H), 2.28 (s, 3H), 1.66 (m, 2H), 1.43–1.31 (m, 4H), 0.91 (t, 3H). 13C NMR (100 MHz, chloroform-d) δ 169.70, 147.22, 131.51, 126.49, 122.34, 118.15, 112.78, 52.11, 44.36, 29.60, 29.39, 22.73, 14.25, 13.77. MS (ESI, positive ion mode) m / z 258.1 [M+Na]+.

[0907] Step 2:

[0908] Lithium hydroxide monohydrate (1.92 g, 46 mmol) was added to a solution of methyl 2-methyl-3-(pentanamino)benzoate (0.30 g, 1.27 mmol) in 40 mL of 1:1 tetrahydrofuran / water, and the mixture was stirred at 60 °C for two days. Due to the slow reaction progress, the temperature was increased to reflux, and more lithium hydroxide monohydrate (1.01 g, 24 mmol) was added. After several hours, the mixture was neutralized to a weakly acidic pH with 140 mL of 0.5 M HCl (aq.). The product was extracted with 2 x 100 mL of ethyl acetate, followed by washing with saturated NaCl (aq.) and drying over MgSO4. The solvent was removed by filtration to give the crude product, which was purified on a silica gel column by elution with 25% ethyl acetate in n-heptane. After combining the pure fractions, the solvent was removed under reduced pressure to give 0.15 g of the title compound as a solid (53% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.30 (dd, ¹H), 7.16 (dd, ¹H), 6.78 (d, ¹H), 3.14 (t, 2H), 2.38 (s, 3H), 1.71 – 1.64 (m, 2H), 1.45–1.32 (m, 4H), 0.92 (t, 3H). ¹³C NMR (100 MHz, chloroform-d) δ 174.63, 147.34, 130.04, 126.55, 123.50, 119.25, 113.80, 44.43, 29.61, 29.39, 22.73, 14.26, 13.84. MS (ESI, negative ion mode) m / z 220.1 [MH]-.

[0909] Example 16: Preparation of 3-(dipentanamino)-2-methylbenzoic acid:

[0910]

[0911] Step 1:

[0912] A mixture of methyl 3-amino-2-methylbenzoate (0.37 g, 2.23 mmol), 1-iodopentane (0.9 ml, 6.9 mmol), and potassium carbonate (0.70 g, 5.1 mmol) in 5 ml of dimethylformamide was stirred at 100 °C. Since the conversion was incomplete after 1 day of reaction, more 1-iodopentane (0.9 ml, 6.9 mmol) was added, and the mixture was stirred at 100 °C for an additional 3 h. The mixture was transferred to a separatory funnel with 100 ml of water and extracted with 2 x 100 ml diethyl ether. The combined organic phases were rinsed with 50 ml of water and then washed twice with 50 ml of saturated NaCl (aq.). After drying over MgSO4 and subsequently filtering and removing the solvent under reduced pressure, the crude product was purified on a silica gel column, eluting with 3% ethyl acetate in n-heptane. The pure fractions were combined, and the solvent was evaporated under reduced pressure to give 0.49 g of methyl 3-(dipentanamino)-2-methylbenzoate, in oil (72% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.48 (dd, 1H), 7.21 (dd, 1H), 7.14 (t, 1H), 3.87 (s, 3H), 2.87 (m, 4H), 2.47 (s, 3H), 1.36 (m, 4H), 1.29–1.14 (m, 8H), 0.83 (t, 3H). 13C NMR (100 MHz, chloroform-d) δ 169.31, 151.73, 136.64, 132.17, 126.10, 125.53, 124.97, 54.17, 52.08, 29.71, 26.92, 22.75, 15.71, 14.30. MS (ESI, positive ion mode) m / z 306.2 [M+H]+, 328.2 [M+Na]+.

[0913] Step 2:

[0914] Lithium hydroxide monohydrate (2.23 g, 53 mmol) was added to a solution of methyl 3-(dipentanamino)-2-methylbenzoate (0.48 g, 1.57 mmol) in 40 mL of 1:1 tetrahydrofuran / water, and the mixture was stirred at 60 °C for four days. The reaction mixture was neutralized to a weakly acidic pH with 110 mL of 0.5 M HCl (aq.). The product was extracted with 2 x 100 mL of ethyl acetate, followed by washing with saturated NaCl (aq.) and drying over MgSO4. The solvent was removed by filtration to give the crude product, which was purified on a silica gel column using a gradient of 5% to 10% ethyl acetate in n-heptane. The solvent was removed from the combined purified fractions under reduced pressure to give 0.33 g of the title compound as an oil that solidified upon standing (72% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.72 (d, ¹H), 7.31 (d, ¹H), 7.22 (t, ¹H), 2.93 (m, 4H), 2.60 (s, 3H), 1.46–1.38 (m, 4H), 1.34–1.19 (m, 8H), 0.88 (t, 6H). ¹³C NMR (100 MHz, chloroform-d) δ 174.25, 151.87, 137.86, 130.98, 127.04, 126.08, 125.58, 54.20, 29.71, 26.92, 22.76, 15.93, 14.31. MS (ESI, negative ion mode) m / z 290.2 [MH]-.

[0915] Example 17: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid:

[0916]

[0917] Step 1:

[0918] Potassium carbonate (0.55 g, 4.0 mmol) was added to a solution of 2-ethyl-3-hydroxybenzoic acid (166 mg, 1.0 mmol) in DMF (10 ml), followed by (Z)-1-bromopent-2-ene (0.59 g, 4.0 mmol). The reaction mixture was heated at 90°C for 1 hour. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 300 mg (99% yield) of (Z)-pent-2-en-1-ol-2-ethyl-3-(((Z)-pent-2-en-1-yl)oxy)benzoate as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39 –7.27 (m, ¹H), 7.14 (dd, ¹H), 6.95 (d, ¹H), 5.74 – 5.52 (m, 4H), 4.82 (d, 2H), 4.58 (d, 2H), 2.89 (dd, 3H), 2.23 – 2.04 (m, 4H), 1.18 – 1.10 (m, 3H), 1.05 – 0.94 (m, 6H). MS (ESI, positive ion mode) m / z 325.1 [M+Na]⁺.

[0919] Step 2:

[0920] To a solution of (Z)-pent-2-en-1-ol-2-ethyl-3-(((Z)-pent-2-en-1-yl)oxy)benzoate (300 mg, 0.92 mmol) in ethanol (10 mL), 10 M NaOH (10 mL) was added, and the reaction mixture was stirred at 90 °C for three days. After cooling to room temperature, the ethanol was removed and 1 M HCl was added. The aqueous phase was extracted with EtOAc (x2), the combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc-80:20) yielded 122 mg (57% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, ¹H), 7.19 (td, ¹H), 7.02 (d, ¹H), 5.65 (dd, 2H), 4.60 (d, 2H), 3.08 – 2.95 (m, 2H), 2.21 – 2.05 (m, 2H), 1.22 – 1.12 (m, 3H), 1.01 (t, 3H). MS (ESI, negative ion mode) m / z 233.1 [MH]⁻.

[0921] Example 18: Preparation of (Z)-2,6-dimethyl-4-(pent-2-en-1-yloxy)benzoic acid:

[0922]

[0923] Step 1:

[0924] Potassium carbonate (167 mg, 1.22 mmol) was added to a solution of methyl 4-hydroxy-2,6-dimethylbenzoate (100 mg, 0.55 mmol) in DMF (5 ml), followed by (Z)-1-bromopent-2-ene (182 mg, 1.22 mmol). The reaction mixture was heated at 90 °C for 1 hour. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 130 mg (95% yield) of methyl (Z)-2,6-dimethyl-4-(pent-2-en-1-yloxy)benzoate as an oil.

[0925] Step 2:

[0926] To a solution of (Z)-2,6-dimethyl-4-(pent-2-en-1-yloxy)benzoate (130 mg, 0.52 mmol) in ethanol (10 mL), 10 M NaOH (10 mL) was added, and the reaction mixture was stirred at 90 °C for three days. After cooling to room temperature, the ethanol was removed, and 1 M HCl was added. The aqueous phase was extracted with EtOAc (x2), the combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated to give 113 mg (93% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl3) δ 6.59 (s, 2H), 5.70–5.58 (m, 2H), 4.56 (d, 2H), 2.41 (s, 6H), 2.22–2.06 (m, 2H), 1.01 (t, 3H). MS (ESI, negative ion mode) m / z 233.1 [MH]-.

[0927] Example 19: Preparation of 2-methyl-6-(pentoxy)benzoic acid:

[0928]

[0929] Step 1:

[0930] Potassium carbonate (1.12 g, 8.10 mmol) was added to a solution of ethyl 6-methylsalicylate (0.73 g, 4.05 mmol) in DMF (10 ml), followed by 1-iodopentane (1.0 ml, 8.10 mmol). The reaction mixture was heated overnight at 90 °C. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 1.00 g (99% yield) of ethyl 2-methyl-6-(pentoxy)benzoate as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (t, ¹H), 6.73 (dd, 2H), 4.36 (q, 2H), 3.94 (t, 2H), 2.27 (s, 3H), 1.72 (dd, 2H), 1.48 – 1.23 (m, 8H), 0.89 (t, 3H). MS (ESI, positive ion mode) m / z 273.1 [M+Na]⁺.

[0931] Step 2:

[0932] LiOH was added to a solution of ethyl 2-methyl-6-(pentoxy)benzoate (1.00 g, 3.99 mmol) in THF (10 ml) and water (10 ml). . H₂O (0.83 g, 20 mmol) was added, and the reaction mixture was stirred at room temperature. TLC showed no conversion. 5 M NaOH (10 ml) and ethanol (10 ml) were added, and the reaction mixture was heated to reflux overnight. After cooling to room temperature, ethanol and THF were removed by rotary evaporation, 1 M HCl was added, and the aqueous phase was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc 95:5-90:10-80:20-70:30) gave 0.154 g (17% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.29 (t, ¹H), 6.85 (dd, 2H), 4.09 (t, 2H), 2.52 (s, 3H), 1.91 – 1.77 (m, 2H), 1.51 – 1.27 (m, 4H), 0.91 (t, 3H). MS (ESI, negative ion mode) m / z 221.1 [MH]⁻.

[0933] Example 20: Preparation of 2-methoxy-6-(pentoxy)benzoic acid:

[0934]

[0935] Step 1:

[0936] Potassium carbonate (1.12 g, 8.10 mmol) was added to a solution of methyl 2-hydroxy-6-methoxybenzoate (0.74 g, 4.05 mmol) in DMF (10 ml), followed by the addition of 1-iodopentane (1.0 ml, 8.10 mmol). The reaction mixture was heated overnight at 90°C. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 1.00 g (98%) of methyl 2-methoxy-6-(pentoxy)benzoate as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, ¹H), 6.52 (dd, 2H), 3.96 (t, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 1.82 – 1.67 (m, 2H), 1.45 – 1.25 (m, 4H), 0.90 (t, 3H). MS (ESI, positive ion mode) m / z 275.1 [M+Na]⁺.

[0937] Step 2:

[0938] LiOH was added to a solution of methyl 2-methoxy-6-(pentoxy)benzoate (1.00 g, 3.96 mmol) in THF (10 ml) and water (10 ml). . H₂O (0.83 g, 20 mmol) was added, and the reaction mixture was stirred at room temperature. TLC showed no conversion. 5 M NaOH (10 mL) and ethanol (10 mL) were added, and the reaction mixture was heated to reflux overnight. After cooling to room temperature, ethanol and THF were removed by rotary evaporation, 1 M HCl was added, and the aqueous phase was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc 95:5–90:10–80:20–70:30) gave 0.22 g (23% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.23 (dd, ¹H), 6.51 (d, 2H), 3.97 (t, 2H), 3.81 (s, 3H), 1.92 – 1.59 (m, 2H), 1.54 – 1.13 (m, 4H), 0.85 (t, 3H). MS (ESI, negative ion mode) m / z 237.1 [MH]⁻.

[0939] Example 21: Preparation of 2-methyl-3-(methyl(pentyl)amino)benzoic acid:

[0940]

[0941] Step 1:

[0942] DIPEA (2.3 ml, 13.2 mmol) and methyl iodoform (0.83 ml, 13.3 mmol) were added to a solution of methyl 3-amino-2-methylbenzoate (1.00 g, 6.02 mmol) in DMF (16 ml). The reaction mixture was heated at 70 °C for 6.5 h in a sealed container and then cooled to room temperature. NaOH (50 ml, 1 M) was added, and the aqueous phase was extracted with EtOAc (x2). The organic layer was dried (Na2SO4), filtered, and concentrated. Rapid chromatography (heptane:EtOAc 85:15) yielded 0.52 g (49% yield) of methyl 2-methyl-3-(methylamino)benzoate as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.22 – 7.05 (m, 2H), 6.72 (dd, 1H), 3.86 (s, 3H), 2.88 (s, 3H), 2.28 (s, 3H). MS (ESI, positive ion mode) m / z 180.1 [M+H]⁺.

[0943] Step 2:

[0944] Potassium carbonate (0.47 g, 3.41 mmol) was added to a solution of methyl 2-methyl-3-(methylamino)benzoate (0.51 g, 2.85 mmol) in DMF (5 ml), followed by 1-iodopentane (0.74 ml, 5.7 mmol). The reaction mixture was heated overnight at 100 °C. The reaction was slow. Therefore, a fresh batch of 1-iodopentane (0.7 ml and 1 ml) was added over two hours and heating continued for another two hours. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude alkylated product was directly hydrolyzed by heating at 100 °C for 1 hour in ethanol (10 ml) and 5M NaOH (10 ml). After removing the ethanol, 1M HCl was added, and the aqueous phase was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc 80:20–70:30) yielded 0.29 g (43% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, ¹H), 7.38–7.09 (m, 2H), 2.96–2.74 (m, 2H), 2.64 (s, 3H), 2.56 (s, 2H), 1.49 (dd, 2H), 1.35–1.19 (m, 3H), 0.86 (t, 3H). MS (ESI, negative ion mode) m / z 234.1 [MH]⁻.

[0945] Example 22: Preparation of potassium 2-methyl-3-(pentoxy)benzoate:

[0946]

[0947] Potassium hydroxide (0.33 g, 5 mmol) was dissolved in ethanol (abs. 30 ml) under sonication. 2-Methyl-3-(pentoxy)benzoic acid (1.11 g, 5 mmol) was added to this solution, and the resulting solution was stirred for 2 hours, then evaporated to dryness. The potassium salt of the product was redissolved in water (10 ml) and freeze-dried overnight to give 1.28 g (98.5% yield) of the title compound as a solid. ¹H NMR (400 MHz, DMSO) δ 7.01 – 6.83 (m, 2H), 6.73 – 6.63 (m, 1H), 3.89 (t, 2H), 2.19 (s, 3H), 1.70 (dd, 2H), 1.50 – 1.24 (m, 4H), 0.90 (t, 3H). 13CNMR(101 MHz, DMSO)δ 172.46, 156.46, 146.05, 124.89, 122.28, 119.55, 109.12, 67.54, 28.63, 27.94, 21.92, 14.00, 12.99.

[0948] Example 23: Preparation of sodium 2-methyl-3-(pentoxy)benzoate:

[0949]

[0950] Sodium hydroxide (0.20 g, 5 mmol) was dissolved in ethanol (abs. 20 ml) under sonication. 2-Methyl-3-(pentoxy)benzoic acid (1.11 g, 5 mmol) was added to this solution, and the resulting solution was stirred for 2 hours, then evaporated to dryness. The sodium salt of the product was suspended in water (10 ml) and freeze-dried overnight to give 1.18 g (97% yield) of the title compound as a solid. ¹H NMR (400 MHz, DMSO) δ 6.97 (q, 2H), 6.75 (dd, 1H), 3.91 (t, 2H), 2.23 (s, 3H), 1.71 (dd, 2H), 1.56–1.24 (m, 4H), 0.90 (t, 3H). 13C NMR (101 MHz, DMSO) δ 172.92, 156.56, 143.74, 125.11, 123.06, 119.91, 110.03, 67.63, 28.61, 27.93, 21.92, 14.00, 12.95.

[0951] Example 24: Preparation of 3-((5-hydroxypentyl)oxy)-2-methylbenzoic acid:

[0952]

[0953] Potassium carbonate (3.00 g, 22.0 mmol) and potassium iodide (1.6 g, 10 mmol) were added to a solution of 3-hydroxy-2-methylbenzoic acid (1.52 g, 10.0 mmol) in DMF (20 mL), followed by the addition of 5-bromoacetic acid pentyl ester (4.60 g, 22.0 mmol). The reaction mixture was heated overnight at 100 °C. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was directly hydrolyzed by heating at 100 °C for 1.5 h in ethanol (10 mL) and 5 M NaOH (10 mL). Rapid chromatography (heptane:EtOAc 80:20–70:30–50:50–EtOAc) gave 0.98 g (41% yield) of the title product as a solid. ¹H NMR (400 MHz, DMSO) δ 7.28 (d, ¹H), 7.20 (t, ¹H), 7.09 (d, ¹H), 3.97 (t, 2H), 3.41 (t, 2H), 2.32 (s, 3H), 1.85 – 1.61 (m, 2H), 1.57 – 1.32 (m, 4H). MS (ESI, negative ion mode) m / z 237.1 [MH]⁻.

[0954] Example 25: Preparation of 3-(pentoxy)-2-(trifluoromethyl)benzoic acid:

[0955]

[0956] Step 1:

[0957] Under a nitrogen atmosphere, boron tribromide (2 ml, 21 mmol) was added to an ice-cold suspension of 3-methoxy-(2-trifluoromethyl)benzoic acid (0.51 g, 2.3 mmol) in 10 ml dichloromethane. After 2 hours of reaction, the reaction was carefully quenched by adding 5 ml of water dropwise. The mixture was transferred to a separatory funnel using 50 ml of water, and the acidic intermediate was extracted twice with 50 ml of ethyl acetate. The combined organic phases were then washed with 50 ml of saturated NaCl (aq.) and dried over magnesium sulfate. After filtration and removal of the solvent under reduced pressure, the crude acidic intermediate was dissolved in 10 ml of dimethylformamide, followed by the addition of potassium carbonate (1.06 g, 7.67 mmol) and 1-iodopentane (0.71 ml, 5.4 mmol). The formation of the product was observed by TLC at room temperature for 1 hour, while complete conversion was achieved by slow heating to 50 °C for an additional hour. The reaction mixture was transferred to a separatory funnel with 100 ml of water and extracted twice with diethyl ether. The combined organic phases were washed twice with 50 ml of water, followed by 50 ml of saturated NaCl (aq.). After drying over magnesium sulfate, the solvent was removed under reduced pressure. The crude product was purified on a silica gel column by elution with 95:5 n-heptane / ethyl acetate to remove the solvent, yielding 0.40 g of 3-(pentoxy)-2-(trifluoromethyl)benzoate (50% in two steps). ¹H NMR (400 MHz, chloroform-d) δ 7.46 (t, ¹H), 7.03 (d, ¹H), 6.97 (d, ¹H), 4.26 (t, 2H), 4.02 (t, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.48–1.30 (m, 8H), 0.93–0.87 (m, 6H). 13C NMR (100 MHz, chloroform-d) δ 168.74, 157.87 (q, JC-F = 2 Hz), 134.77 (q, JC-F = 3 Hz), 133.08, 123.48 (q, JC-F = 274 Hz), 119.47, 115.92 (q, JC-F = 31 Hz), 114.59, 69.49, 66.46, 28.88, 28.25, 28.16, 28.14, 22.50, 22.48, 14.17, 14.14. MS (ESI, positive ion mode) m / z 369.1 [M+Na]+, 111.1 (“baseline”).

[0958] Step 2:

[0959] To a solution of 0.20 g (0.58 mmol) of 3-(pentoxy)-2-(trifluoromethyl)benzoate in 10 mL abs. ethanol, 10 mL of 10 M potassium hydroxide (aq.) was added. After reflux for 2.5 hours, the reaction mixture was placed on an ice bath and quenched with 110 mL of 1.0 M HCl (aq.). The crude product was extracted with 2 x 100 mL of ethyl acetate. The combined organic phases were washed with saturated NaCl (aq.) and dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure to give the crude product as a solid. Purification was performed on a silica gel column using a gradient elution of 40:60 n-heptane / ethyl acetate to give 0.06 g of the title product as a solid (37% yield). ¹H NMR (400 MHz, chloroform-d) δ 9.89 (br s, ¹H), 7.50 (t, ¹H), 7.11–7.08 (m, 2H), 4.05 (t, 2H), 1.82 (m, 2H), 1.48–1.32 (m, 4H), 0.92 (t, 3H). 13C NMR (100 MHz, chloroform-d) δ 173.74, 158.00 (q, JC-F = 1 Hz), 133.29 (q, JC-F = 3 Hz), 133.19, 123.32 (q, JC-F = 274 Hz), 119.56, 116.04 (q, JC-F = 31 Hz), 115.32, 69.59, 28.87, 28.16, 22.50, 14.18. MS (ESI, negative ion mode) m / z 275.0 [MH]-.

[0960] Example 26: Preparation of magnesium 2-methyl-3-(pentoxy)benzoate:

[0961]

[0962] Magnesium hydroxide (15 mg, 0.25 mmol) was added to a solution of 2-methyl-3-(pentoxy)benzoic acid (111 mg, 0.50 mmol) in ethanol (abs. 50 mL) and water (50 mL). The reaction was stirred at 50 °C for 1 h, and then evaporated to dryness (116 mg, ~quantitative yield). ¹H NMR (400 MHz, DMSO) δ 7.19 (d, 1H), 7.06 (t, 1H), 6.89 (d, 1H), 3.93 (t, 2H), 2.30 (s, 3H), 1.82–1.63 (m, 2H), 1.51–1.25 (m, 4H), 0.89 (t, 3H). 13C NMR (101 MHz, DMSO) δ 174.78, 156.67, 139.43, 125.30, 124.88, 120.87, 111.77, 67.77, 28.53, 27.89, 21.89, 13.96, 12.81.

[0963] Example 27: Preparation of 2-methyl-3-pentamidobenzoic acid:

[0964]

[0965] Step 1:

[0966] At 0 °C, Et3N (0.44 ml, 3.15 mmol) was added to a stirred solution of methyl 3-amino-2-methylbenzoate (0.5 g, 3.0 mmol) in EtOAc (10 ml), followed by pentanoyl chloride (0.37 ml, 3.15 mmol). The reaction mixture was then stirred overnight at room temperature, poured into brine, and the aqueous phase was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 0.4 g (58% yield) of methyl 2-methyl-3-pentanoamide benzoate as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, ¹H), 7.63 (d, ¹H), 7.26 – 7.19 (m, ¹H), 7.03 (s, ¹H), 3.87 (s, 3H), 2.50 – 2.33 (m, 5H), 1.71 (m, 2H), 1.41 (m, 2H), 0.92 (t, 3H). MS (ESI, positive ion mode) m / z 272.1 [M+Na]⁺.

[0967] Step 2:

[0968] To a solution of methyl 2-methyl-3-pentamidobenzoate (0.41 g, 1.64 mmol) in ethanol (20 mL), 2.5 M NaOH (20 mL) was added, and the reaction mixture was stirred at 95 °C for 30 min. After cooling to room temperature, the ethanol was removed by rotary evaporation, 1 M HCl was added, and the aqueous phase was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to give 0.30 g (78% yield) of the title compound as a solid. ¹H NMR (400 MHz, DMSO) δ 12.92 (s, ¹H), 9.42 (s, ¹H), 7.56 (d, ¹H), 7.44 (d, ¹H), 7.23 (t, ¹H), 2.43–2.23 (m, 5H), 1.58 (tt, 2H), 1.35 (tq, 2H), 0.91 (t, 3H). MS (ESI, negative ion mode) m / z 234.1 [MH]⁻.

[0969] Example 28: Preparation of 3-(2-ethoxyethoxy)-2-methylbenzoic acid:

[0970]

[0971] Step 1:

[0972] 3-Hydroxy-2-methylbenzoic acid (3.0 g, 19.7 mmol) in methanol (30 mL) was heated overnight at 90 °C in the presence of 0.5 mL H₂SO₄. After cooling to room temperature, the methanol was removed by rotary evaporation, and 1 M HCl (100 mL) was added. The aqueous phase was extracted with EtOAc (x3), and the combined organic phases were washed with brine, dried (Na₂SO₄), filtered, and concentrated to give 3.2 g (98% yield) of methyl 3-hydroxy-2-methylbenzoate as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (dd, 1H), 7.08 (t, 1H), 6.93 (d, 1H), 5.43 (s, 1H), 3.88 (s, 3H), 2.43 (s, 3H).

[0973] Step 2:

[0974] Potassium carbonate (1.38 g, 10.0 mmol) and potassium iodide (0.83 g, 5.00 mmol) were added to a solution of methyl 3-hydroxy-2-methylbenzoate (0.83 g, 5.00 mmol) in DMF (10 ml), followed by 2-bromoethyl ether (0.7 ml, 6.00 mmol). The reaction mixture was heated at 100 °C with stirring. After 30 minutes, 2-bromoethyl ether (0.5 ml, 4.3 mmol) was added, and heating was continued for another 45 minutes. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc 95:5-90:10-80:20) yielded 0.85 g (71% yield) of methyl 3-(2-ethoxyethoxy)-2-methylbenzoate as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, 1H), 7.14 (t, 1H), 6.96 (d, 1H), 4.09 (m, 2H), 3.85 (s, 3H), 3.78 (m, 2H), 3.59 (q, 2H), 2.42 (s, 3H), 1.21 (t, 3H). MS (ESI, positive ion mode) m / z 261.1 [M+Na]⁺.

[0975] Step 3:

[0976] To a solution of methyl 3-(2-ethoxyethoxy)-2-methylbenzoate (0.85 g, 3.57 mmol) in ethanol (25 ml), 2.5 M NaOH (25 ml) was added, and the reaction mixture was stirred at 95 °C for 15 min. After cooling to room temperature, the ethanol was removed by rotary evaporation, 1 M HCl was added, and the aqueous phase was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated to give 0.73 g (91%) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 12.25 (s, ¹H), 7.72–7.55 (m, ¹H), 7.24 (t, ¹H), 7.09 (d, ¹H), 4.13 (m, 2H), 3.82 (m, 2H), 3.67 (q, 2H), 2.57 (s, 3H), 1.29 (t, 3H). MS (ESI, negative ion mode) m / z 223.1 [MH]⁻.

[0977] Example 29: Preparation of 2-methyl-3-((5,5,5-trifluoropentyl)oxy)benzoic acid:

[0978]

[0979] Step 1:

[0980] Potassium carbonate (0.83 g, 6.00 mmol) and potassium iodide (0.50 g, 3.00 mmol) were added to a solution of methyl 3-hydroxy-2-methylbenzoate (0.50 g, 3.00 mmol) in DMF (10 ml), followed by the addition of 5-bromo-1,1,1-trifluoropentane (1.00 g, 4.80 mmol). The reaction mixture was heated at 100 °C for 1.5 h with stirring. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Dry column vacuum chromatography (heptane:EtOAc 95:5–90:10) yielded 0.67 g (77% yield) of methyl 2-methyl-3-((5,5,5-trifluoropentyl)oxy)benzoate as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, ¹H), 7.16 (t, ¹H), 6.93 (d, ¹H), 3.97 (t, 2H), 3.87 (s, 3H), 2.41 (s, 3H), 2.27 – 2.08 (m, 2H), 1.97 – 1.85 (m, 2H), 1.85 – 1.69 (m, 2H). MS (ESI, positive ion mode) m / z 313.1 [M+Na]⁺.

[0981] Step 2:

[0982] To a solution of methyl 2-methyl-3-((5,5,5-trifluoropentyl)oxy)benzoate (0.66 g, 2.27 mmol) in ethanol (25 mL), 2.5 M NaOH (25 mL) was added, and the reaction mixture was stirred at 95 °C for 30 min. After cooling to room temperature, the ethanol was removed by rotary evaporation, 1 M HCl was added, and the aqueous phase was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated to give 0.57 g (90% yield) of the title compound as a solid. ¹H NMR (400MHz, CDCl₃) δ 12.04 (br s, ¹H), 7.58 (d, ¹H), 7.20 (t, ¹H), 7.00 (d, ¹H), 3.99 (t, 2H), 2.50 (s, 3H), 2.26 – 2.09 (m, 2H), 1.98 – 1.75 (m, 4H). MS (ESI, negative ion mode) m / z 275.1 [MH]⁻.

[0983] Example 30: Preparation of magnesium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0984]

[0985] Magnesium hydroxide (15 mg, 0.25 mmol) was added to a solution of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (110 mg, 0.50 mmol) in ethanol (abs. 50 ml) and water (50 ml). The reaction was stirred at 50 °C for 1 h, and then evaporated to dryness to give the title compound in quantitative yield as a solid. ¹H NMR (400 MHz, DMSO) δ 7.19 (d, 1H), 7.06 (t, 1H), 6.91 (d, 1H), 5.73 – 5.50 (m, 2H), 4.57 (d, 2H), 2.30 (s, 3H), 2.22 – 1.99 (m, 2H), 0.95 (t, 3H).

[0986] Example 31: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzyl acetate:

[0987]

[0988] Et3N (0.16 ml, 1.2 mmol) was added to a solution of (Z)-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)methanol (206 mg, 1.00 mmol) in DCM (20 ml) at 0 °C, followed by the addition of acetyl chloride (85 µl, 1.2 mmol). The ice bath was removed, and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into water, and the aqueous phase was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by dry column vacuum chromatography (heptane:EtOAc gradient) to give 235 mg (95% yield) of the title compound as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.14 (t, ¹H), 6.94 (d, ¹H), 6.85 (d, ¹H), 5.76 – 5.54 (m, 2H), 5.11 (s, 2H), 4.58 (m, 2H), 2.21 (s, 3H), 2.15 (m, 2H), 2.08 (s, 3H), 1.02 (t, 3H). MS (ESI, positive ion mode) m / z 271.1 [M+Na]⁺.

[0989] Example 32: Preparation of calcium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0990]

[0991] Calcium hydroxide (19 mg, 0.25 mmol) was added to a solution of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (110 mg, 0.50 mmol) in ethanol (abs. 50 ml) and water (50 ml). The reaction was stirred at 50 °C for 1 h, and then evaporated to dryness to give the title compound in quantitative yield as a solid. ¹H NMR (400 MHz, DMSO) δ 7.16 (d, 1H), 7.04 (t, 1H), 6.88 (d, 1H), 5.70–5.54 (m, 2H), 4.57 (m, 2H), 2.31 (s, 3H), 2.12 (m, 2H), 0.96 (t, 3H). 13C NMR (101 MHz, DMSO) δ 174.92, 156.30, 135.20, 125.11, 124.84, 124.43, 120.89, 111.51, 63.92, 20.63, 14.01, 13.02.

[0992] Example 33: Preparation of potassium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0993]

[0994] Potassium hydroxide (0.33 g, 5 mmol) was dissolved in ethanol (abs. 30 ml) under sonication. (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (1.10 g, 5 mmol) was added to this solution, and the mixture was sonicated until completely dissolved. The reaction mixture was stirred for two hours and then evaporated to dryness. The potassium salt of the product was redissolved in water (10 ml) and freeze-dried overnight to give 1.28 g (99% yield) of the title compound as a solid. 1H NMR(400 MHz, DMSO)δ 7.10 – 6.88(m, 2H), 6.75(d,1H), 5.73 – 5.50(m, 2H), 4.55(m, 2H), 2.26(s, 3H), 2.21 – 2.05(m, 2H), 0.98(t, 3H). 13C NMR (101 MHz, DMSO) δ 173.10, 156.22, 145.50, 134.99, 125.08, 124.90, 122.85, 120.07, 109.85, 63.85, 20.70, 14.05, 13.18.

[0995] Example 34: Preparation of sodium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0996]

[0997] Sodium hydroxide (0.20 g, 5 mmol) was dissolved in ethanol (20 ml absolute) under sonication. (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (1.10 g, 5 mmol) was added to this solution, and the mixture was sonicated until completely dissolved. The reaction mixture was stirred for two hours and then evaporated to dryness. The sodium salt of the product was redissolved in water (10 ml) and freeze-dried overnight to give 1.20 g (99% yield) of the title compound as a solid. 1H NMR(400MHz, DMSO)δ 7.00-6.94(m, 2H), 6.76(m,1H), 5.65-5.57(m, 2H), 4.55(m, 2H), 2.23(s, 3H), 2.20 – 2.04(m, 2H), 0.96(t, 3H). 13C NMR (101 MHz, DMSO) δ 173.29, 156.19, 144.80, 135.03, 125.02, 124.92, 122.95, 120.06, 110.06, 63.81, 20.64, 14.02, 13.07.

[0998] Example 35: Preparation of 2-methyl-3-(pentathio)benzoic acid:

[0999] Step 1:

[1000] A solution of lithium hydroxide (6.24 g, 150 mmol) in water (50 ml) was added to a solution of methyl 3-amino-2-methylbenzoate (2.30 g, 13.9 mmol) in THF (50 ml). The reaction mixture was heated to 95 °C for 2.5 h with stirring. After cooling to room temperature, the reaction mixture was acidified with 3 M HCl, and the aqueous phase was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated to give 1.00 g (48% yield) of 3-amino-2-methylbenzoic acid as a solid. ¹H NMR (400 MHz, DMSO) δ 7.10 – 6.86 (m, 2H), 6.76 (dd, 1H), 5.02 (s, 2H), 2.18 (s, 3H). MS (ESI, negative ion mode) m / z 150.1 [MH]-.

[1001] Step 2:

[1002] 3-Amino-2-methylbenzoic acid (0.60 g, 3.96 mmol) was placed in a reaction flask containing ice (1.62 g) and concentrated hydrochloric acid (0.80 g) and cooled to 0 °C. A solution of sodium nitrite (0.27 g, 3.91 mmol) in water (1.62 g) was added dropwise. In another flask, sodium carbonate (0.50 g, 4.72 mmol) and potassium ethyl xanthate (0.63 g, 3.96 mmol) were dissolved in water (2.7 g), and the suspension was heated to 70 °C. Then, a pre-prepared diazo solution was carefully added, and heating continued for one hour, followed by the addition of sodium hydroxide (0.63 g, 15.8 mmol) in water (1.62 g). The reaction mixture was heated for two hours, cooled, and acidified with hydrochloric acid. The precipitate was filtered off and dried to give 0.55 g (83% yield) of 3-mercapto-2-methylbenzoic acid as a solid. MS (ESI, negative ion mode) m / z 167.1 [MH]-.

[1003] Step 3:

[1004] Potassium carbonate (0.69 g, 5.00 mmol) was added to a solution of 3-mercapto-2-methylbenzoic acid (168 mg, 1.00 mmol) in DMF (2 ml) at 0°C, followed by the addition of iodopentane (0.50 ml, 4.00 mmol). The ice bath was removed, and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated. Rapid chromatography (heptane:EtOAc gradient) gave 80 mg (34% yield) of the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, ¹H), 7.46 (d, ¹H), 7.32 – 7.13 (m, 2H), 2.88 (m, 2H), 2.66 (s, 3H), 1.65 (m, 2H), 1.46 – 1.22 (m, 4H), 0.89 (t, 3H). MS (ESI, negative ion mode) m / z 237.1 [MH]⁻.

[1005] Example 36: Preparation of 2-methyl-3-(pentylsulfinyl)benzoic acid:

[1006]

[1007] 2-Methyl-3-(pentathio)benzoic acid (119.1 mg, 0.500 mmol) was dissolved in 10 mL of methanol and cooled on an ice bath. A solution of sodium periodate (124.6 mg, 0.583 mmol) in 2 mL of water was added dropwise over 5 minutes. The ice bath was then removed, and the mixture was stirred at room temperature for 1 day. The reaction mixture was transferred to a separatory funnel using a 1:1 mixture of 1 M HCl (aq.) and saturated NaCl (aq.), and the product was extracted with 2 x 100 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated NaCl (aq.), dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the crude product. Purification was achieved by gradient elution of 75%–100% ethyl acetate in n-heptane on a silica gel column to obtain the pure product. The title compound was obtained from the pure fraction after solvent removal, as an oil that solidified upon standing (40.2 mg, 32% yield). 1H NMR(400 MHz, chloroform-d)δ 8.98(br s,1H), 8.14(d,1H), 8.11(d,1H), 7.52(t,1H), 2.84(m,1H), 2.71(m,1H), 2.61(s, 3H), 1.84(m,1H), 1.66(m,1H), 1.49-1.26(m, 4H), 0.87(s, 3H). 13C NMR (100 MHz, chloroform-d) δ 171.19, 144.23, 136.92, 133.76, 130.61, 128.48, 127.26, 55.49, 30.92, 22.48, 22.27, 16.77, 14.02. MS (ESI, negative ion mode) m / z 253.1 [MH]-.

[1008] Example 37: Preparation of 2-methyl-3-(benzenesulfonyl)benzoic acid:

[1009]

[1010] 2-Methyl-3-(pentathio)benzoic acid (125.5 mg, 0.527 mmol) and potassium permanganate (332 mg, 2.10 mmol) were separately suspended and dissolved in 10 mL of water, and then 5 drops of 10% NaOH (aq.) were added. The mixture was heated to reflux for 1 hour. After cooling on an ice bath, dilute H₂SO₄ (aq.) was added to pH ~2, and the permanganate was quenched with solid NaHSO₃. The mixture was transferred to a separatory funnel using another 50 mL of water and extracted with 3 x 50 mL ethyl acetate, acidified with dilute H₂SO₄ (aq.) between each extraction. The combined organic phases were washed with 50 mL of saturated NaCl (aq.), dried over MgSO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by elution using a silica gel column with a gradient of ethyl acetate (50%–100%) in n-heptane. The solvent was removed from the target fraction to give the title compound as a solid (15.6 mg, 11% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.26 (d, ¹H), 8.18 (d, ¹H), 7.47 (t, ¹H), 3.18 (m, 2H), 2.95 (s, 3H), 1.70 (m, 2H), 1.40–1.20 (m, 4H), 0.85 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 172.11, 140.32, 139.75, 136.16, 134.56, 132.48, 126.56, 55.76, 30.56, 22.30 (approximately two resonances), 17.66, 13.88. MS (ESI, negative ion mode) m / z 269.0 [MH]-.

[1011] Example 38: Preparation of calcium 2-methyl-3-(pentoxy)benzoate:

[1012] Calcium hydroxide (19 mg, 0.25 mmol) was added to a solution of 2-methyl-3-(pentoxy)benzoic acid (111 mg, 0.50 mmol) in ethanol (abs. 50 ml) and water (50 ml). The reaction was stirred at 50 °C for 1 h, and then evaporated to dryness (quantitative yield). ¹H NMR (400 MHz, DMSO) δ 7.12 (d, 1H), 7.02 (t, 1H), 6.82 (d, 1H), 3.92 (t, 2H), 2.30 (s, 3H), 1.72 (m, 2H), 1.59 – 1.21 (m, 4H), 0.90 (t, 3H). 13C NMR (101MHz, DMSO) δ 156.61, 125.10, 124.15, 120.63, 110.90, 67.67, 28.56, 27.89, 21.89, 13.96, 12.90 (Two resonances were not identified due to excessive signal broadening).

[1013] Example 39: Preparation of (Z)-2-methyl-5-(pent-2-en-1-yloxy)benzoic acid:

[1014] Step 1:

[1015] Potassium carbonate (1.80 g, 13.0 mmol) was added to a solution of 5-hydroxy-2-methylbenzoic acid (278 mg, 1.82 mmol) in DMF (10 mL), followed by (Z)-1-bromopent-2-ene (1.93 g, 13.0 mmol). The reaction mixture was heated overnight at 90 °C. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 500 mg (95% yield) of 2-methyl-5-(((Z)-pent-2-en-1-yl)oxy)benzoic acid (Z)-pent-2-en-1-ester, as an oil. MS (ESI, positive ion mode) m / z 311.1 [M+Na]+.

[1016] Step 2:

[1017] To a solution of (Z)-pent-2-en-1-ol-2-methyl-5-(((Z)-pent-2-en-1-yl)oxy)benzoate (500 mg, 1.73 mmol) in ethanol (25 mL), 2.5 M NaOH (10 mL) was added, and the reaction mixture was stirred at 95 °C for 40 min. After cooling to room temperature, the ethanol was removed and 1 M HCl was added. The aqueous phase was extracted with EtOAc (x2), and the combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. Rapid chromatography (heptane:EtOAc 70:30) yielded 350 mg (92% yield) of the title compound as a solid. ¹H NMR (400 MHz, chloroform-d) δ 12.35 (br s, ¹H), 7.60 (d, ¹H), 7.16 (d, ¹H), 7.02 (dd, ¹H), 5.93–5.86 (m, 0.30H), 5.71–5.59 (m, 1.7H), 4.59 (d, 1.4H), 4.49 (d, 0.60H), 2.57 (s, 3H), 2.21–2.07 (m, 2H), 1.02 (t, 3H). (¹H NMR indicates that some products are in the (E)- configuration). MS (ESI, negative ion mode) m / z 219.1 [MH]-.

[1018] Example 40: Preparation of 2-methyl-3,5-bis(pentoxy)benzoic acid:

[1019] Step 1:

[1020] Piperidine (7.6 ml, 77 mmol) was slowly added to a stirred solution of CH2O (37%, 5.43 ml, 72.6 mmol) in acetic acid (4.5 ml). The temperature was maintained between 18 and 25 °C by occasional cooling with an ice bath. Stirring was continued for 30 minutes. In another flask, a solution of 3,5-dihydroxybenzoic acid (10 g, 65.0 mmol) in 38% aq. EtOH (23 ml) was prepared. One-third of the above Mannich solution was added to this solution at room temperature. After stirring for 30 minutes, the remaining solution was added and stirring was continued overnight. The precipitate was collected by filtration, washed with EtOAc, and dried to give 15.59 g (96% yield) of the intermediate 3,5-dihydroxy-2-(piperidin-1-ylmethyl)benzoic acid. The compound (2 g, 7.96 mmol) was hydrogenated overnight (balloon) in MeOH (20 ml), water (1.5 ml), and piperidine (1 ml) in the presence of Pd / C (0.2 g) to give 360 ​​mg (27% yield) of 3,5-dihydroxy-2-methylbenzoic acid as a solid.

[1021] Step 2:

[1022] Potassium carbonate (1.38 g, 10.0 mmol) was added to a solution of 3,5-dihydroxy-2-methylbenzoic acid (360 mg, 2.14 mmol) in DMF (10 ml), followed by the addition of 1-iodopentane (1.3 ml, 10.5 mmol). The reaction mixture was heated at 90°C for 9 hours. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give the intermediate 2-methyl-3,5-bis(pentoxy)benzoate pentyl ester, as an oil. The compound was dissolved in ethanol (20 ml) and heated with 20 ml of 2.5 NaOH for 4 hours. After cooling to room temperature, the ethanol was removed, and 1 M HCl was added. The aqueous phase was extracted with EtOAc (x3), and the combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. Rapid chromatography (heptane:EtOAc 70:30) yielded 200 mg (30% yield) of the title compound as a solid. ¹H NMR (400 MHz, chloroform-d) δ 7.07 (d, 1H), 6.61 (d, 1H), 3.99–3.91 (m, 4H), 2.42 (s, 3H), 1.84–1.74 (m, 4H), 1.49–1.33 (m, 8H), 0.94–0.91 (m, 6H). MS (ESI, negative ion mode) m / z 307.2 [MH]⁻.

[1023] Example 41: Preparation of 5-hexanoyl-2-methylbenzoic acid:

[1024]

[1025] BuLi (2.5 M in hexane, 0.84 ml, 2.10 mmol) was added to a solution of 5-bromo-2-methylbenzoic acid (215 mg, 1.00 mmol) in dry THF (10 ml) at -78 °C. After 5 minutes, hexanoyl chloride (0.35 ml, 2.45 mmol) in dry THF (2 ml) was added, and the resulting mixture was stirred at -78 °C for 45 minutes. The reaction mixture was poured into 1 M HCl and extracted with EtOAc (x2). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by rapid chromatography (heptane:EtOAc, 0-50%EtOAc) to give 37 mg (16% yield) of the title compound as a solid. MS (ESI, negative ion mode) m / z 233.1 [MH]-.

[1026] Biological Examples

[1027] Evaluation of APOE of compounds B and A on a high-fat diet Effects on blood lipids in 3 Leiden mice.

[1028] In addition to human apolipoprotein C1 (APOC1), APOE 3. Leiden mice also express a variant of human apolipoprotein E3 (APOE3), namely APOE. 3Leiden. APOE 3Leiden mice exhibited elevated plasma cholesterol and triglyceride levels, primarily limited to the VLDL / LDL-sized lipoprotein fraction.

[1029] The study was conducted on an APOE diet with a strong semi-synthetic high-fat diet (24% fat w / w) and 0.25% cholesterol w / w. The study was conducted in 3 Leiden mice (13-15 weeks old). After a 4-week adjustment period, the mice were divided into groups of 5 and administered compound A, compound B, or a mediator individually. Compound B and compound A were administered via diet at a dose of 0.3 mmol / kg body weight / day. Sunflower oil (10 ml v / w) was used as a mediator to facilitate mixing. After 4 weeks of treatment, the mice were sacrificed by CO2 asphyxiation, and plasma cholesterol and triglycerides were measured using commercially available kits (Roche® / Hitachi®).

[1030] In a further study as described above, the effects of compounds A, B, and C on triglyceride levels were compared with those of reference compounds 1 ((Z)-3-(pent-2-en-1-yloxy)benzoic acid) and 2 ((Z)-4-(pent-2-en-1-yloxy)benzoic acid). All compounds were administered at a dose of 0.3 mmol / kg body weight / day. The results of this study are described in Example 17.

[1031]

[1032] Evaluation of the effects of compounds B and A on glycemic control and liver target gene expression in ob / ob A MLN mice.

[1033] When a high-calorie diet (i.e., the A MLN diet) was supplemented with cholesterol (2%), 40% fat (containing 18% trans fatty acids), and 20% fructose, ob / ob mice consistently showed a tendency towards fibrosis (liver). Compared to wild-type C57BL / 6 mice (AMLN mice) fed the same diet, ob / ob mice on the A MLN diet (referred to as “ob / ob A MLN mice”) developed fatty liver inflammation and fibrosis over a shorter timeframe (≤12 weeks). The ob / ob A MLN mouse model provides an obese diet-induced model of NASH, which can also be used to study the effects on glycemic control.

[1034] Thirty male ob / ob mice (5 weeks old) were fed an A MLN diet for 15 weeks, then randomly assigned to three groups of 10 mice each to receive either compound B or compound A (both 0.3 mmol / kg body weight per day) or no treatment (the mediator) for an additional 4 weeks. Hepatic expression of key genes regulating plasma lipid concentration (LDLr), liver fibrosis (col1A1), bile acid transport / reuptake (Slc51b and Slc10a2), and inflammation (CD68) was assessed by RNA sequencing at week 4. An oral glucose tolerance test (OGTT) was also performed at week 3 to assess the effects of compounds B and A on glycemic control. Another group of mice (n=5) was also treated with a PPAR-γ agonist (pioglitazone, 30 mg / kg body weight per day) to compare the effect on body weight.

[1035] Evaluation of the effects of compounds A and B on hepatic steatosis in C57BL / 6 mice fed with oral parenteral nutrition (PN) diet.

[1036] Male C57BL / 6 mice aged 6 to 8 weeks were used in all experimental groups at the start of the experiment. Mice were randomly fed a standard rodent diet (caloric composition: 26% protein, 14% fat, 60% carbohydrates) and water, or a parenteral nutrition (PN) solution simulating the PN diet used in neonatal intensive care units. The PN solution was a fat-free, high-carbohydrate liquid diet (20% glucose, 2% essential and non-essential amino acids, 0.2% pediatric trace elements, 0.5% pediatric multivitamins, 30 mEq sodium, 20 mEq potassium, 15 mEq calcium (as calcium gluconate), 10 mEq magnesium, 10 mEq phosphate, 5 mEq acetate, and 30 mEq chloride per liter), administered in a single 50 ml bottle per cage, which mice could drink freely. Random PN diet feeding has been shown to induce hepatic steatosis (a precursor to more severe liver damage) in mice, providing a model for PNALD. Prince et al., JPEN J Parenter Enteral Nutr., 2014; 38(5): 608-616.

[1037] In the initial experiment, only compound A was tested. The results of this experiment are described in Example 14.

[1038] At the start of the experiment, 6-week-old male C57BL / 6 mice were divided into three groups (n=10 per group). One group was randomly fed standard rodent diet and water. This group, fed standard rodent diet, received no further treatment during the experiment and served as a negative control. The other two groups were fed the aforementioned PN diet.

[1039] In the two groups receiving the PN diet, one group received medium-chain triglyceride oil (MCT) via gavage at a dose of 7.4 g fat / kg body weight every other day (Nestle™ HealthCare Nutrition, Florham Park, NJ). In the other group, MCT was used as a medium for delivering compound A (0.3 mmol / kg body weight per day) via gavage.

[1040] Nineteen days after treatment, the liver was obtained, fixed, frozen on dry ice, and then stored at -80 °C for Oil Red O analysis.

[1041] In subsequent experiments, both compound A and compound B were tested at two different dosages. The results of these experiments are described in Example 15.

[1042] Male C57BL / 6 mice aged 6 to 8 weeks were used in all experimental groups at the start of the experiment. One group was randomly fed standard rodent diet and water. This group fed standard rodent diet did not receive any additional treatment during the experiment and served as a negative control group. The other seven groups (ten mice per group) were randomly fed the aforementioned PN solution.

[1043] In the seven groups receiving the PN diet, each group received one of the following oral regimens every other day for 19 days:

[1044] (1) Physiological saline: with Omegaven ® The groups were given equal volumes of physiological saline solution;

[1045] (2) MCT: Medium chain triglyceride oil (MCT) (Nestle™ HealthCare Nutrition, FlorhamPark, NJ), dosage is 7.4 g fat / kg body weight;

[1046] (3) Omegaven ® Omegaven ® (Commercial fish oil lipid emulsion), dosage is 2.4 g fat / kg body weight;

[1047] (4) Compound A LOW: Compound A, at a dose of 0.3 mmol / kg body weight per day (diluted to 0.0375 mmol / ml in MCT, resulting in administration of 7.4 g MCT / kg body weight);

[1048] (5) Compound A HI: Compound A, at a dose of 0.6 mmol / kg body weight per day (diluted to 0.075 mmol / ml in MCT, resulting in administration at 7.4 g MCT / kg body weight);

[1049] (6) Compound B LOW: Compound B, at a dose of 0.3 mmol / kg body weight per day (diluted to 0.0375 mmol / ml in MCT, resulting in an administration of 7.4 g MCT / kg body weight); and

[1050] (7) Compound B HI: Compound B, at a dose of 0.6 mmol / kg body weight per day (diluted to 0.075 mmol / ml in MCT, resulting in administration at 7.4 g MCT / kg body weight).

[1051] Nineteen days after treatment, organs, including the liver, kidneys, and spleen, were collected, and their relative weights were analyzed between groups. The livers were also fixed and frozen on dry ice, then stored at -80 °C for hematoxylin and eosin (H&E) staining analysis and Oil Red O analysis.

[1052] Evaluation of compound A in intravenous administration of normal saline and intralipid ® or Omegaven ® Effects of C57BL / 6 mice on hepatic steatosis

[1053] Male C57BL / 6 mice aged 6 to 8 weeks were used in all experiments at the start of the experiment. One group was randomly fed standard rodent food and water. The other six groups (10 mice per group) were randomly fed the above-mentioned parenteral nutrition (PN) solution.

[1054] The PN-fed group received intravenous injections of saline solution at a dose of 2.4 g / kg / day every other day. ® Or Intralipid at a dose of 2.4 g / kg / day ® (Commercial soybean oil lipid emulsion) was administered via gavage (every other day) of 0.6 mmol / kg body weight of MCT or compound A. Intravenous saline was administered in equal volumes to the Intralipid group. MCT was administered via gavage in equal volumes to compound A (200 μl). The following are six experimental PN diet groups:

[1055] (1) Normal saline (intravenous) + PN + MCT (gastric)

[1056] (2) Intralipid ® (Intravenous) + PN + MCT (gastric)

[1057] (3) Omegaven ® (Intravenous) + PN + MCT (gastric)

[1058] (4) Normal saline (intravenous) + PN + compound A (gastric)

[1059] (5) Intralipid ® (Intravenous) + PN + Compound A (Gavage)

[1060] (6) Omegaven ® (Intravenous) + PN + Compound A (Gavage)

[1061] The PN diet utilizes intravenous lipids as a source of non-protein, non-carbohydrate calories. However, plant-based intravenous lipid emulsions, such as soy-based Interlipid, have been shown to be effective. ®It can lead to parenteral nutrition-associated liver disease (PNALD). Javid et al., J. Pediatr. Surg., 2005; 40:1446-1453. Intravenous injection of Omegaven ® It has been shown to alleviate hepatic steatosis induced by the PN diet in mice. Meisel et al., J. Pediatr. Surg., 2011;46:666–667.

[1062] Example 1.

[1063] Effects of compounds B and A (both 0.3 mmol / kg body weight per day) on postprandial blood glucose (AUC 0-240 min) in ob / ob A MLN mice: After 3 weeks of treatment, in response to oral glucose loading, both compounds B and A significantly reduced total plasma glucose (AUC 0-240 min) compared to the mediator. Figure 1 ).

[1064] Example 2.

[1065] Effects of treatment with compounds B and A (both 0.3 mmol / body weight per day) for 4 weeks on postprandial blood glucose in ob / ob A MLN mice: After 3 weeks of treatment, in response to oral glucose loading, both compounds B and A significantly reduced plasma glucose at 30 and 60 minutes compared to the medium. Figure 2 ).

[1066] Example 3.

[1067] Effects of treatment with compounds B and A (both 0.3 mmol / day) for 4 weeks on fasting insulin in ob / ob A MLN mice: After 4 weeks of treatment, both compounds B and A (p < 0.05) reduced fasting plasma insulin (area under the curve from 0 to 240 minutes) compared to the mediator. Figure 3 ).

[1068] Example 4.

[1069] Effects of treatment with compounds B and A (both 0.3 mmol / day) for 4 weeks on fasting blood glucose in ob / ob A MLN mice: After 4 weeks of treatment, both compounds B and A significantly reduced fasting blood glucose (area under the curve from 0 to 240 minutes) compared to the mediator. Figure 4 ).

[1070] Example 5.

[1071] Effects of treatment with compounds B and A (both 0.3 mmol / kg body weight per day) for 4 weeks on hepatic collagen 1a1 gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compared with the mediator, both compounds B and A significantly reduced hepatic expression of Col1a1 (a key gene involved in liver fibrosis). Figure 5 ).

[1072] Example 6.

[1073] Effects of treatment with compounds B and A (both 0.3 mmol / day) for 4 weeks on liver Slc10a2 gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compound A significantly reduced liver expression of Slc10a2 (encoding the apical sodium-dependent bile acid transporter [ASBT] that regulates the reabsorption of bile acids bound in the ileum) compared to the mediator. Figure 6 )

[1074] Example 7.

[1075] Effects of treatment with compounds B and A (both 0.3 mmol / day) for 4 weeks on liver Slc51b gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compound A significantly reduced liver expression of Slc51b (encoding organic solute transporter β [OSTb], which regulates bile acid reabsorption) compared to the mediator. Figure 7 ).

[1076] Example 8.

[1077] Effects of treatment with compounds B and A (both 0.3 mmol / day) for 4 weeks on hepatic ABCC2 gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compound A significantly increased hepatic expression of ABCC2 (encoding Mrp2, which regulates bilirubin tubule effluent) compared to the mediator. Figure 8 ).

[1078] Example 9.

[1079] Effects of treatment with compounds B and A (both 0.3 mmol / body weight per day) for 4 weeks on hepatic CYP7A1 gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compound A reduced hepatic CYP7A1 expression. CYP7A1 is the rate-limiting enzyme in hepatic bile acid synthesis (…). Figure 9 ).

[1080] Example 10.

[1081] Effects of treatment with compounds B and A (both 0.3 mmol / kg body weight per day) for 4 weeks on hepatic CD68 gene expression in ob / ob A MLN mice: After 4 weeks of treatment, compound A significantly reduced hepatic CD68 (a marker of hepatic macrophages) expression compared to the mediator. Figure 10 ).

[1082] Example 11.

[1083] APOE patients were treated with compounds B and A for 4 weeks on a high-fat, high-cholesterol diet. Effects on plasma triglycerides (TG) and total cholesterol in 3 Leiden mice: After 4 weeks of treatment, both compound B (2 doses) and compound A significantly reduced total plasma cholesterol and TG relative to the response of the mediator (Table 1).

[1084] Table 1

[1085]

[1086] P<0.01 compared to the control, P<0.005 compared to the control

[1087] Example 12.

[1088] Effects of treatment with compounds B, A, and pioglitazone for 4 weeks on relative body weight in ob / ob A MLN mice: After 4 weeks of treatment, pioglitazone (30 mg / kg body weight per day) significantly increased body weight, while compound B had no effect compared to the mediator, and compound A significantly decreased body weight. Figure 11 ).

[1089] Example 13.

[1090] Effects of treatment with compounds B and A for 4 weeks on hepatic low-density lipoprotein receptor (LDLr) gene expression in ob / ob A MLN mice: After 4 weeks of treatment, both compounds B and A significantly increased hepatic LDLr expression (a key gene regulating hepatic uptake of plasma atherosclerotic lipoproteins) compared to the mediator. Figure 12 ).

[1091] Example 14.

[1092] Effects of a 19-day oral PN diet combined with medium-chain triglycerides (MCT) or compound A on hepatic steatosis in C57BL / 6 mice: Compound A, rather than MCT, was confirmed by Oil Red O staining in isolated liver sections to prevent the development of oral PN-induced steatosis. Figure 13 Normal liver structure was observed in both mice fed with feed and mice fed with compound A.

[1093] Example 15.

[1094] A 19-day oral PN diet with saline, medium-chain triglycerides (MCT), and omegaven ® Effects of compound A or compound B administered by gavage on hepatic steatosis in C57BL / 6 mice: H&E staining of isolated liver sections confirmed that compounds A and B, but not MCT, prevented the development of oral PN diet-induced steatosis. Figure 14-17 Normal liver structure was observed in all mice. Arrows are used to indicate lipid accumulation.

[1095] Weight, liver / body weight, and spleen / body weight were also analyzed for all groups. Figure 18 The results showed that the body weight, liver / body weight, and spleen / body weight of mice treated with high and low doses of compounds A and B were not significantly different from those of mice fed with feed or PN-fed saline.

[1096] Example 16.

[1097] Compared to oral PN diet and intravenous saline, intravenous infusion of feed is a more effective treatment. ® or Omegaven ® Effects of MCT or Compound A administered by gavage on hepatic steatosis in C57BL / 6 mice: As confirmed by H&E staining in isolated liver sections, treatment with Compound A prevented steatosis in all groups (intravenous saline, intralipid) ® or Omegaven ® The development of fatty degeneration induced by oral PN diet ( Figure 22-25 The arrows are used to indicate lipid accumulation.

[1098] Oil Red O staining of isolated liver sections also indicated that treatment with compound A prevented all groups (intravenous saline, Intralipid) from responding to treatment. ® or Omegaven ® The development of fatty degeneration ( Figure 26-29 The arrows indicate lipid accumulation. Quantitative analysis of lipid accumulation confirmed that compound A prevented the development of fatty degeneration compared to the feed-fed control. Figure 30 ).

[1099] Weight was analyzed over 19 days. Figure 19-21Standardized body, liver, kidney, and spleen mass values ​​were also analyzed, showing that these values ​​in mice treated with compound A were not significantly different from any other experimental group. Figure 20-21 ).

[1100] Example 17.

[1101] Compound A showed effects on APOE within 4 weeks of treatment. Effects of compound A on triglyceride levels in Leiden mice: Compound A significantly reduced triglyceride levels over 4 weeks. Figure 31 Reference compounds 1 and 2 do indeed affect triglyceride levels.

[1102] This application also relates to the following implementation schemes:

[1103] 1. Compounds of formula (I):

[1104] (I),

[1105] in

[1106] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[1107] R2, R3, and R4 may be the same or different, and are independently selected from hydrogen atoms or halogen atoms; and

[1108] R5 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, heteroalkyl with 4-12 atoms, of which 1-4 atoms are heteroatoms, C4-C12 alkenyl with 1-3 double bonds, heteroalkenyl with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, C4-C12 haloalkenyl with 1-3 double bonds, C4-C12 alkynyl with 1-3 triple bonds, C(O)R10 group, OR10 group, S(O)nR10 group or NR9R10 group;

[1109] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[1110] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[1111] R9 is a hydrogen atom or a C1-C11 alkyl group;

[1112] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[1113] R11 is a C1-C4 alkyl group;

[1114] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[1115] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[1116] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[1117] ·m is 3 or 4; and

[1118] n is 0, 1, or 2;

[1119] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[1120] 2. The compound according to embodiment 1, wherein

[1121] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, or an OR11 group; and

[1122] R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl with 4-9 atoms, of which 1-3 atoms are heteroatoms, C4-C9 alkenyl with 1-2 double bonds, heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms, C4-C9 haloalkenyl with 1-2 double bonds, C4-C9 ynyl with 1-2 triple bonds, C(O)R14 group, OR14 group, S(O)nR14 group or NR9R14 group;

[1123] in

[1124] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

[1125] 3. The compound according to embodiment 1 or 2, wherein R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl or -O-(C1-C4)alkyl.

[1126] 4. The compound according to any one of embodiments 1 to 3, wherein R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl.

[1127] 5. A compound according to any one of embodiments 1 to 4, wherein R5 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, having 5-8 atoms, wherein... -O-heteroalkenyl with one heteroatom and one double bond, -O-(C3-C8)haloalkenyl with one to two double bonds, -O-(C3-C8)ynyl with one to two triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, -S-(C3-C8)alkyl with 4 to 8 atoms, of which 1 to 2 are heteroatoms, -S-(C3-C8)alkenyl with one to two double bonds, -S-heteroalkenyl with 5 to 8 atoms, of which one is a heteroatom and has one double bond, -S-(C3-C8)haloalkenyl with one to two double bonds, or -S-(C3-C8)ynyl with one to two triple bonds.

[1128] 6. The compound according to any one of embodiments 1 to 5, wherein R5 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is an O-type -O-heteroalkyl or an -O-(C5-C8) alkenyl having one double bond. In some embodiments, the double bond is at the ω-3 position. In some embodiments, the double bond is Z-configured.

[1129] 7. The compound according to any one of embodiments 1 to 6, wherein R2, R3 and R4 are each hydrogen atoms.

[1130] 8. The compound according to embodiment 1, wherein

[1131] R1 is a C1-C2 alkyl, C1-C2 hydroxyalkyl, or -O-(C1-C2)alkyl;

[1132] R2, R3, and R4 are each hydrogen atoms; and

[1133] R5 is a C4-C9 alkyl group with 4-9 atoms, of which 1-3 atoms are heteroatomic heteroalkyl groups; a C4-C9 alkenyl group with 1-2 double bonds; a C4-C9 alkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatomic heteroalkenyl groups; an -O-(C3-C8) alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group with 4-8 atoms, of which 1-2 are heteroatomic -O-heteroalkyl groups; or a C4-C9 alkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms ... -O-(C3-C8)alkenyl, having 5-8 atoms, one of which is a heteroatom and having one double bond; -O-(C3-C8)haloalkenyl, having 1-2 double bonds; -S-(C3-C8)alkyl, having 4-8 atoms, one-2 of which are heteroatoms; -S-(C3-C8)alkenyl, having 1-2 double bonds; or -S-alkenyl, having 5-8 atoms, one of which is a heteroatom and having one double bond.

[1134] 9. The compound according to embodiment 1, wherein

[1135] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[1136] R2, R3, and R4 are each hydrogen atoms; and

[1137] R5 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl with one double bond, an -O-(C4-C6)alkyl, an -O-(C4-C6)hydroxyalkyl, an -O-(C4-C6) haloalkyl, having 4-6 atoms, one of which is a heteroatom, and said heteroatom is an O-O-heteroalkyl, or an -O-(C5-C8) alkenyl with one double bond.

[1138] 10. Compounds of formula (I):

[1139] (I),

[1140] in

[1141] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[1142] R2 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group;

[1143] R3 and R4 may be the same or different, and can be selected from hydrogen atoms or halogen atoms.

[1144] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group;

[1145] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R2 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[1146] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[1147] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[1148] R9 is a hydrogen atom or a C1-C11 alkyl group;

[1149] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[1150] R11 is a C1-C4 alkyl group;

[1151] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[1152] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[1153] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[1154] ·m is 3 or 4; and

[1155] n is 0, 1, or 2;

[1156] Or a pharmaceutically acceptable salt, solvate, solvate of the salt, or a prodrug thereof, provided that the compound of formula (I) is not 2-methyl-3-(pentoxy)benzoic acid.

[1157] 11. The compound according to embodiment 10, wherein

[1158] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or a heteroalkyl having 3-4 atoms, one of which is a heteroatom;

[1159] R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[1160] R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms, one of which is a heteroatom;

[1161] in

[1162] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

[1163] 12. The compound according to embodiment 10 or 11, wherein R1 is a C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl or phenyl.

[1164] 13. The compound according to embodiment 10 or 11, wherein R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl atom, or phenyl.

[1165] 14. The compound according to embodiment 10 or 11, wherein R1 is a C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl or phenyl.

[1166] 15. The compound according to embodiment 10 or 11, wherein R1 is methyl or ethyl.

[1167] 16. The compound according to embodiment 10 or 11, wherein R1 is methyl.

[1168] 17. A compound according to any one of embodiments 10, 11, or 12 to 16, wherein R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, a heteroalkyl having 4-9 atoms, wherein 1-3 atoms are heteroatoms, a C4-C9 alkenyl having 1-2 double bonds, a heteroalkenyl having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatoms, a C4-C9 alkynyl having 1-2 triple bonds, an -O-(C3-C8)alkyl, an -O-(C3-C8)hydroxyalkyl, an -O-(C3-C8) haloalkyl, an -O-(C3-C8) alkenyl having 1-2 double bonds, an -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, or an -O-heteroalkyl having 5-8 atoms, wherein one is a heteroatom and has one double bond. Alkenyl, -O-(C3-C8) haloalkenyl with 1-2 double bonds, -O-(C3-C8) ynyl with 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl with 1-2 double bonds, It has 5-8 atoms, one of which is a heteroatom and has a double bond, such as -S-heterenyl, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl, -S(O)2-(C3-C8)alkyl, amino group with hydrogen atom and C3-C8 alkyl, amino group with hydrogen atom and (C1-C6) ketone group, or amino group with C1-C9 alkyl and C3-C8 alkyl.

[1169] 18. A compound according to any one of embodiments 10, 11, or 12 to 16, wherein R2 is a C4-C9 alkyl group having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl groups, a C4-C9 alkenyl group having 1-2 double bonds, a C4-C9 alkenyl group having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl groups, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl group having 4-8 atoms, wherein 1-2 are heteroatomic heteroalkyl groups. -O-heteroalkyl, -O-(C4-C8)alkenyl with 1-2 double bonds, -O-heteroalkenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond, -O-(C4-C8)haloalkenyl with 1-2 double bonds, -S-(C3-C8)alkyl, -S-heteroalkyl with 4-8 atoms, one-2 of which are heteroatoms, -S-(C4-C8)alkenyl with 1-2 double bonds, or -S-heteroalkenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond.

[1170] 19. The compound according to any one of embodiments 10, 11, or 12 to 16, wherein R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl, or an -O-(C5-C8) alkenyl having one double bond at the ω-3 position.

[1171] 20. The compound according to any one of embodiments 10 to 19, wherein R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or a heteroalkyl having 3-4 atoms, wherein one atom is a heteroatom.

[1172] 21. The compound according to any one of embodiments 10 to 19, wherein R3, R4 and R5 are each hydrogen atoms.

[1173] 22. The compound according to embodiment 10, wherein

[1174] R1 is methyl or ethyl;

[1175] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[1176] • R3, R4, and R5 are each hydrogen atoms;

[1177] n is 0 or 1;

[1178] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and methyl groups; and

[1179] X is selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as acetate group.

[1180] 23. The compound according to embodiment 10, wherein

[1181] R1 is a methyl group;

[1182] R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl group, or an -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[1183] • R3, R4, and R5 are each hydrogen atoms;

[1184] ·n is 0; and

[1185] X is a carboxylic acid.

[1186] 24. The compound according to embodiment 10, wherein the compound is

[1187] ·

[1188] ·(Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid.

[1189] 25. Compounds of formula (I):

[1190] (I),

[1191] in

[1192] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group;

[1193] R2 and R4 may be the same or different, and are independently selected from hydrogen atoms and halogen atoms.

[1194] R3 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, heteroalkyl with 4-12 atoms, of which 1-4 atoms are heteroatoms, C4-C12 alkenyl with 1-3 double bonds, heteroalkenyl with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, C4-C12 haloalkenyl with 1-3 double bonds, C4-C12 alkynyl with 1-3 triple bonds, C(O)R10 group, OR10 group, S(O)nR10 group or NR9R10 group;

[1195] R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group;

[1196] • The condition is that if R1 is a haloalkyl, C1-C4 alkyl, SR11 group or NR12R13 group and R5 is a hydrogen atom or OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[1197] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[1198] R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[1199] ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds;

[1200] R9 is a hydrogen atom or a C1-C11 alkyl group;

[1201] R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds;

[1202] R11 is a C1-C4 alkyl group;

[1203] • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups;

[1204] X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylic acid ester, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof;

[1205] • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group;

[1206] ·m is 3 or 4; and

[1207] n is 0, 1, or 2;

[1208] Or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof.

[1209] 26. The compound according to embodiment 25, wherein

[1210] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroatom, or an OR11 group;

[1211] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and

[1212] • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, having 3-4 atoms, one of which is a heteroatom, or an OR11 group;

[1213] The condition is that if R1 is a haloalkyl or C1-C4 alkyl and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl, or C4-C6 alkyl-Y- group; and

[1214] • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl or an OR11 group, then R3 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group.

[1215] in

[1216] R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, heteroalkyl with 4-8 atoms, of which 1-2 atoms are heteroatoms, C3-C8 alkenyl with 1-2 double bonds, heteroalkenyl with 1 double bond and 4-8 atoms, of which 1 atom is a heteroatom, C3-C8 haloalkenyl with 1-2 double bonds, or C3-C8 alkynyl with 1-2 triple bonds.

[1217] 27. The compound according to embodiment 25, wherein

[1218] R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl atom;

[1219] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a heteroalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; or a group with 5-8 atoms, of which 1 is a heteroatom. The following are considered compounds with the following characteristics: -O-heterenyl group having one double bond; -O-(C3-C8)haloalkenyl group having one or two double bonds; -O-(C3-C8)ynyl group having one or two triple bonds; -S-(C3-C8)alkyl group; -S-(C3-C8)hydroxyalkyl group; -S-(C3-C8)haloalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; -S-(C3-C8)alkenyl group having one or two double bonds; -S-heterenyl group having 5-8 atoms, of which one is a heteroatom and has one double bond; -S-(C3-C8)haloalkenyl group having one or two double bonds; or -S-(C3-C8)ynyl group having one or two triple bonds; and

[1220] R5 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, or C1-C4 haloalkyl group having 3-4 atoms, one of which is a heteroatom.

[1221] 28. The compound according to embodiment 25, wherein

[1222] R1 is a heteroalkyl group having 3-4 atoms, one of which is a heteroatom;

[1223] R3 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, or C4-C9 haloalkyl group, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl group with 1-2 double bonds; a heteroalkenyl group with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 alkynyl group with 1-2 triple bonds; an -O-(C3-C8)alkyl group; an -O-(C3-C8) hydroxyalkyl group; an -O-(C3-C8) haloalkyl group, having 4-8 atoms, of which 1-2 are heteroatoms; an -O-(C3-C8) alkenyl group with 1-2 double bonds; or a group with 5-8 atoms, of which 1 is a heteroatom. The following are considered compounds with the following characteristics: -O-heterenyl group having one double bond; -O-(C3-C8)haloalkenyl group having one or two double bonds; -O-(C3-C8)ynyl group having one or two triple bonds; -S-(C3-C8)alkyl group; -S-(C3-C8)hydroxyalkyl group; -S-(C3-C8)haloalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; -S-(C3-C8)alkenyl group having one or two double bonds; -S-heterenyl group having 5-8 atoms, of which one is a heteroatom and has one double bond; -S-(C3-C8)haloalkenyl group having one or two double bonds; or -S-(C3-C8)ynyl group having one or two triple bonds; and

[1224] R5 is a hydrogen atom or an -O-(C1-C4) alkyl group.

[1225] 29. The compound according to embodiment 25

[1226] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[1227] R3 is a heteroalkyl group having 4-9 atoms, of which 1-3 atoms are heteroatoms; a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms; a -O-(C4-C8)alkenyl group having 1 double bond at the ω-3 position; and a -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and 1 double bond at the ω-3 position.

[1228] R5 is a hydrogen atom, a C1-C2 alkyl group, or an -O-(C1-C4) alkyl group.

[1229] 30. The compound according to any one of embodiments 25 to 29, wherein R2 and R4 are each hydrogen atoms.

[1230] 31. The compound according to embodiment 25, wherein

[1231] R1 is a C1-C2 alkyl or -O-(C1-C2) alkyl;

[1232] R3 is an -O-(C4-C8) alkenyl group having one double bond at the ω-3 position;

[1233] Both R2 and R4 are hydrogen atoms;

[1234] R5 is a hydrogen atom, a C1-C2 alkyl group, or an -O-(C1-C4) alkyl group;

[1235] ·n is 0; and

[1236] X is a carboxylic acid.

[1237] 32. Compounds of formula (I):

[1238] (I),

[1239] in

[1240] R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 ...

Claims

1. Compounds of formula (I): (I), in R1 is a C1-C12 alkyl, C1-C12 hydroxyalkyl, C1-C12 haloalkyl, a heteroalkyl group having 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group having 1-3 double bonds, a C3-C12 alkynyl group having 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl or benzyl group; R2 is a C4-C12 alkyl, C4-C12 hydroxyalkyl, C4-C12 haloalkyl, a heteroalkyl group having 4-12 atoms, of which 1-4 atoms are heteroatoms, a C4-C12 alkenyl group having 1-3 double bonds, a heteroalkenyl group having 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C4-C12 haloalkenyl group having 1-3 double bonds, a C4-C12 alkynyl group having 1-3 triple bonds, a C(O)R10 group, an OR10 group, a S(O)nR10 group, or an NR9R10 group; R3 and R4 may be the same or different, and can be selected from hydrogen atoms or halogen atoms. R5 can be a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group with 3-12 atoms, of which 1-4 atoms are heteroatoms, a C3-C12 alkenyl group with 1-3 double bonds, a heteroalkenyl group with 1-3 double bonds and 5-12 atoms, of which 1-3 atoms are heteroatoms, a C3-C12 haloalkenyl group with 1-3 double bonds, a C3-C12 alkynyl group with 1-3 triple bonds, a C(O)R8 group, an OR8 group, an S(O)nR8 group or an NR8R9 group, a phenyl group or a benzyl group; • The condition is that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl, a C1-C4 alkyl, an OR11 group, an SR11 group or an NR12R13 group, then R2 is not a C4-C6 alkyl, C4-C6 alkenyl, C4-C6 alkynyl or C4-C6 alkyl-Y- group. R6 and R7 may be the same or different, and are independently selected from hydrogen atoms and C1-C6 alkyl groups, wherein R6 and R7 together can form cycloalkyl groups, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane; ·R8 is a C1-C11 alkyl, C2-C11 hydroxyalkyl, C2-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl with 1-3 double bonds, having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a haloalkenyl with 1-3 double bonds, or a C3-C11 alkynyl with 1-3 triple bonds; R9 is a hydrogen atom or a C1-C11 alkyl group; R10 is a C3-C11 alkyl, C3-C11 hydroxyalkyl, C3-C11 haloalkyl, having 4-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 alkenyl having 1-3 double bonds, a heteroalkenyl having 1-3 double bonds and 5-11 atoms, of which 1-3 atoms are heteroatoms, a C3-C11 haloalkenyl having 1-3 double bonds, or a C3-C11 alkynyl having 1-3 triple bonds; R11 is a C1-C4 alkyl group; • R12 and R13 are independently selected from hydrogen atoms and C1-C4 alkyl groups; X is hydroxymethyl or carboxylic acid or a derivative thereof, wherein the derivative is a carboxylation, such as a carboxylic acid ester, glycerol ester, acid anhydride, carboxamide or phospholipid, or a prodrug thereof; • Y represents an oxygen atom, a sulfur atom, or an NR12R13 group; ·m is 3 or 4; and n is 0, 1, or 2; Or a pharmaceutically acceptable salt, solvate, solvate of the salt, or a prodrug thereof, provided that the compound of formula (I) is not 2-methyl-3-(pentoxy)benzoic acid.

2. The compound according to claim 1, wherein... R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or a heteroalkyl having 3-4 atoms, one of which is a heteroatom; R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, of which 1-3 atoms are heteroatoms; a C4-C9 alkenyl with 1-2 double bonds; a heteroalkenyl with 1-2 double bonds and 5-9 atoms, of which 1-2 atoms are heteroatoms; a C4-C9 haloalkenyl with 1-2 double bonds; a C4-C9 alkynyl with 1-2 triple bonds; a C(O)R14 group; an OR14 group; an S(O)nR14 group; or an NR9R14 group; and R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms, one of which is a heteroatom; in R14 is a C3-C8 alkyl, C3-C8 hydroxyalkyl, C3-C8 haloalkyl, having 4-8 atoms, of which 1-2 atoms are heteroatoms, a C3-C8 alkenyl with 1-2 double bonds, a heteroalkenyl with 1 double bond and 5-8 atoms, of which 1 atom is a heteroatom, a C3-C8 haloalkenyl with 1-2 double bonds, or a C3-C8 alkynyl with 1-2 triple bonds.

3. The compound according to claim 1 or 2, wherein R1 is a C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl, or phenyl.

4. The compound according to claim 1 or 2, wherein R1 is a C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, having 3-4 atoms, one of which is a heteroalkyl atom, or phenyl.

5. The compound according to claim 1 or 2, wherein R1 is a C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl, or phenyl.

6. The compound according to claim 1 or 2, wherein R1 is methyl or ethyl.

7. The compound according to claim 1 or 2, wherein R1 is methyl.

8. The compound according to any one of claims 1, 2, or 3 to 7, wherein R2 is a C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl, a C4-C9 alkenyl having 1-2 double bonds, having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl, a C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-(C3-C8) alkenyl having 1-2 double bonds, having 4-8 atoms, wherein 1-2 are heteroatomic -O-heteroalkyl, having 5-8 atoms, wherein one is heteroatomic and has 1 double bond -O-heteroalkenyl, -O-(C3-C8) haloalkenyl groups with 1-2 double bonds, -O-(C3-C8) ynyl groups with 1-2 triple bonds, -S-(C3-C8) alkyl groups, -S-(C3-C8) hydroxyalkyl groups, -S-(C3-C8) haloalkenyl groups, -S-heteroalkyl groups with 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl groups with 1-2 double bonds, and others. It has 5-8 atoms, one of which is a heteroatom and has a double bond, such as -S-heterenyl, -C(O)-(C3-C8)alkyl, -S(O)-(C3-C8)alkyl, -S(O)2-(C3-C8)alkyl, amino group with hydrogen atom and C3-C8 alkyl, amino group with hydrogen atom and (C1-C6) ketone group, or amino group with C1-C9 alkyl and C3-C8 alkyl.

9. The compound according to any one of claims 1, 2, or 3 to 7, wherein R2 is a C4-C9 alkyl group having 4-9 atoms, wherein 1-3 atoms are heteroatomic heteroalkyl groups, a C4-C9 alkenyl group having 1-2 double bonds, a C4-C9 alkenyl group having 1-2 double bonds and 5-9 atoms, wherein 1-2 atoms are heteroatomic heteroalkenyl groups, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl group having 4-8 atoms, wherein 1-2 are heteroatomic. -O-heteroalkyl, -O-(C4-C8)alkenyl with 1-2 double bonds, -O-heteroalkenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond, -O-(C4-C8)haloalkenyl with 1-2 double bonds, -S-(C3-C8)alkyl, -S-heteroalkyl with 4-8 atoms, one-2 of which are heteroatoms, -S-(C4-C8)alkenyl with 1-2 double bonds, or -S-heteroalkenyl with 5-8 atoms, one of which is a heteroatom and has 1 double bond.

10. The compound according to any one of claims 1, 2 or 3 to 7, wherein R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having one double bond at the ω-3 position, an -O-(C4-C6) straight-chain alkyl, or an -O-(C5-C8) alkenyl having one double bond at the ω-3 position.

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