Aromatic compounds and their medical uses

Abstract

The present disclosure relates to compounds of general formula (I): wherein R1, R2, R3, R4, R5, R6 and R7 can 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 acid ester, glyceride, anhydride, phospholipid, carboxamide, phospholipid, or a prodrug thereof; or a pharmaceutically acceptable salt, solvate, solvate of said salt, or a prodrug thereof. The present disclosure also relates to pharmaceutical compositions and lipid compositions comprising at least one compound according to the present disclosure, and to the use of such compounds as medicaments or for treatment, in particular for the treatment of diseases associated with metabolic diseases and liver diseases, such as non-alcoholic fatty liver disease and cholestatic diseases.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application 62 / 744,461, filed Oct. 11, 2018, the content of which is incorporated herein by reference. FIELD OF THE INVENTION

[0003] The present invention relates to substituted aromatic compounds, methods for their preparation, pharmaceutical compositions comprising the aromatic compounds, and their use in treating various diseases and disorders in a subject in need thereof. BACKGROUND OF THE INVENTION

[0004] The growing global prevalence of obesity and its comorbidities (e.g., type 2 diabetes and hyperlipidemia) impose a substantial burden on public health (mortality and morbidity) as well as the available public health resources required to treat these diseases.

[0005] Current drugs for treating hyperlipidemia (e.g., statins, ω-3 fatty acids, fibrates) generally have a neutral effect on glycemic control, while drugs for glycemic control (e.g., insulin, thiazolidinediones (TZD)) have an adverse effect on body weight and (for TZD) other harmful side effects, thus limiting their use.

[0006] 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 associated with the epidemics of obesity and type 2 diabetes. Non-alcoholic steatohepatitis (NASH) is a form of NAFLD associated with liver inflammation and hepatocyte ballooning, and its incidence in the United States is expected 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 in 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.

[0007] Therefore, the development of novel compounds that simultaneously target hyperlipidemia and glycemic control without the adverse side effects (e.g., weight gain) typically associated with insulin-sensitizing drugs is a desirable goal. If such compounds can additionally prevent the progression of liver fibrosis / reverse liver fibrosis and reduce hepatic steatosis, they would be even more attractive. The new therapeutic methods, compounds, and pharmaceutical compositions of the present invention meet these needs. SUMMARY OF THE INVENTION

[0008] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of these salts or prodrug thereof, pharmaceutical compositions of these compounds, methods for their preparation and the use of these compounds or pharmaceutical compositions in the treatment of various diseases and disorders.

[0009] Preferred aspects of the present invention relate to compounds of formula (I) as described by group (2). Other aspects of the present invention relate to compounds of formula (I) as described by group (1). Other aspects of the present invention relate to compounds of formula (I) as described by group (3). Other aspects of the present invention relate to compounds of formula (I) as described by group (4). Still other aspects of the present invention also relate to compounds of formula (I) as described by group (5).

[0010] Aspects of the present invention relate to pharmaceutically acceptable salts of compounds of formula (I) as described by any one of groups (1), (2), (3), (4) or (5). The salts may be selected from sodium salts, potassium salts, calcium salts and magnesium salts.

[0011] Aspects of the present invention relate to pharmaceutical compositions of compounds of formula (I) as described by any one of groups (1), (2), (3), (4) or (5). Preferred aspects of the present invention relate to pharmaceutically acceptable compositions of compounds of formula (I) as described by group (2).

[0012] Aspects of the present invention relate to the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of these salts, or prodrug thereof, or a pharmaceutical composition of these compounds for the treatment of diseases associated with metabolic diseases and liver diseases. Additionally, the present invention relates to a pharmaceutical composition of a compound of formula (I) or a salt thereof for use in:

[0013] · Treating liver inflammation;

[0014] · Increasing glucose tolerance and / or reducing postprandial glucose levels;

[0015] · Reducing fasting blood glucose levels;

[0016] · Reducing plasma insulin levels, which includes reducing fasting plasma insulin levels;

[0017] · Treating diabetes, such as type 2 diabetes;

[0018] · Reducing plasma triglycerides and / or total cholesterol;

[0019] · Treating weight gain;

[0020] · Treating metabolic syndrome;

[0021] · Treating dyslipidemic conditions, such as hypertriglyceridemia and / or hypercholesterolemia;

[0022] · Treating non-alcoholic fatty liver disease, which includes non-alcoholic steatohepatitis;

[0023] · Preventively treating liver fibrosis or reducing the development of liver fibrosis or reducing existing liver fibrosis in non-alcoholic steatohepatitis;

[0024] · Preventively treating steatosis or reducing the development of steatosis or reducing hepatic steatosis;

[0025] · Treating parenteral nutrition-associated liver disease (PNALD);

[0026] · Treating sclerosing cholangitis; and

[0027] · Treating hepatobiliary disorders.

[0028] The present invention also relates to a method for treating the above-listed disorders, which comprises 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 prodrug thereof, or a pharmaceutical composition of these compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 . Effects of Compound B and Compound A on postprandial blood glucose in ob / ob A MLN mice

[0030] Figure 2 . Effects of treating with Compound B and Compound A for 4 weeks on postprandial blood glucose in ob / ob A MLN mice

[0031] Figure 3 . Effects of treating with Compound B and Compound A for 4 weeks on fasting insulin in ob / ob A MLN mice

[0032] Figure 4 . Effects of treating with Compound B and Compound A for 4 weeks on fasting blood glucose in ob / ob A MLN mice

[0033] Figure 5 . Effects of treating with Compound B and Compound A for 4 weeks on hepatic collagen 1a1 gene expression in ob / ob A MLN mice

[0034] Figure 6 . Effects of treating with Compound B and Compound A for 4 weeks on hepatic Slc10a2 gene expression in ob / ob A MLN mice

[0035] Figure 7 . Effects of treating with Compound B and Compound A for 4 weeks on hepatic Slc51b gene expression in ob / ob A MLN mice

[0036] Figure 8. Effect of 4-week treatment with Compound B and Compound A on hepatic ABCC2 gene expression in ob / ob A MLN mice

[0037] Figure 9 . Effect of 4-week treatment with Compound B and Compound A on hepatic CYP7A1 gene expression in ob / ob A MLN mice

[0038] Figure 10 . Effect of 4-week treatment with Compound B and Compound A on hepatic CD68 gene expression in ob / ob A MLN mice

[0039] Figure 11 . Effect of 4-week treatment with Compound B, Compound A, and pioglitazone on relative body weight in ob / ob A MLN mice

[0040] Figure 12 . Effect of 4-week treatment with Compound B and Compound A on hepatic low-density lipoprotein receptor (LDLr) gene expression in ob / ob A MLN mice

[0041] Figure 13 . Effect of 19-day oral parenteral nutrition (PN) diet combined with medium-chain triglycerides (MCT) or Compound A on hepatic steatosis in C57BL / 6 mice compared to chow control

[0042] Figure 14 . Effect of 19-day oral PN diet combined with MCT, . Effect of 19-day oral PN diet combined with MCT, Compound A, or Compound B on hepatic steatosis in C57BL / 6 mice compared to chow control. Mouse hepatocytes stained with hematoxylin and eosin (H&E) at 400× magnification: (A) diet control; and (B) saline administered by orogastric gavage to PN-fed mice. Arrows indicate lipid accumulation.

[0043] Figure 15 . Effect of 19-day oral PN diet combined with MCT, . Effect of 19-day oral PN diet combined with MCT, Compound A, or Compound B on hepatic steatosis in C57BL / 6 mice compared to chow control. Mouse hepatocytes stained with hematoxylin and eosin (H&E) at 400× magnification: (A) MCT administered by orogastric gavage to PN-fed mice; and (B) . Arrows indicate lipid accumulation.

[0044] Figure 16 . Effect of 19-day oral PN diet combined with MCT, Effect of combination of Compound A or Compound B on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) were magnified 400-fold: (A) PN-fed mice treated with 0.3 mmol of Compound A by gavage; and (B) orally PN-fed mice treated with 0.6 mmol of Compound A by gavage. Arrows indicate lipid accumulation.

[0045] Figure 17 . Compared with the diet control, the 19-day oral PN diet with MCT, Effect of combination of Compound A or Compound B on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) were magnified 400-fold: (A) PN-fed mice treated with 0.3 mmol of Compound B by gavage; and (B) PN-fed mice treated with 0.6 mmol of Compound B by gavage. Arrows indicate lipid accumulation.

[0046] Figure 18 . Compared with the diet control, the 19-day oral PN diet with MCT, Effect of combination of Compound A or Compound B on: (A) body weight; (B) liver / body weight; (C) spleen / body weight in C57BL / 6 mice.

[0047] Figure 19 . Body weight of C57BL / 6 mice within 19 days: (A) diet; (B) PN diet with intravascular administration of saline and gavage administration of MCT; (C) PN diet with intravascular administration and gavage administration of MCT; (D) PN diet with intravascular administration and gavage administration of MCT; (E) PN diet with intravascular administration of saline and 0.6 mmol of Compound A by gavage; (F) PN diet with intravascular administration and 0.6 mmol of Compound A by gavage; and (G) PN diet with intravascular administration and 0.6 mmol of Compound A by gavage.

[0048] Figure 20 . Effect of combination of saline, or and MCT or Compound A administered by gavage on PN-fed C57BL / 6 mice within 19 days: (A) percentage change in body weight; (B) normalized liver mass.

[0049] Figure 21 . Effect of combination of saline, or Effect within 19 days in combination with MCT or compound A administered by gavage: (A) Standardized kidney mass; (B) Standardized spleen mass.

[0050] Figure 22 . Compared to the diet control, the effect of oral PN diet with intravenous saline, or in combination with MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) were magnified 400-fold: (A) Diet control; and (B) PN diet with intravenous saline and MCT administered by gavage.

[0051] Figure 23 . Compared to the diet control, the effect of oral PN diet with intravenous saline, or in combination with MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) were magnified 400-fold: (A) PN diet with intravenous and MCT administered by gavage; and (B) PN diet with intravenous and MCT administered by gavage.

[0052] Figure 24 . Compared to the diet control, the effect of oral PN diet with intravenous saline, or and MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) were magnified 400-fold: (A) PN diet with intravenous saline and 0.6 mmol compound A administered by gavage; and (B) PN diet with intravenous and 0.6 mmol compound A administered by gavage.

[0053] Figure 25 . Compared to the diet control, the effect of oral PN diet with intravenous saline, or and MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with hematoxylin and eosin (H&E) corresponding to PN diet with intravenous and 0.6 mmol compound A administered by gavage were magnified 400-fold.

[0054] Figure 26 . Compared to the diet control, the effect of oral PN diet with intravenous saline, or Effect of combination of MCT or compound A administered by gavage and intravenously in C57BL / 6 mice on hepatic steatosis. Mouse liver sections stained with Oil Red O were magnified 400×: (A) chow control; and (B) PN diet combined with intravenous saline and MCT administered by gavage.

[0055] Figure 27 . Compared with the chow control, effect of oral PN diet combined with intravenous saline, or and combination of MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with Oil Red O were magnified 400×: (A) PN diet combined with intravenous and MCT administered by gavage; and (B) PN diet combined with intravenous and MCT administered by gavage.

[0056] Figure 28 . Compared with the chow control, effect of oral PN diet combined with intravenous saline, or and combination of MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with Oil Red O were magnified 400×: (A) PN diet combined with intravenous saline and 0.6 mmol compound A administered by gavage; and (B) PN diet combined with intravenous and 0.6 mmol compound A administered by gavage.

[0057] Figure 29 . Compared with the chow control, effect of oral PN diet combined with intravenous saline, or Combined with MCT or compound A administered by gavage on hepatic steatosis in C57BL / 6 mice. Mouse liver sections stained with Oil Red O were magnified 400×: PN diet combined with intravenous and 0.6 mmol compound A administered by gavage.

[0058] Figure 30 . Compared with the chow control, Oil Red O histological quantitative analysis of hepatic steatosis in C57BL / 6 mice with oral PN diet combined with intravenous saline, or Combined with MCT or compound A administered by gavage.

[0059] Figure 31 . Effect of compound A, compound C and reference compounds (reference 1 and reference 2) on triglyceride levels in APOE*3Leiden mice over 4 weeks. Detailed Description of the Invention

[0061] Compounds of the Invention

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

[0063]

[0064] Group I

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

[0066] · R1 is a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, 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 group or a benzyl group;

[0067] · R2, R3 and R4 are the same or different and are independently selected from a hydrogen atom or a halogen atom; and

[0068] · R5 is a C4-C12 alkyl group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, 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, an S(O)nR10 group or an NR9R10 group;

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

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

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

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

[0073] · R11 is a C1-C4 alkyl group;

[0074] · R12 and R13 are independently selected from a hydrogen atom and a C1-C4 alkyl group;

[0075] · X is a hydroxymethyl group or a carboxylic acid or a derivative thereof, where the derivative is a carboxylate, such as a carboxylic acid ester, glyceride, anhydride, carboxamide, or phospholipid, or a prodrug thereof;

[0076] · Y is 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 the salt, or a prodrug thereof.

[0080] Group 2

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

[0082] · R1 is a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group having 3-12 atoms, where 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, where 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 group, or a benzyl group;

[0083] ·R2 is a C4-C12 alkyl group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, 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, an S(O)nR10 group or an NR9R10 group;

[0084] ·R3 and R4 are the same or different and may each independently be selected from a hydrogen atom or a halogen atom,

[0085] ·R5 is a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, 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 group or a benzyl group;

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

[0087] ·R6 and R7 are the same or different and are each independently selected from a hydrogen atom and a C1-C6 alkyl group, where R6 and R7 together may form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

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

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

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

[0091] · R11 is a C1-C4 alkyl group;

[0092] · R12 and R13 are independently selected from a hydrogen atom and a C1-C4 alkyl group;

[0093] · X is a hydroxymethyl group or a carboxylic acid or a derivative thereof, where the derivative is a carboxylate, such as a carboxylic acid ester, glyceride, anhydride, carboxamide or phospholipid, or a prodrug thereof;

[0094] · Y is 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 the salt, or a prodrug thereof.

[0098] Group 3

[0099] The present disclosure also relates to a compound of formula (I) described by group (3), wherein:

[0100] · R1 is a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group having 3-12 atoms, where 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, where 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 group or a benzyl group;

[0101] · R2 and R4 are the same or different and are independently selected from a hydrogen atom and a halogen atom,

[0102] ·R3 is a C4-C12 alkyl group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, 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, an S(O)nR10 group or an NR9R10 group;

[0103] ·R5 is a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, 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 group or a benzyl group;

[0104] ·Provided that if R1 is a haloalkyl group, a C1-C4 alkyl group, an SR11 group or an NR12R13 group and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, a C4-C6 alkynyl group or a C4-C6 alkyl-Y- group;

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

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

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

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

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

[0110] · R11 is C1-C4 alkyl;

[0111] · R12 and R13 are independently selected from a hydrogen atom and C1-C4 alkyl;

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

[0113] · Y is 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] The present disclosure also relates to a compound of formula (I) described by group (4), wherein:

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

[0120] · R2 and R3 are the same or different and are independently selected from a hydrogen atom and a halogen atom;

[0121] · R4 is a C4-C12 alkyl group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, 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, an S(O)nR10 group or an NR9R10 group;

[0122] · R5 is a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, 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 group or a benzyl group;

[0123] · Provided that if R1 is a haloalkyl group, a C1-C4 alkyl group, an OR11 group, an SR11 group or an NR12R13 group and R5 is a hydrogen atom or an OR11 group, then R4 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, a C4-C6 alkynyl group or a C4-C6 alkyl-Y-group;

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

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

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

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

[0128] · R11 is a C1-C4 alkyl group;

[0129] · R12 and R13 are independently selected from a hydrogen atom and a C1-C4 alkyl group;

[0130] · X is a hydroxymethyl group or a carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic acid ester, a glyceride, an acid anhydride, a carboxamide or a phospholipid, or a prodrug thereof;

[0131] · Y is 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 the salt, or a prodrug thereof.

[0135] Group 5

[0136] The present disclosure also relates to a compound of formula (I) described by group (5), wherein:

[0137] · R1 is a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, 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, an NR8R9 group or a phenyl group,

[0138] · R2 is a C4-C12 alkyl group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, a heteroalkyl group having 4-12 atoms, where 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, where 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, an 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 group, a C4-C12 hydroxyalkyl group, a C4-C12 haloalkyl group, a heteroalkyl group having 4-12 atoms, where 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, where 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, an S(O)nR10 group or an NR9R10 group;

[0141] · R5 is a hydrogen atom, a halogen atom, a C1-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl group, a heteroalkyl group having 3-12 atoms, where 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, where 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, an NR8R9 group or a phenyl group;

[0142] · R6 and R7 are the same or different and are independently selected from a hydrogen atom and a C1-C6 alkyl group, where R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane;

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

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

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

[0146] · R11 is a C1-C4 alkyl group;

[0147] · R12 and R13 are independently selected from a hydrogen atom and a C1-C4 alkyl group;

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

[0149] · Y is 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 the salt, or prodrug thereof. In some embodiments, the aromatic compound of formula (I) is described by the following embodiments of the compounds of group (I), (II), (III), (IV) or (V).

[0153] Group 1

[0154] In some embodiments, for the compound of formula (I) described by group (1):

[0155] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, of which 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group or a benzyl group; and

[0156] · R5 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, 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 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group,

[0157] wherein

[0158] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, wherein 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, wherein 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.

[0159] Group 2

[0160] In some embodiments, for the compounds of formula (I) described by group (2):

[0161] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, wherein 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group or an NR9R11 group, a phenyl group or a benzyl group;

[0162] · R2 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, wherein 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, wherein 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group; and

[0163] · 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 having 3-4 atoms, wherein 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group or a benzyl group;

[0164] · provided that if R1 is an OR11 group and R5 is a hydrogen atom, a haloalkyl group, a C1-C4 alkyl group, an OR11 group, an SR11 group or an NR12R13 group, then R2 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, a C4-C6 alkynyl group or a C4-C6 alkyl-Y- group;

[0165] wherein

[0166] ·R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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.

[0167] Group 3

[0168] In some embodiments, for the compounds of formula (I) described by group (3):

[0169] ·R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group;

[0170] ·R3 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group, or an NR9R14 group; and

[0171] and

[0172] ·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 having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group;

[0173] ·Provided that if R1 is a haloalkyl group, a C1-C4 alkyl group, an SR11 group, or an NR12R13 group and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, a C4-C6 alkynyl group, or a C4-C6 alkyl group; and

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

[0175] where

[0176] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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.

[0177] Group 4

[0178] In some embodiments, for the compounds of formula (I) described by group (4):

[0179] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group;

[0180] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group, or an NR9R14 group; and

[0181] · 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 having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group;

[0182] · provided that if R1 is a C1-C4 haloalkyl group, a C1-C4 alkyl group, an OR11 group, an SR11 group, or an NR12R13 group and R5 is a hydrogen atom or an OR11 group, then R4 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, a C4-C6 alkynyl group, or a C4-C6 alkyl-Y- group;

[0183] where

[0184] ·R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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

[0185] Group 5

[0186] In some embodiments, for the compounds of formula (I) described by group (5):

[0187] ·R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, or a phenyl group;

[0188] ·R2 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group, or an NR9R14 group;

[0189] ·R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group, or an NR9R14 group; and

[0190] ·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 having 3-4 atoms, where 1 atom is a heteroatom, a C(O)R11 group, an OR11 group, an S(O)nR11 group, an NR9R11 group, a phenyl group, or a benzyl group;

[0191] where

[0192] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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.

[0193] In some embodiments, the aromatic compounds of general formula (I) are described by the following embodiments of the compounds of groups (I), (II), (III), (IV) or (V).

[0194] Group 1

[0195] In some embodiments, for the compounds of formula (I) described by group (1):

[0196] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom, or an OR11 group; and

[0197] · R5 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group;

[0198] where

[0199] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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.

[0200] Group 2

[0201] In some embodiments, for the compounds of formula (I) described by group (2):

[0202] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group or a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom;

[0203] · R2 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group; and

[0204] · 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, where 1 atom is a heteroatom;

[0205] where

[0206] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, where 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, where 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.

[0207] Group 3

[0208] In some embodiments, for the compounds of formula (I) described by group (3):

[0209] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 atom is a heteroatom or an OR11 group;

[0210] · R3 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group; and

[0211] · 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 having 3-4 atoms, where 1 atom is a heteroatom or an OR11 group;

[0212] · Provided that if R1 is a haloalkyl or a C1-C4 alkyl and R5 is a hydrogen atom or an OR11 group, then R3 is not a C4-C6 alkyl, a C4-C6 alkenyl, a C4-C6 alkynyl or a C4-C6 alkyl-Y- group; and

[0213] · Provided 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, a C4-C6 alkenyl, a C4-C6 alkynyl or a C4-C6 alkyl-Y- group;

[0214] wherein

[0215] · R14 is a C3-C8 alkyl, a C3-C8 hydroxyalkyl, a C3-C8 haloalkyl, a heteroalkyl having 4-8 atoms, wherein 1-2 atoms are heteroatoms, a C3-C8 alkenyl having 1-2 double bonds, a heteroalkenyl having 1 double bond and 4-8 atoms, wherein 1 atom is a heteroatom, a C3-C8 haloalkenyl having 1-2 double bonds or a C3-C8 alkynyl having 1-2 triple bonds.

[0216] Group 4

[0217] In some embodiments, for the compounds of formula (I) described by group (4):

[0218] · R1 is a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 haloalkyl, a heteroalkyl having 3-4 atoms, wherein 1 atom is a heteroatom or an OR11 group;

[0219] · R4 is a C4-C9 alkyl, a C4-C9 hydroxyalkyl, a 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 haloalkenyl having 1-2 double bonds, a C4-C9 alkynyl having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group; and

[0220] · R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl, a C1-C4 hydroxyalkyl, a C1-C4 haloalkyl, a heteroalkyl having 3-4 atoms, wherein 1 atom is a heteroatom or an OR11 group;

[0221] · Provided that if R1 is a haloalkyl, a C1-C4 alkyl or an OR11 group and R5 is a hydrogen atom or an OR11 group, then R4 is not a C4-C6 alkyl, a C4-C6 alkenyl, a C4-C6 alkynyl or a C4-C6 alkyl-Y- group;

[0222] Wherein

[0223] · R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, a heteroalkyl group having 4-8 atoms, wherein 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, wherein 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.

[0224] Group 5

[0225] In some embodiments, for the compounds of formula (I) described by group (5):

[0226] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, wherein 1 atom is a heteroatom or an OR11 group;

[0227] · R2 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, wherein 1-3 atoms are heteroatoms, a C4-C9 alkenyl group having 1-2 double bonds, a heteroalkenyl group having 5-9 atoms (wherein 1-2 atoms are heteroatoms) and 1-2 double bonds, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group;

[0228] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, wherein 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, wherein 1-2 atoms are heteroatoms, a C4-C9 haloalkenyl group having 1-2 double bonds, a C4-C9 alkynyl group having 1-2 triple bonds, a C(O)R14 group, an OR14 group, an S(O)nR14 group or an NR9R14 group; and

[0229] · 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 having 3-4 atoms, wherein 1 atom is a heteroatom or an OR11 group;

[0230] Wherein

[0231] ·R14 is a C3-C8 alkyl group, a C3-C8 hydroxyalkyl group, a C3-C8 haloalkyl group, 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.

[0232] Embodiment

[0233] The following embodiments relate to compounds of formula (I) described by any one of groups (1), (2), (3), (4) or (5).

[0234] "Alkyl" means a straight-chain, branched-chain 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.

[0235] "Alkenyl" means a straight-chain or branched-chain alkenyl group. In at least some embodiments, the alkenyl group may be selected from allyl, 2-butenyl, 3-hexenyl, 4-heptenyl, 5-octenyl and 6-nonenyl. In some embodiments, the alkenyl group has 1 double bond. In some embodiments, the alkenyl group has 2 double bonds. In some embodiments, the alkenyl group has 3 double bonds. In some embodiments, the alkenyl group has an ω-3 double bond. In some embodiments, the alkenyl group has 1 double bond and is in the ω-3 position. In some embodiments, the alkenyl group is a C4-C9 straight-chain alkenyl group having 1 double bond in the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0236] In some embodiments, the alkenyl group has 1-3 double bonds and each double bond is in the Z configuration. In some embodiments, the alkenyl group is a C5-C9 straight-chain alkenyl group having 1 double bond in the ω-3 position and is in the Z configuration.

[0237] In some embodiments, the alkenyl group is a C5 straight-chain alkenyl group having 1 double bond in the ω-3 position. In some embodiments, the alkenyl group is a C6 straight-chain alkenyl group having 1 double bond in the ω-3 position. In some embodiments, the alkenyl group is a C7 straight-chain alkenyl group having 1 double bond in the ω-3 position. In some embodiments, the alkenyl group is a C8 straight-chain alkenyl group having 1 double bond in the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0238] "Alkynyl" refers to a straight-chain or branched alkynyl group. In some embodiments, the alkynyl group may be selected from C4-C12 alkynyl groups 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 C5-C10 alkynyl groups having 1 triple bond. In some embodiments, the triple bond is in the ω-3 position.

[0239] "Hydroxyalkyl" refers to a hydroxy 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.

[0240] "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.

[0241] The 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.

[0242] Under this definition, hydroxyalkyl is not considered a heteroalkyl. For example, according to this definition, the group of formula -C6H12OH is not a heteroalkyl. The group having the formula -C4H8OC2H4OH is considered a heteroalkyl having 7 atoms, where 1 is a heteroatom (oxygen) and further contains a hydroxyl group.

[0243] 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, where 1-3 are heteroatoms.

[0244] In some embodiments, the heteroalkyl has 4-8 atoms, with 1 being a heteroatom. In some embodiments, the heteroatom is in the second position of the heteroalkyl. In some embodiments, the heteroatom is in the third position of the heteroalkyl. In some embodiments, the heteroatom is in the fourth position of the heteroalkyl. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur. In some embodiments, the formula of the heteroalkyl may be selected from -CH2OC4H9, -C2H4OC3H7, -C2H4OC2H3, -C3H6OCH3, -CH2OC5H11, -CH2OC3H7, -C2H4OC3H7, -C3H6OC2H7.

[0245] The "alkyl-Y-" group is a heteroalkyl having 1 heteroatom at the α-position relative to the aromatic ring. Y may be selected from an oxygen atom, a sulfur atom, and an NR12NR13 group, where R12 and R13 are independently selected from a hydrogen group and a C1-C4 group. For example, in some embodiments, Y may 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.

[0246] "Heteroalkenyl" refers to a straight-chain or branched-chain alkenyl containing one or more heteroatoms selected from S, O, and N in the main chain, where the alkenyl chain may optionally contain a hydroxyl group, a halogen atom, and / or a carbonyl group. In some embodiments, the heteroatom is sulfur. In some embodiments, the heteroatom is oxygen. In some embodiments, the alkenyl has 2 double bonds. In some embodiments, the alkenyl has 3 double bonds. In some embodiments, the alkenyl has an ω-3 double bond. In some embodiments, the alkenyl has 1 double bond and it is in the ω-3 position. In some embodiments, the heteroalkenyl has 3-9 atoms, with 1 atom being a heteroatom and 1 double bond. In some embodiments, the heteroalkenyl has 6-9 atoms, with 1 atom being a heteroatom and 1 double bond, where the heteroatom is oxygen, and where the double bond is in the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0247] The heteroatom cannot be in the first or last position of the heteroalkenyl. For example, the heteroalkenyl group cannot contain a heteroatom at the first position of the chain relative to the aromatic ring. For example, under this definition, a group of the formula -OCH2CH=CHCH2CH3 is not a heteroalkyl.

[0248] "Halogenated alkyl" refers to a straight-chain or branched-chain alkyl group in which one or more hydrogen atoms have been replaced by halogen atoms. For example, the halogen atoms may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the halogen atom is F. In some embodiments, the halogenated alkyl group contains a -CF3 group.

[0249] In some embodiments, the halogenated alkyl group may also be a heteroalkyl group. In some embodiments, the halogenated alkyl group may be a heteroalkyl group having 6-9 atoms, where 1-3 atoms are heteroatoms. In some embodiments, the halogenated alkyl 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.

[0250] "Halogenated alkenyl" refers to a straight-chain or branched-chain alkenyl group in which one or more hydrogen atoms have been replaced by halogen atoms. For example, the halogen atoms may be selected from fluorine, chlorine, bromine, and iodine.

[0251] In some embodiments, the halogenated alkenyl group may also be a heteroalkenyl group.

[0252] 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 acid 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 a triglyceride, 1,2-diglyceride, 1,3-diglyceride, 1-monoacylglycerol, or 2-monoacylglycerol. 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

[0253] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, carboxamide, or hydroxymethyl. 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.

[0254] 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 a hydrogen atom and a C1-C6 alkyl group. 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.

[0255] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C2 alkyl. 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.

[0256] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxylic acid ester, and carboxamide.

[0257] Group 1 embodiments

[0258] The following embodiments relate to the compounds of formula (I) described by group (1).

[0259] In some embodiments, R1 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, heteroalkyl having 3-4 atoms, where 1 is a heteroatom, or -O-(C1-C4) alkyl.

[0260] In some embodiments, R5 is 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, 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, wherein 1-2 are heteroatoms, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkynyl having 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, an amino group having a hydrogen atom and a C3-C8 alkyl, an amino group having a hydrogen atom and a (C1-C6) ketone group, or an amino group having a C1-C9 alkyl and a C3-C8 alkyl.

[0261] In some embodiments, R5 is 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, C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, or -S-(C3-C8) alkynyl having 1-2 triple bonds.

[0262] In some embodiments, R1 is C1-C2 alkyl, C1-C2 hydroxyalkyl, C1-C2 haloalkyl, or -O-(C1-C2) alkyl. In some embodiments, R5 is 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, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, or -S-(C3-C8) alkynyl having 1-2 triple bonds.

[0263] In some embodiments, R1 is C1-C2 alkyl, C1-C2 hydroxyalkyl, or -O-(C1-C2)alkyl. In some embodiments, R5 is C4-C9 alkyl, heteroalkyl having 4-9 atoms, where 1-3 atoms are heteroatoms, C4-C9 alkenyl having 1-2 double bonds, heteroalkenyl having 1-2 double bonds and 5-9 atoms, where 1-2 atoms are heteroatoms, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -O-(C3-C8)alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, where 1 atom 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, where 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, or -S-heteroalkenyl having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond.

[0264] In some embodiments, R1 is C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond, -O-(C4-C6)alkyl, -O-(C4-C6)hydroxyalkyl, -O-(C4-C6)haloalkyl, -O-heteroalkyl having 4-6 atoms, where 1 atom is a heteroatom and the heteroatom is O, -O-(C5-C8)alkenyl having 1 double bond. In some embodiments, the double bond is in the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0265] 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 -O-(C3-C8)alkenyl 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 -S-(C3-C8)alkenyl 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.

[0266] In some embodiments, R2, R3 and R4 are each a hydrogen atom. 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.

[0267] In some embodiments, R1 is methyl or -OCH3; R5 is C4-C8 alkyl, -O-(C4-C8)alkyl, C4-C8 alkenyl having 1 double bond or -O-(C4-C8)alkenyl having 1 double bond; R2, R3 and R4 are each a hydrogen atom; n is 0; and X is a carboxylic acid.

[0268] 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 a hydrogen atom and C1-C6 alkyl. In some embodiments, R6 and R7 together may form a cycloalkyl, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0269] 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.

[0270] 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 a hydrogen atom and C1-C6 alkyl. In some embodiments, R6 and R7 together may 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 ester, such as an acetate group.

[0271] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C2 alkyl. 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 carboxylic acid. In some embodiments, n is 1 and both R6 and R7 are methyl groups and X is carboxylic acid.

[0272] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as an acetate group.

[0273] In some embodiments, the compound of formula (I) described by group (1) is described by formula (IA):

[0274]

[0275] wherein R1 and R5 are each defined by any one of the embodiments of group (1) above. In some embodiments, Z’ is H or C1-C4 alkyl.

[0276] In some embodiments, R1 is C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having 1 double bond, -O-(C4-C6)alkyl, -O-(C4-C6)hydroxyalkyl, -O-(C4-C6)haloalkyl, an -O-heteroalkyl group having 4-6 atoms, wherein 1 is a heteroatom and the heteroatom is O, an -O-(C5-C8)alkenyl group having 1 double bond. In some embodiments, the double bond is in the ω-3 position. In some embodiments, the double bond is in the Z configuration. In some embodiments, Z’ is H. In some embodiments, Z’ is methyl or ethyl.

[0277] Group 2 embodiments

[0278] The following embodiments relate to the compound of formula (I) described by group (2).

[0279] In some embodiments, R1 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, heteroalkyl having 3-4 atoms, where 1 is a heteroatom, or phenyl.

[0280] In some embodiments, R2 is 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, C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkynyl having 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -C(O)-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -C(O)-(C3-C8) alkenyl having 1-2 double bonds, -S(O)-(C3-C8) alkyl, -S(O)-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S(O)-(C3-C8) alkenyl having 1-2 double bonds, -S(O)-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S(O)2-(C3-C8) alkyl, -S(O)2-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S(O)2-(C3-C8) alkenyl having 1-2 double bonds, -S(O)2-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms; an amino group having a hydrogen atom and a C3-C8 alkyl; an amino group having a hydrogen atom and a heteroalkyl, said heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms; an amino group having a hydrogen atom and a keto group; an amino group having a C1-C9 alkyl and a C3-C8 alkyl; an amino group having a C1-C9 alkyl and a heteroalkyl having 4-8 atoms, wherein 1 is a heteroatom, or an amino group having a C1-C9 alkyl and a C3-C8 alkenyl having 1-2 double bonds.

[0281] In some embodiments, R1 is C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C2 haloalkyl, or phenyl. In some embodiments, R1 is selected from methyl, ethyl, isopropyl, -CF3 group, -(CH2)3OH group, and phenyl.

[0282] In some embodiments, R2 is C4-C9 alkyl, C4-C9 hydroxyalkyl, C4-C9 haloalkyl, heteroalkyl having 4-9 atoms, where 1-3 atoms are heteroatoms, C4-C9 alkenyl having 1-2 double bonds, heteroalkenyl having 1-2 double bonds and 5-9 atoms, where 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, where 1-2 are heteroatoms, -O-heteroalkenyl having 5-8 atoms, where 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, where 1 is a heteroatom and having 1 double bond, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, an amino group having a hydrogen atom and a C3-C8 alkyl, an amino group having a hydrogen atom and a (C1-C6) ketone group, or an amino group having a C1-C9 alkyl and a C3-C8 alkyl.

[0283] In some embodiments, R1 is a C1-C3 alkyl or a C1-C3 hydroxyalkyl. In some embodiments, R2 is a C4-C9 alkyl, a heteroalkyl having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -O-(C4-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, -O-(C4-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkyl, an -S-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -S-(C4-C8) alkenyl having 1-2 double bonds, an -S-heteroalkenyl having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond; -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, an amino group having a hydrogen atom and a C3-C8 alkyl, an amino group having a hydrogen atom and a (C1-C6) ketone group; an amino group having a C1-C9 alkyl and a C3-C8 alkyl.

[0284] In some embodiments, R1 is a C1-C2 alkyl or a C1-C2 hydroxyalkyl. In some embodiments, R2 is a C4-C9 alkyl, a heteroalkyl having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -O-(C4-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, -O-(C4-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkyl, an -S-heteroalkyl having 4-8 atoms, where 1-2 are heteroatoms, -S-(C4-C8) alkenyl having 1-2 double bonds or an -S-heteroalkenyl having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond.

[0285] In some embodiments, R2 is a C5-C8 straight-chain alkyl, a C6-C8 alkenyl having 1 double bond and the double bond at the ω-3 position, -O-(C4-C6) straight-chain alkyl or -O-(C5-C8) alkenyl having 1 double bond and the double bond at the ω-3 position.

[0286] In some embodiments, R1 is C1-C2 alkyl or C1-C2 hydroxyalkyl and R2 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond, -O-(C4-C6) alkyl, -O-(C4-C6) hydroxyalkyl, -O-(C4-C6) haloalkyl, -O-heteroalkyl having 4-6 atoms, where 1 is a heteroatom and the heteroatom is O, or -O-(C5-C8) alkenyl having 1 double bond.

[0287] In some embodiments, R1 is methyl or ethyl and R2 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond, -O-(C4-C6) straight-chain alkyl, -O-(C4-C6) hydroxyalkyl, -O-(C4-C6) haloalkyl, -O-heteroalkyl having 4-6 atoms, where 1 is a heteroatom and the heteroatom is O, or -O-(C5-C8) alkenyl having 1 double bond.

[0288] In some embodiments, R1 is methyl or ethyl and R2 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond and the double bond is in the ω-3 position, -O-(C4-C6) straight-chain alkyl, or -O-(C5-C8) alkenyl having 1 double bond.

[0289] In some embodiments, R1 is methyl and R2 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond and the double bond is in the ω-3 position, -O-(C4-C6) straight-chain alkyl, or -O-(C5-C8) alkenyl having 1 double bond and the double bond is in the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0290] In some embodiments, R1 is methyl. In some embodiments, R2 is -O-(C3-C8)alkyl and has the formula -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15 or -OC8H17. In some embodiments, R2 is -S-(C3-C8)alkyl and has the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15 or -SC8H17. In some embodiments, R2 is -O-(C3-C8)alkenyl 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 -S-(C3-C8)alkenyl 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.

[0291] In some embodiments, R3, R4 and R5 are each a hydrogen atom. In some embodiments, R5 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl or heteroalkyl having 3-4 atoms, where 1 atom 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 a hydrogen atom and R4 is a fluorine atom.

[0292] 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 a hydrogen atom and C1-C6 alkyl. In some embodiments, R6 and R7 together may form a cycloalkyl, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0293] 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.

[0294] 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 a hydrogen atom and a C1-C6 alkyl group. 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 ester, such as an acetate group.

[0295] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and a C1-C2 alkyl group. 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 a methyl group and R7 is a hydrogen atom. 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.

[0296] In some embodiments, X can be selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as an acetate group.

[0297] In some embodiments:

[0298] · R1 is a methyl or ethyl group;

[0299] · R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, -O-(C4-C6) straight-chain alkyl group or -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0300] · R3, R4 and R5 are each a hydrogen atom;

[0301] · n is 0 or 1;

[0302] · R6 and R7 are the same or different and are independently selected from a hydrogen atom and a methyl group;

[0303] · and X is selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as an acetate group.

[0304] In some embodiments:

[0305] · R1 is a methyl group;

[0306] · R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having one double bond at the ω-3 position, -O-(C4-C6) straight-chain alkyl group or -O-(C5-C8) alkenyl group having one double bond at the ω-3 position;

[0307] · R3, R4 and R5 are each a hydrogen atom;

[0308] · n is 0;

[0309] · and X is a carboxylic acid.

[0310] In some embodiments:

[0311] · R1 is methyl;

[0312] · R2 is a C5-C8 straight-chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond at the ω-3 position, -O-(C4-C6) straight-chain alkyl group or -O-(C5-C8) alkenyl group having 1 double bond and the double bond at the ω-3 position;

[0313] · R3, R4 and R5 are each a hydrogen atom;

[0314] · n is 1;

[0315] · R6 and R7 are each a hydrogen atom

[0316] · and X is a carboxylic acid.

[0317] In some embodiments, the compound of formula (I) described by group (2) is described by formula (IB-1), (IB-2), (IB-3) or (IB-4):

[0318]

[0319]

[0320] wherein R1, R2, R6 and R7 are each defined by any one of the embodiments of group (2) above;

[0321] and wherein, in some embodiments:

[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 1 double bond and the double bond at the ω-3 position, -O-(C4-C6) straight-chain alkyl group or -O-(C5-C8) alkenyl group having 1 double bond and the double bond at the ω-3 position;

[0328] · R6 and R7 are the same or different and are independently selected from a hydrogen atom and a C1-C6 alkyl group;

[0329] · Z1 is -O-, -S(O)n-, or -N(R14)-;

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

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

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

[0333] In some embodiments, R1 is C1-C2 alkyl or -O-(C1-C2)alkyl. In some embodiments, R5 is C5-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond, -O-(C4-C6)alkyl, -O-(C4-C6)hydroxyalkyl, -O-(C4-C6)haloalkyl, -O-heteroalkyl having 4-6 atoms, where 1 atom is a heteroatom and the heteroatom is O, -O-(C5-C8)alkenyl having 1 double bond. In some embodiments, the double bond is in the ω-3 position. In some embodiments, the double bond is in the Z configuration. In some embodiments, Z’ is H. In some embodiments, Z’ is methyl or ethyl. In some embodiments, R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C6 alkyl. In some embodiments, R6 and R7 together can form a cycloalkyl, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

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

[0335] Group 3 embodiments

[0336] The following embodiments relate to compounds of formula (I) described by group (3).

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

[0338] In some embodiments,

[0339] · R1 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, heteroalkyl having 3-4 atoms, wherein 1 atom is a heteroatom;

[0340] · R3 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, 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, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, an -S-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds or -S-(C3-C8) alkynyl having 1-2 triple bonds; and

[0341] · R5 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroaryl group having 3-4 atoms, of which 1 atom is a heteroatom.

[0342] In some embodiments,

[0343] · R1 is a heteroalkyl group having 3-4 atoms, of which 1 is a heteroatom;

[0344] · R3 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, 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, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, an -S-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds or -S-(C3-C8) alkynyl having 1-2 triple bonds; and

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

[0346] In some embodiments,

[0347] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group or a heteroalkyl group having 3-4 atoms, of which 1 is a heteroatom;

[0348] · 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, an -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, an -S-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds or -S-(C3-C8) alkynyl having 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, a heteroaryl group having 3-4 atoms, where 1 atom is a heteroatom.

[0350] In some embodiments,

[0351] · R1 is -O-(C1-C4)alkyl;

[0352] · R3 is a heteroalkyl group having 4-9 atoms, where 1-3 atoms are heteroatoms, a heteroalkenyl group having 1-2 double bonds and 5-9 atoms, where 1-2 atoms are heteroatoms, an -O-heteroalkyl group having 4-8 atoms, where 1-2 atoms are heteroatoms, an -O-(C3-C8)alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, an -O-(C3-C8)haloalkenyl group having 1-2 double bonds, an -O-(C3-C8)alkynyl group having 1-2 triple bonds, an -S-heteroalkyl group having 4-8 atoms, where 1-2 are heteroatoms, an -S-(C3-C8)alkenyl group having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, an -S-(C3-C8)haloalkenyl group having 1-2 double bonds or an -S-(C3-C8)alkynyl group having 1-2 triple bonds; and

[0353] · 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 having 3-4 atoms, where 1 atom is a heteroatom or -O-(C1-C4)alkyl.

[0354] In some embodiments,

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

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

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

[0358] In some embodiments,

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

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

[0361] · R2 and R4 are both hydrogen atoms;

[0362] · R5 is a hydrogen atom, a C1-C2 alkyl group or -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 a hydrogen atom. In some embodiments, any one of R2 and R4 or both R2 and R4 are halogen atoms. In some embodiments, any one of 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 a hydrogen atom and a C1-C6 alkyl group. 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, a carboxamide, a hydroxymethyl group or a 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 a hydroxymethyl group.

[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 a hydrogen atom and a C1-C6 alkyl group. 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 a hydroxymethyl group, a carboxylic acid, a carboxamide or a carboxylic acid ester, such as an acetate group.

[0369] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C2 alkyl. 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 ester, such as an acetate group.

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

[0372]

[0373] wherein R1, R3, and R5 are each defined by any one of the embodiments of group (3) above.

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

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

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

[0377] In some embodiments, R5 is a hydrogen atom, a halogen atom, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, heteroalkyl having 3-4 atoms, where 1 atom is a heteroatom, or -O-(C1-C4) alkyl.

[0378] Group 4 embodiments

[0379] The following embodiments relate to compounds of formula (I) described by group (4).

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

[0381] In some embodiments,

[0382] · R1 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, heteroalkyl having 3-4 atoms, wherein 1 is a heteroatom, -O-(C1-C4) alkyl or phenyl;

[0383] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, 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, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, an -O-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -O-(C3-C8)alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -O-(C3-C8)haloalkenyl having 1-2 double bonds, -O-(C3-C8)alkynyl having 1-2 triple bonds, -S-(C3-C8)alkyl, -S-(C3-C8)hydroxyalkyl, -S-(C3-C8)haloalkyl, an -S-heteroalkyl group having 4-8 atoms, of which 1-2 are heteroatoms, -S-(C3-C8)alkenyl having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, of which 1 is a heteroatom and having 1 double bond, -S-(C3-C8)haloalkenyl having 1-2 double bonds, -S-(C3-C8)alkynyl having 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 group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroaryl group having 3-4 atoms, of which 1 atom is a heteroatom.

[0385] In some embodiments,

[0386] · R1 is a heteroalkyl group having 3-4 atoms, of which 1 atom is a heteroatom or phenyl;

[0387] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms, where 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, an -S-heteroalkyl group having 4-8 atoms, where 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, an -S-heteroalkenyl group having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds, -S-(C3-C8) alkynyl having 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 -O-(C1-C4) alkyl.

[0389] In some embodiments,

[0390] · R1 is a phenyl group;

[0391] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms, where 1-2 are heteroatoms, -O-(C4-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, where 1 atom is a heteroatom and having 1 double bond; and

[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, where 1 atom is a heteroatom; or -O-(C1-C4) alkyl. In some embodiments,

[0393] · R1 is a C1-C4 alkyl group, a C1-C4 haloalkyl group, -O-(C1-C4)alkyl group, a heteroalkyl group having 3 to 4 atoms, where 1 atom is a heteroatom, or a phenyl group;

[0394] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4 to 9 atoms, where 1 to 3 atoms are heteroatoms, a C4-C9 alkenyl group having 1 to 2 double bonds, a heteroalkenyl group having 1 to 2 double bonds and 5 to 9 atoms, where 1 to 2 atoms are heteroatoms, a C4-C9 alkynyl group having 1 to 2 triple bonds, -O-(C3-C8)alkyl group, -O-(C3-C8)hydroxyalkyl group, -O-(C3-C8)haloalkyl group, an -O-heteroalkyl group having 4 to 8 atoms, where 1 to 2 are heteroatoms, -O-(C3-C8)alkenyl group having 1 to 2 double bonds, an -O-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and having 1 double bond, -O-(C3-C8)haloalkenyl group having 1 to 2 double bonds, -O-(C3-C8)alkynyl group having 1 to 2 triple bonds, -S-(C3-C8)alkyl group, -S-(C3-C8)hydroxyalkyl group, -S-(C3-C8)haloalkyl group, an -S-heteroalkyl group having 4 to 8 atoms, where 1 to 2 are heteroatoms, -S-(C3-C8)alkenyl group having 1 to 2 double bonds, an -S-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and having 1 double bond, -S-(C3-C8)haloalkenyl group having 1 to 2 double bonds, -S-(C3-C8)alkynyl group having 1 to 2 triple bonds, -C(O)-(C3-C8)alkyl group, -S(O)-(C3-C8)alkyl group or -S(O)2-(C3-C8)alkyl group; and

[0395] · R5 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, or a heteroalkyl group having 3 to 4 atoms, where 1 atom is a heteroatom.

[0396] In some embodiments,

[0397] · R1 is a C1-C4 alkyl group, a C1-C4 haloalkyl group or -O-(C1-C4)alkyl group;

[0398] · R4 is a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, where 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, where 1-2 atoms are heteroatoms, a C4-C9 alkynyl group having 1-2 triple bonds, -O-(C3-C8) alkyl, -O-(C3-C8) hydroxyalkyl, -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms, where 1-2 are heteroatoms, -O-(C4-C8) alkenyl having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms, where 1 is a heteroatom and having 1 double bond; and

[0399] · R5 is a C1-C4 alkyl group or a C1-C4 haloalkyl group.

[0400] In some embodiments,

[0401] · R1 is a C1-C4 alkyl group or -O-(C1-C4) alkyl;

[0402] · R4 is a C4-C9 alkyl group, -O-(C3-C8) alkyl or -C(O)-(C3-C8) alkyl; and

[0403] · R5 is a C1-C4 alkyl group or a C1-C4 haloalkyl group.

[0404] In some embodiments,

[0405] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, where 1 is a heteroatom, -O-(C1-C4) alkyl or phenyl;

[0406] · R4 is a heteroalkyl group having 4 to 9 atoms, where 1 to 3 atoms are heteroatoms, a heteroalkenyl group having 1 to 2 double bonds and 5 to 9 atoms, where 1 to 2 atoms are heteroatoms, an -O-heteroalkyl group having 4 to 8 atoms, where 1 to 2 are heteroatoms, an -O-(C3-C8) alkenyl group having 1 to 2 double bonds, an -O-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and having 1 double bond, an -O-(C3-C8) haloalkenyl group having 1 to 2 double bonds, an -O-(C3-C8) alkynyl group having 1 to 2 triple bonds, an -S-heteroalkyl group having 4 to 8 atoms, where 1 to 2 are heteroatoms, an -S-(C3-C8) alkenyl group having 1 to 2 double bonds, an -S-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and having 1 double bond, an -S-(C3-C8) haloalkenyl group having 1 to 2 double bonds, an -S-(C3-C8) alkynyl group having 1 to 2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl or -S(O)2-(C3-C8) alkyl; and

[0407] · R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroaryl group having 3 to 4 atoms, where 1 atom is a heteroatom.

[0408] In some embodiments,

[0409] · R1 is a C1-C2 alkyl group, a C1-C2 haloalkyl group, -O-(C1-C2) alkyl or phenyl;

[0410] · R4 is a heteroalkyl group having 4 to 9 atoms, where 1 to 3 atoms are heteroatoms, a heteroalkenyl group having 1 to 2 double bonds and 5 to 9 atoms, where 1 to 2 atoms are heteroatoms, an -O-(C4-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and 1 double bond and the double bond is in the ω-3 position; and

[0411] · R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group or -O-(C1-C2) alkyl.

[0412] In some embodiments,

[0413] · R1 is a C1-C2 alkyl group or -O-(C1-C2) alkyl;

[0414] · R4 is a heteroalkenyl group having 1 to 2 double bonds and 5 to 9 atoms, where 1 to 2 atoms are heteroatoms, an -O-(C4-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-heteroalkenyl group having 5 to 8 atoms, where 1 atom is a heteroatom and 1 double bond and the double bond is in the ω-3 position; and

[0415] · R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group or an -O-(C1-C2) alkyl group.

[0416] In some embodiments,

[0417] · R1 is a C1-C2 alkyl group or an -O-(C1-C2) alkyl group;

[0418] · R4 is an -O-(C4-C8) alkenyl group having 1 double bond and the double bond at the ω-3 position or a -C(O)-(C3-C8) alkyl group;

[0419] · R5 is a hydrogen atom, a halogen atom, a C1-C2 alkyl group or an -O-(C1-C2) alkyl group;

[0420] · R2 and R3 are each a hydrogen atom;

[0421] · n is 0; and

[0422] · X is a carboxylic acid.

[0423] In some embodiments, R2 and R3 are each a hydrogen atom. In some embodiments, any one of R2, R4 or both R2 and R4 are halogen atoms. In some embodiments, any one of R2, R4 or both R2 and R4 are fluorine atoms.

[0424] 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 a hydrogen atom and a C1-C6 alkyl group. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0425] In some embodiments, n is 0. In some embodiments, X is a carboxylic acid, a carboxamide, a hydroxymethyl group or a 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 a hydroxymethyl group.

[0426] 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 a hydrogen atom and a C1-C6 alkyl group. 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 a hydroxymethyl group, a carboxylic acid, a carboxamide or a carboxylic acid ester, such as an acetate group.

[0427] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C2 alkyl. 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.

[0428] In some embodiments, X may be selected from hydroxymethyl, carboxylic acid, carboxamide, and carboxylic acid ester, such as an acetate group.

[0429] In some embodiments, the compound of formula (I) described by group (4) is described by formula (ID-1) or (ID-2):

[0430]

[0431] wherein R1, R4, and R5 are each defined by any one of the embodiments of group (4) above.

[0432] In some embodiments, Z’ is H or C1-C4 alkyl. In some embodiments, Z’ is H. In some embodiments, Z’ is methyl or ethyl.

[0433] In some embodiments, R1 is C1-C2 alkyl, C1-C2 haloalkyl, -O-(C1-C2)alkyl, or phenyl.

[0434] In some embodiments, R4 is 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, C4-C9 alkynyl having 1-2 triple bonds, -O-(C3-C8)alkyl, -O-(C3-C8)hydroxyalkyl, -O-(C3-C8)haloalkyl, -O-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -O-(C4-C8)alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, wherein 1 atom is a heteroatom and having 1 double bond.

[0435] In some embodiments, R5 is a hydrogen atom, a halogen atom, C1-C2 alkyl, or -O-(C1-C2)alkyl.

[0436] Embodiments of Group 5

[0437] The following embodiments relate to the compounds of formula (I) described by group (5).

[0438] In some embodiments,

[0439] · R1 is a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 haloalkyl group, a heteroalkyl group having 3-4 atoms, wherein 1 is a heteroatom, or -O-(C1-C4) alkyl;

[0440] In some embodiments, R2 and R4 are the same or different and are independently selected from a C4-C9 alkyl group, a C4-C9 hydroxyalkyl group, a C4-C9 haloalkyl group, a heteroalkyl group having 4-9 atoms, wherein 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, wherein 1-2 atoms are heteroatoms, a C4-C9 alkynyl group 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, wherein 1-2 are heteroatoms, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) alkynyl having 1-2 triple bonds, -C(O)-(C3-C8) alkyl, -S(O)-(C3-C8) alkyl, -S(O)2-(C3-C8) alkyl, an amino group having a hydrogen atom and a C3-C8 alkyl group, an amino group having a hydrogen atom and a (C1-C6) keto group, and an amino group having a C1-C9 alkyl group and a C3-C8 alkyl group; and

[0441] · 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 having 3-4 atoms, wherein 1 is a heteroatom, or -O-(C1-C4) alkyl.

[0442] In some embodiments, R2 and R4 are 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, -O-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -O-(C3-C8) haloalkenyl having 1-2 double bonds, -O-(C3-C8) alkynyl having 1-2 triple bonds, -S-(C3-C8) alkyl, -S-(C3-C8) hydroxyalkyl, -S-(C3-C8) haloalkyl, -S-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds, -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond, -S-(C3-C8) haloalkenyl having 1-2 double bonds or -S-(C3-C8) alkynyl having 1-2 triple bonds.

[0443] In some embodiments, R2 and R4 are the same or different and are independently selected from C4-C9 alkyl, 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-heteroalkyl having 4-8 atoms, wherein 1-2 are heteroatoms, -O-(C3-C8) alkenyl having 1-2 double bonds, -O-heteroalkenyl having 5-8 atoms, wherein 1 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, wherein 1-2 are heteroatoms, -S-(C3-C8) alkenyl having 1-2 double bonds or -S-heteroalkenyl having 5-8 atoms, wherein 1 is a heteroatom and having 1 double bond.

[0444] In some embodiments, R2 and R4 are the same or different and are independently selected from C4-C8 straight-chain alkyl, C6-C8 alkenyl having 1 double bond, -O-(C4-C6) alkyl, -O-(C4-C6) hydroxyalkyl, -O-(C4-C6) haloalkyl, -O-heteroalkyl having 4-6 atoms, wherein 1 is a heteroatom and the heteroatom is O, or -O-(C5-C8) alkenyl having 1 double bond. In some embodiments, the double bond is at the ω-3 position. In some embodiments, the double bond is in the Z configuration.

[0445] In some embodiments, R2 and R4 are 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 are 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 are the same or different and are independently selected from -O-(C3-C8) alkenyl having 1-2 double bonds and have the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3 or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 and R4 are the same or different and are independently selected from -S-(C3-C8) alkenyl having 1-2 double bonds and have the formula -SCH2CH=CHCH2CH3, -S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3 or -S(CH2)4CH=CHCH2CH3.

[0446] In some embodiments, R2 and R4 are 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, wherein 1 is a heteroatom and the heteroatom is O;

[0447] In some embodiments, R1 and R5 are the same or different and are independently selected from C1-C4 alkyl. In some embodiments, R1 and R5 are the same or different and are independently selected from methyl or ethyl. In some embodiments, R1 and R5 are the same and are both methyl.

[0448] In some embodiments, R1 and R5 are the same or different and are independently selected from -O-(C1-C4)alkyl. In some embodiments, both R1 and R5 are -OCH3.

[0449] In some embodiments, R5 is a hydrogen atom. In some embodiments, R1 is 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.

[0450] In some embodiments, R3 is a hydrogen atom. In other embodiments, R3 is a halogen atom. In some embodiments, R3 is a fluorine atom.

[0451] In some embodiments,

[0452] · R1 is methyl or -OCH3;

[0453] · R2 and R4 are 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, where 1 is a heteroatom and the heteroatom is O;

[0454] · R3 is a hydrogen atom;

[0455] · R5 is a hydrogen atom, methyl, or -OCH3;

[0456] · n is 0; and

[0457] · X is a carboxylic acid.

[0458] In some embodiments,

[0459] · R1 is methyl or -OCH3;

[0460] · R2 and R4 are the same and are selected from C4-C8 straight-chain alkyl and -O-(C4-C6)alkyl;

[0461] · R3 is a hydrogen atom;

[0462] · R5 is a hydrogen atom, methyl, or -OCH3;

[0463] · n is 0; and

[0464] · X is a carboxylic acid.

[0465] 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 a hydrogen atom and C1-C6 alkyl. In some embodiments, R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0466] 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.

[0467] 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 a hydrogen atom and C1-C6 alkyl. 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 ester, such as an acetate group.

[0468] In some embodiments, n is 1 and R6 and R7 are the same or different and are independently selected from a hydrogen atom and C1-C2 alkyl. 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.

[0469] In some embodiments, X can be selected from hydroxymethyl, carboxylic acid, carboxamide and carboxylic acid ester, such as an acetate group.

[0470] In some embodiments, the compound of formula (I) described by group (5) is described by formula (IE-1) or (IE-2):

[0471]

[0472] wherein R1, R2, R4 and R5 are each defined by any one of the embodiments of group (5) above.

[0473] In some embodiments, Z’ is H or C1-C4 alkyl. In some embodiments, Z’ is H. In some embodiments, Z’ is methyl or ethyl.

[0474] In some embodiments, R1 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, a heteroalkyl having 3-4 atoms, where 1 is a heteroatom, or -O-(C1-C4) alkyl.

[0475] In some embodiments, R2 and R4 are the same or different and 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 are the same or different and independently selected from -S-(C3-C8) alkyl and have the formula -SC3H7, -SC4H9, -SC5H11, -SC6H13, -SC7H15 or -SC8H17. In some embodiments, R2 and R4 are the same or different and independently selected from -O-(C3-C8) alkenyl having 1-2 double bonds and have the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, -O(CH2)3CH=CHCH2CH3 or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 and R4 are the same or different and independently selected from -S-(C3-C8) alkenyl 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.

[0476] In some embodiments, R5 is a hydrogen atom, a methyl group or -OCH3. In some embodiments, R5 is a fluorine atom.

[0477] Salt

[0478] The present disclosure also relates to salts of the compounds of formula (I). Such salts can be represented as

[0479]

[0480] Wherein X is COO−, and Z+ can be NH4+; a metal ion such as Li+, Na+, K+, Mg2+ or Ca2+; a protonated primary amine such as tert-butylammonium, (3S,5S,7S)-adamantan-1-ammonium, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-ammonium, a protonated aminopyridine (e.g., pyridin-2-ammonium); a protonated secondary amine such as diethylammonium, 2,3,4,5,6-pentahydroxy-N-methylhexan-1-ammonium, N-ethylnaphthalen-1-ammonium, a protonated tertiary amine such as 4-methylmorpholin-4-ammonium, a quaternary amine such as 2-hydroxy-N,N,N-trimethylethan-1-ammonium and a protonated guanidine such as amino((4-amino-4-carboxybutyl)amino)methanammonium or a protonated heterocycle 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.

[0481] or

[0482]

[0483] Wherein X = COO−, and Z2+ can be Mg2+ or Ca2+, or a diprotonated diamine such as ethane-1,2-diammonium or piperazine-1,4-diammonium.

[0484] Examples of pharmaceutically acceptable salts are also described, for example, in Pharmaceutical Salts: Properties, Selection, and Use, Second Revised Edition, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor).

[0485] Certain compounds of the present invention may exist in zwitterionic form, and the present invention includes the zwitterionic forms of these compounds and mixtures thereof.

[0486] The present disclosure also relates to prodrugs of the compounds of formula (I). Examples of such prodrugs include pharmaceutically acceptable esters or amides obtained after reaction of an alcohol or an amine (including an amino acid) with the free acid defined by formula I.

[0487] The compounds of formula (I) are capable of existing in stereoisomeric forms. It is to be understood that the present invention encompasses all the optical isomers of the compounds of formula (I) and mixtures thereof. Accordingly, the compounds of formula (I) in the form of diastereoisomers, racemates and enantiomers are included within the scope of the present disclosure. The present disclosure also relates to at least one lipid compound according to formula (I) for use as a medicament.

[0488] It should also be understood that certain compounds of formula (I) can exist in solvated and non-solvated forms, such as hydrated forms. It is understood that the present invention encompasses all such solvated forms having biological activity.

[0489] Formulation

[0490] A "pharmaceutical composition" is any form of a compound according to the present invention that is suitable for medical purposes. The term "pharmaceutically acceptable" refers to drugs, agents, inert ingredients, etc. that are suitable for contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic reactions, etc., and that proportionally have a reasonable benefit / risk ratio.

[0491] A "pharmaceutically acceptable vehicle" is a diluent, adjuvant, excipient or carrier administered together with the compound. A pharmaceutically acceptable vehicle can be a solvent or dispersion medium that includes, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. Other examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles, such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, such as, but not limited to, ethanol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

[0492] The action of microorganisms can be prevented by adding antibacterial and antifungal agents. Examples of such agents are parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. Isotonic agents can be included in the formulation. Examples of isotonic agents in the composition include sugars, sodium chloride or polyols, such as mannitol and sorbitol.

[0493] The compounds of the present invention can be formulated using available techniques and methods before administering the pharmaceutical composition. For example, the pharmaceutical composition can be formulated in a manner suitable for administration by topical, oral, intravenous (iv), intramuscular (im), intramuscular depot (depo-im), subcutaneous (sc), subcutaneous depot (depo-sc), sublingual, intranasal, intrathecal topical or rectal routes.

[0494] Preferably, the compounds of the present invention can be administered orally or intravenously. The formulations can conveniently be in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of the therapeutic agent in such a therapeutically useful composition is the appropriate dose to be obtained.

[0495] 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, dispersions, suspensions, syrups, emulsions, sprays, etc., using conventional excipients, such as solvents, diluents, binders, sweeteners, aroma, pH regulators, viscosity regulators, antioxidants (such as tocopherol), corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerol, sorbitol, polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose or fatty substances such as stearin or suitable mixtures thereof, etc. Conventional formulation techniques known in the art can be used.

[0496] The formulations of the present invention suitable for oral administration can be capsules (e.g., hard or soft shell gelatin capsules), cachets, pills, tablets, lozenges, powders, granules, pellets, dragees, e.g., 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 pastilles or mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as the active ingredient. The compounds of the present invention can also be administered in the form of boluses, troches or pastes, or directly incorporated into the diet of the subject. In addition, in certain embodiments, these pellets can be formulated to (a) provide immediate or rapid drug release (i.e., without a coating thereon); (b) be coated, e.g., to provide sustained drug release over time; or (c) be coated with an enteric coating to improve gastrointestinal tolerance. The coating can be achieved by conventional methods, usually with pH or time-varying coatings, such that the compound of the present invention is released near the desired location or at different times to extend the desired effect. Such dosage forms generally include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, waxes and shellac.

[0497] In solid dosage forms for oral administration, the compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers such as sodium citrate or dibasic calcium phosphate, or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose or acacia; humectants such as glycerol; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution blockers such as paraffin wax; absorption promoters 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 lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0498] Oral compositions include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable vehicles suitable for the preparation of such compositions are well known in the art. Typical ingredients of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, tragacanth and sodium alginate. Typical wetting agents include lecithin and polysorbate 80; in addition, typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweetening agents, flavoring agents and coloring agents.

[0499] Pharmaceutical preparations suitable for injectable use (e.g., by i.v.) may include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Dispersions can be prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the other ingredients required as above. For sterile powders for the preparation of sterile injectable solutions, the method of preparation is to vacuum dry and lyophilize 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 required ingredients. Prolonged absorption of injectable compositions can be achieved by including in the composition a reagent which delays absorption such as, for example, aluminum monostearate or gelatin.

[0500] The injectable composition must be sterile and must be a fluid to an extent that allows for easy injection. It must remain stable under the conditions of production and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Sterile injectable solutions can be prepared by incorporating the required amount of the therapeutic agent in a suitable solvent into one or a combination of the ingredients listed above (if required), followed by filtration sterilization.

[0501] The compounds according to the invention can be administered parenterally, intraperitoneally, intraspinally or intracerebrally. The compounds of the invention can be prepared as such compositions in glycerol, liquid polyethylene glycol and mixtures thereof and oils. Under normal storage and use conditions, the preparation may contain preservatives to prevent the growth of microorganisms.

[0502] There are also provided pharmaceutical preparations suitable for administration in the form of an aerosol for inhalation. These preparations contain the required compound of any of the formulas herein or a solution or suspension of multiple solid particles of such a compound. For example, it is expected that the metal salts of the compounds of the invention rather than the free acid forms of these compounds have the physicochemical properties suitable for preparing fine particles of the active pharmaceutical ingredient (API) for administration by inhalation. The required preparation can be placed in a chamber and atomized. Atomization can be accomplished by compressed air or ultrasonic energy to form multiple 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 microns. Solid particles can be obtained by micronizing any solid reagent or its salt of any of the formulas described herein in any suitable manner known in the art. The size of the solid particles or droplets will be, for example, about 1 to about 2 microns. In this regard, commercial atomizers can be used for this purpose. The pharmaceutical preparation suitable for administration as an aerosol can be in liquid form and the preparation will contain a water-soluble reagent or its salt of any of the formulas described herein in a carrier containing water. A surfactant can be present which reduces the surface tension of the preparation so as to be sufficient to cause the formation of droplets within the required size range upon atomization.

[0503] The compositions of the present invention can also be administered topically to a subject, for example, by directly spreading or applying the composition onto the epidermis or epithelial tissue of the subject, or by transdermal administration using a "patch". Such compositions include, for example, lotions, creams, solutions, gels, emulsions, and solids. These topical compositions can contain an effective amount, usually about 0.01% to about 10% (w / w), or about 0.1% to about 5% (w / w), or about 1% to about 5% (w / w) of the compounds of the present invention. Suitable carriers for topical administration typically remain on the skin in the form of a continuous film and resist removal due to sweating or immersion in water. Generally, the carrier is organic in nature and is capable of dispersing or dissolving the therapeutic agent therein. The carrier can include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents, etc. The carrier can include vernix. Topical formulations include one or more excipients, such as, but not limited to, protectants, adsorbents, emollients, emollients, preservatives, antioxidants, humectants, buffers, solubilizers, skin penetrants, and surfactants.

[0504] Suitable protectants and adsorbents include, but are not limited to, dusting powders, zinc stearate, collodion, dimethicone, silicone, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide. Suitable emollients include, but are not limited to, animal and vegetable oils, myristyl alcohol, alum, and aluminum acetate.

[0505] Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercury agents, such as phenylmercuric nitrate, phenylmercuric acetate, and merthiolate; alcohol agents, such as, chlorobutanol, phenethyl alcohol, and benzyl alcohol; antibacterial esters, such as, esters of p-hydroxybenzoic acid; and other antimicrobial agents, such as chlorhexidine, chlorocresol, benzoic acid, and polymyxin.

[0506] 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.

[0507] Suitable humectants include, but are not limited to, glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Buffers suitable for use in the present invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactate buffers, and borate buffers.

[0508] Suitable solubilizers include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.

[0509] Suitable skin penetration enhancers include, but are not limited to, ethanol, isopropanol, octylphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate); and N-methylpyrrolidone.

[0510] Other compositions for achieving systemic delivery of the subject agent may include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filling substances such as sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents may also be included.

[0511] Use

[0512] The compounds of formula (I) and their pharmaceutical formulations can be used to treat various diseases and disorders. In particular, the compounds of formula (I) can be used to treat diseases and disorders associated with dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, and cholestasis.

[0513] "Treatment" includes any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatments are within the scope of the present invention. Treatment can be for an existing condition or prophylactic, i.e., preventive.

[0514] Dyslipidemia and Metabolic Syndrome

[0515] Factors such as high LDL / non-HDL cholesterol, hypertriglyceridemia (HTG), and low HDL cholesterol are characteristic of metabolic syndrome, which represents a collection of lipid and non-lipid (e.g., hypertension) risk factors of metabolic origin. Metabolic syndrome is closely related to a widespread metabolic disorder called insulin resistance, in which the normal action of insulin is impaired. The condition is characterized by abnormally high blood cholesterol and / or lipid values, which include hypercholesterolemia, hyperlipidemia (hyperlipoproteinemia), HTG, and mixed dyslipidemia. Current drugs for treating hyperlipidemia (e.g., statins, omega-3 fatty acids, fibrates) generally have a neutral effect on blood glucose control, while drugs for blood glucose control (e.g., insulin, thiazolidinediones (TZDs)) have an adverse effect on body weight and (for TZDs) other harmful side effects, thus limiting their use.

[0516] Surprisingly, it has been found that the compounds of formula (I) lower the plasma triglyceride and total cholesterol levels in APOE*3Leiden mice fed a high-fat, high-cholesterol diet. Additionally, it has surprisingly been found that in the ob / ob mouse model, the compounds of formula (I) also improve glycemic control by lowering the postprandial total plasma glucose level, lowering the fasting glucose level, and lowering the fasting plasma insulin level. Surprisingly, unlike currently used drugs for targeting glycemic control (e.g., insulin, thiazolidinediones), the compounds of formula (I) have also been found to reduce body weight in this model.

[0517] In some embodiments, the compounds of formula (I) can be used to lower plasma triglycerides and / or total cholesterol. In some embodiments, the compounds of formula (I) can be used to treat dyslipidemic conditions such as hypertriglyceridemia and / or hypercholesterolemia. In some embodiments, the treatment of dyslipidemic conditions such as hypertriglyceridemia and / or hypercholesterolemia can be prophylactic.

[0518] Some embodiments can include the use of the compounds of formula (I) for lowering plasma triglycerides and / or total cholesterol. Some embodiments can include the use of the compounds of formula (I) for treating dyslipidemic conditions such as hypertriglyceridemia and / or hypercholesterolemia. The use can be prophylactic.

[0519] In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for lowering plasma triglycerides and / or total cholesterol. In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for treating dyslipidemic diseases (such as hypertriglyceridemia and / or hypercholesterolemia). In some embodiments, the use or treatment can be prophylactic.

[0520] In some embodiments, the compounds of formula (I) can be used to lower plasma insulin levels. In some embodiments, the compounds of formula (I) can be used to lower fasting plasma insulin levels. In some embodiments, the compounds of formula (I) can be used to increase glucose tolerance and / or lower postprandial glucose levels. In some embodiments, the compounds of formula (I) can be used to lower fasting glucose levels. In some embodiments, the compounds of formula (I) can be used to treat diabetes, such as type 2 diabetes. In some embodiments, the treatment of the diabetes (such as type 2 diabetes) can be prophylactic.

[0521] Some embodiments may include the use of a compound of formula (I) for reducing plasma insulin levels. Some embodiments may include the use of a compound of formula (I) for reducing fasting plasma insulin levels. Some embodiments may include the use of a compound of formula (I) for increasing tolerance and / or reducing postprandial glucose levels. Some embodiments may include the use of a compound of formula (I) for reducing 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 prophylactic.

[0522] In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing plasma insulin levels. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing fasting plasma insulin levels. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for increasing glucose tolerance and / or reducing postprandial glucose levels. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing fasting blood glucose levels. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for treating diabetes (such as type 2 diabetes). In some embodiments, the use or treatment may be prophylactic.

[0523] In some embodiments, a compound of formula (I) can be used to reduce body weight. In some embodiments, a compound of formula (I) can be used to reduce body weight in overweight individuals. In some embodiments, a compound of formula (I) can be used to reduce body weight in individuals with metabolic syndrome.

[0524] Some embodiments may include the use of a compound of formula (I) for reducing body weight. Some embodiments may include the use of a compound of formula (I) for reducing body weight in overweight individuals. Some embodiments may include the use of a compound of formula (I) for reducing body weight in individuals with metabolic syndrome.

[0525] In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing body weight. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing body weight in overweight individuals. In some embodiments, a compound of formula (I) can be used to manufacture a medicament for reducing body weight in individuals with metabolic syndrome.

[0526] Non - alcoholic Fatty Liver and Steatohepatitis

[0527] Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver diseases characterized by the accumulation of lipids in the liver, which includes isolated hepatic steatosis (histologically >5% of hepatocytes) that is not due to alcohol consumption. A subgroup of NAFLD patients, in addition to hepatic steatosis, has a condition called non-alcoholic steatohepatitis (NASH), along with hepatocyte injury and inflammation. NASH greatly increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

[0528] The main histological components of NASH are steatosis, hepatocyte ballooning, and lobular inflammation. Fibrosis is not part of the histological definition of NASH. Hepatocyte ballooning is typically defined as an increase in cell size to 1.5 - 2 times the diameter of normal hepatocytes, with sparse cytoplasm, and has been shown to be associated with fibrosis and liver injury. However, the degree (stage) of fibrosis on liver biopsy is prognostically predictive, while the degree (grade) of inflammation and necrosis on liver biopsy is not. Despite the importance of fibrosis in clinical outcomes, regulatory approval of new and effective drugs for the treatment of NASH involves the clinical NAFLD activity score (NAS score) without involving worsening of fibrosis. The NAS score involves steatosis, lobular inflammation, and hepatocyte ballooning.

[0529] New findings are that the compound of formula (I) can significantly reduce the hepatic expression of collagen type 1 alpha-11, a key gene involved in liver fibrosis after 4 weeks of treatment, in the NASH model of ob / ob A MLN-diet mice. It was also found that in this model, the compound of formula (I) reduced the hepatic expression of the liver macrophage marker (and thus a sign of inflammation) CD68. It was also found that the compound of formula (I) can significantly reduce hepatic steatosis in mice fed a high-carbohydrate, fat-free diet.

[0530] In some embodiments, the compound of formula (I) can be used for the treatment of NAFLD. In some embodiments, the treatment of NAFLD can be prophylactic. In some embodiments, the compound of formula (I) can be used for the treatment of NASH. In some embodiments, the treatment of NASH can be prophylactic. In some embodiments, the compound of formula (I) can be used to reduce or prophylactically treat the development of liver fibrosis or reduce existing liver fibrosis. In some embodiments, the compound of formula (I) can be used to reduce or prophylactically treat 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 prophylactically treat hepatic steatosis in NAFLD or NASH or reduce existing hepatic steatosis.

[0531] 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 hepatic fibrosis or reduction of existing hepatic fibrosis in NASH. Some embodiments may include the use of a compound of formula (I) for the treatment of the development of hepatic inflammation or reduction of existing hepatic inflammation in NASH. Some embodiments may include the use of a compound of formula (I) for the reduction or prophylactic treatment of the development of hepatic steatosis or reduction of existing hepatic steatosis in NAFLD or NASH.

[0532] In some embodiments, a compound of formula (I) can be used in the manufacture of a medicament for the treatment of NAFLD. In some embodiments, the treatment of NAFLD can be prophylactic. In some embodiments, a compound of formula (I) can be used in the manufacture of a medicament for the treatment of NASH. In some embodiments, the treatment of NASH can be prophylactic. In some embodiments, a compound of formula (I) can be used in the manufacture of a medicament for reducing or preventing the development of hepatic fibrosis or reducing existing hepatic fibrosis in NASH. In some embodiments, a compound of formula (I) can be used in the manufacture of a medicament for reducing or prophylactically treating the development of hepatic inflammation or alleviating existing hepatic inflammation in NASH. In some embodiments, a compound of formula (I) can be used in the manufacture of a medicament for reducing or prophylactically treating the development of hepatic steatosis or reducing existing hepatic steatosis in NAFLD or NASH.

[0533] Cholestasis

[0534] Cholestasis is a reduction or cessation of bile flow, which results in impaired bile salt homeostasis. Several liver diseases are associated with cholestasis, including hepatobiliary disorders such as primary biliary cholangitis and sclerosing cholangitis, and parenteral nutrition-related liver disease (PNALD). NAFLD and NASH are also associated with impaired bile salt homeostasis.

[0535] Primary biliary cholangitis is characterized by progressive deterioration of the bile ducts, which results in retention of intrahepatic bile acids. Sclerosing cholangitis is characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts, which results in stenosis of the bile ducts that normally drain bile from the gallbladder. These diseases can lead to hepatic inflammation, fibrosis, and cirrhosis.

[0536] Parenteral nutrition (PN) is a life-saving therapy for patients with intestinal failure who are unable to absorb nutrients via the enteral route. However, long-term PN dependence places patients at risk of developing PN-related liver disease (PNALD), which is characterized by hepatic steatosis, inflammation, and cholestasis, which can progress to fibrosis and cirrhosis, end-stage liver disease requiring liver transplantation, and death if untreated.

[0537] Impaired bile salt homeostasis (one of the causes of cholestasis) has been shown to be associated with increased expression of CYP7A1 (mediating the rate-limiting step of bile acid synthesis) and decreased hepatic expression of ABBC2 (mediating canalicular excretion of bilirubin via Mrp2). Dysregulation of CYP7A1 and ABBC2 has been shown to occur in the PNALD model. Zhan et al., Am J Physiol Gastrointest Liver Physiol., 2016; 310(2): G93-G102; Koelfat et al., Clin Nutr., 2017; 36(5): 1403-1410.

[0538] The new finding is that the compound of formula (I) affects the hepatic expression of genes involved in bile salt homeostasis in the ob / ob AML-N diet mouse model. Specifically, the compound of formula (I) simultaneously reduces CYP7A1 expression and increases ABBC2 expression, which may be beneficial in the treatment or prevention of PNALD and other hepatobiliary disorders involving cholestasis.

[0539] Another new finding is that the compound of formula (I) reduces hepatic steatosis in the oral PN diet mouse model. It has also been found that the compound of formula (I) reduces the expression of type α-11 collagen in the ob / ob AMLN-diet mouse model, which may be beneficial in reducing or prophylactically treating fibrosis and / or reducing existing fibrosis in PNALD and disorders characterized by liver fibrosis.

[0540] In some embodiments, the compound of formula (I) can be used to treat hepatobiliary disorders. In some embodiments, the treatment of the hepatobiliary disorder is prophylactic. In some embodiments, the compound of formula (I) can be used to treat sclerosing cholangitis. In some embodiments, the treatment of the sclerosing cholangitis can be prophylactic. In some embodiments, the compound of formula (I) can be used to treat primary biliary cholangitis. In some embodiments, the treatment of the primary biliary cholangitis can be prophylactic. 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).

[0541] 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 improving bile salt homeostasis. Some embodiments may include the use of a compound of formula (I) for improving bile salt homeostasis in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis).

[0542] In some embodiments, a compound of formula (I) may be used in the manufacture of a medicament for the treatment of hepatobiliary disorders. In some embodiments, the treatment of the hepatobiliary disorder is prophylactic. In some embodiments, a compound of formula (I) may be used in the manufacture of a medicament for the treatment of sclerosing cholangitis. In some embodiments, the treatment of sclerosing cholangitis may be prophylactic. In some embodiments, a compound of formula (I) may be used in the manufacture of a medicament for the treatment of primary biliary cholangitis. In some embodiments, the treatment of primary biliary cholangitis may be prophylactic. In some embodiments, a compound of formula (I) may be used in the manufacture of a medicament for improving bile salt homeostasis. In some embodiments, a compound of formula (I) may be used in the manufacture of a medicament for improving bile salt homeostasis in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis).

[0543] In some embodiments, a compound of formula (I) may be used to reduce or prophylactically treat the development of liver inflammation or reduce existing liver inflammation in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis). In some embodiments, a compound of formula (I) may be used to reduce or prophylactically treat the development of liver fibrosis or reduce existing liver fibrosis in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis).

[0544] Some embodiments may include the use of a compound of formula (I) for reducing or prophylactically treating the development of liver inflammation or reducing existing liver inflammation in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis). Some embodiments may include the use of a compound of formula (I) for reducing or prophylactically treating the development of liver fibrosis or reducing existing liver fibrosis in a hepatobiliary disorder (such as sclerosing cholangitis or primary biliary cholangitis).

[0545] In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for reducing or prophylactically treating the development of liver inflammation or reducing existing liver inflammation in hepatobiliary disorders (such as sclerosing cholangitis or primary biliary cholangitis). In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for reducing or prophylactically treating liver fibrosis or reducing existing liver fibrosis in hepatobiliary disorders (such as sclerosing cholangitis or primary biliary cholangitis).

[0546] In some embodiments, the compounds of formula (I) can be used to treat PNALD. In some embodiments, the treatment of PNALD can be prophylactic. In some embodiments, the compounds of formula (I) can be used to improve bile salt homeostasis in PNALD. In some embodiments, the compounds of formula (I) can be used to reduce or prophylactically treat hepatic steatosis or reduce existing hepatic steatosis in PNALD. In some embodiments, the compounds of formula (I) can be used to reduce or prophylactically treat the development of liver inflammation or reduce existing liver inflammation in PNALD. In some embodiments, the compounds of formula (I) can be used to reduce or prophylactically treat the development of liver fibrosis or reduce existing liver fibrosis in PNALD.

[0547] Some embodiments can include the use of the compounds of formula (I) for treating PNALD. Some embodiments can include the use of the compounds of formula (I) for improving bile salt homeostasis in PNALD. Some embodiments can include the use of the compounds of formula (I) for reducing or prophylactically treating the development of liver inflammation or reducing existing liver inflammation in PNALD. Some embodiments can include the use of the compounds of formula (I) for reducing or prophylactically treating the development of liver fibrosis or reducing existing liver fibrosis in PNALD.

[0548] In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for treating PNALD. In some embodiments, the treatment of PNALD can be prophylactic. In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for improving bile salt homeostasis in PNALD. In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for reducing or prophylactically treating hepatic steatosis or reducing existing hepatic steatosis in PNALD. In some embodiments, the compounds of formula (I) can be used to manufacture a medicament for reducing or prophylactically treating the development of liver inflammation or reducing existing liver inflammation in PNALD. In some embodiments, the compounds 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.

[0549] Dosage and Administration

[0550] For the disclosed compounds, such as the compounds of formula (I), suitable daily doses can range from about 5 mg to about 2 g, such as from about 25 mg to about 1 g. For example, in some embodiments, the daily dose is in the range of about 10 mg to about 1 g, about 25 mg to about 750 mg, about 30 mg to about 600 mg, about 35 mg to about 500 mg, about 40 mg to about 300 mg, about 45 mg to about 250 mg, about 50 mg to about 200 mg, about 20 to about 100 mg, or about 25 to about 75 mg. In at least one embodiment, the daily dose is in the range of 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, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg. The compounds can be administered, for example, once, twice, or three times a day. In at least one embodiment, the compound of formula (I) is administered in an amount in the range of about 20 mg to about 300 mg per dose. In some embodiments, the compound of formula (I) is administered in an amount in the range of about 25 mg to about 100 mg. In at least one embodiment, the compound of formula (I) is administered once a day.

[0551] In some embodiments, the dose can be provided as one dose per day or multiple doses per day. For example, the daily dose can be provided as two doses per day, three doses per day, or four doses per day. In some embodiments, the daily dose is provided as a single dose per day.

[0552] In some embodiments, the dose does not necessarily have to be administered every day. In some embodiments, the dose can be administered every other day, every three days, every four days, twice a week, or once a week.

[0553] 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.

[0554] "Pharmaceutically active amount" means an amount that will result in a desired pharmacological and / or therapeutic effect, i.e., the amount of the combination product that effectively achieves its intended purpose. Although the needs of individual patients may vary, determining the optimal range of the effective amount of the combination product is within the skill of the art. Generally, the dosage regimen for treating a disorder with the combination product of the present invention is selected based on a variety of factors including the type, age, weight, sex, diet, and medical condition of the patient.

[0555] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, etc. used in the specification and claims are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the property sought to be obtained. While the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors resulting from variations in experiments, test measurements, statistical analysis, etc.

[0556] The present invention is not intended to be limited to the embodiments shown herein, but rather should be accorded the broadest scope consistent with the principles and novel features disclosed herein. Using only routine experimentation, one of ordinary skill in the art will recognize or be able to ascertain many equivalents to the specific methods, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention. The disclosed invention is further illustrated by the following examples, which should not be construed as limiting the invention.

[0557] Examples of Compounds of Formula (I)

[0558] The present disclosure relates to the following non-limiting examples of compounds of formula (I).

[0559] Group 1

[0560] Example 1.

[0561]

[0562] 2-Methyl-6-(pentyloxy)benzoic acid

[0563] Example 2.

[0564]

[0565] 2-Methoxy-6-(pentyloxy)benzoic acid

[0566] Example 3.

[0567]

[0568] (Z)-2-(Hex-3-en-1-yl)-6-methylbenzoic acid

[0569] Group 2

[0570] Example 1.

[0571]

[0572] 3-Butoxy-2-methylbenzoic acid

[0573] Example 2.

[0574]

[0575] 3-(Hexyloxy)-2-methylbenzoic acid

[0576] Example 3.

[0577]

[0578] 3-Hexyl-2-methylbenzoic acid

[0579] Example 4.

[0580]

[0581] 2-Methyl-3-octylbenzoic acid

[0582] Example 5.

[0583]

[0584] (Z)-2-Methyl-3-(oct-5-en-1-yl)benzoic acid

[0585] Example 6.

[0586]

[0587] (Z)-3-(Hex-3-en-1-yloxy)-2-methylbenzoic acid

[0588] Example 7.

[0589]

[0590] (Z)-2-Methyl-3-(oct-5-en-1-yloxy)benzoic acid

[0591] Example 8.

[0592]

[0593] (Z)-3-(Hex-3-en-1-yl)-2-methylbenzoic acid

[0594] Example 9.

[0595]

[0596] (Z)-2-Methyl-3-(pent-2-en-1-yloxy)benzoic acid (“Compound B”)

[0597] Example 10.

[0598]

[0599] 2-Methyl-3-(pentyloxy)benzoic acid (“Compound A”)

[0600] Example 11.

[0601]

[0602] (Z)-2-Methyl-3-(pent-2-en-1-yloxy)benzamide (“Compound C”)

[0603] Example 12.

[0604]

[0605] (Z)-(2-Methyl-3-(pent-2-en-1-yloxy)phenyl)methanol

[0606] Example 13.

[0607]

[0608] (Z)-2-(3-(Hept-4-en-1-yloxy)-2-methylphenyl)acetic acid

[0609] Example 14.

[0610]

[0611] (Z)-2-(2-Methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid

[0612] Example 15.

[0613]

[0614] (Z)-2-Ethyl-3-(pent-2-en-1-yloxy)benzoic acid

[0615] Example 16.

[0616]

[0617] 2-Methyl-3-octylbenzoic acid

[0618] Example 17.

[0619]

[0620] 3-(2-Ethoxyethoxy)-2-methylbenzoic acid

[0621] Example 18.

[0622]

[0623] 2-Methyl-3-(pent-2-yn-1-yloxy)benzoic acid

[0624] Example 19.

[0625]

[0626] 3-((5-Hydroxypentyl)oxy)-2-methylbenzoic acid

[0627] Example 20.

[0628]

[0629] 2-Methyl-3-((5,5,5-trifluoropentyl)oxy)benzoic acid

[0630] Example 21.

[0631]

[0632] 3-(Pentyloxy)-2-(trifluoromethyl)benzoic acid

[0633] Example 22.

[0634]

[0635] 6-(Pentyloxy)-[1,1'-biphenyl]-2-carboxylic acid

[0636] Example 23.

[0637]

[0638] 2-Isopropyl-3-(pentyloxy)benzoic acid

[0639] Example 24.

[0640]

[0641] 2-(3-Hydroxypropyl)-3-(pentyloxy)benzoic acid

[0642] Example 25.

[0643]

[0644] 5-Fluoro-2-methyl-3-(pentyloxy)benzoic acid

[0645] Example 26.

[0646]

[0647] 2-Methyl-3-(pentylthio)benzoic acid

[0648] Example 27.

[0649]

[0650] 2-Methyl-3-(pentylsulfinyl)benzoic acid

[0651] Example 28.

[0652]

[0653] 2-Methyl-3-(phenylsulfonyl)benzoic acid

[0654] Example 29.

[0655]

[0656] 2-Methyl-3-(pentylamino)benzoic acid

[0657] Example 30.

[0658]

[0659] 3-(Dipentylamino)-2-methylbenzoic acid

[0660] Example 31.

[0661]

[0662] 2-Methyl-3-(methyl(pentyl)amino)benzoic acid

[0663] Example 32.

[0664]

[0665] 2-Methyl-3-pentanamidobenzoic acid

[0666] Example 33.

[0667]

[0668] (Z)-2-Methyl-3-(pent-2-en-1-yloxy)benzyl acetate

[0669] Example 34.

[0670]

[0671] 6-Fluoro-2-methoxy-3-(pentoxy)benzoic acid

[0672] Example 35.

[0673]

[0674] 2-Methyl-2-(2-methyl-3-(pentoxy)phenyl)propanoic acid

[0675] Example 36.

[0676]

[0677] 2-(Hydroxymethyl)-3-(pentoxy)benzoic acid

[0678] Example 37.

[0679]

[0680] Sodium 2-methyl-3-(pentoxy)benzoate

[0681] Example 38.

[0682]

[0683] Potassium 2-methyl-3-(pentoxy)benzoate

[0684] Example 39.

[0685]

[0686] Magnesium 2-methyl-3-(pentyloxy)benzoate

[0687] Example 40.

[0688]

[0689] Calcium 2-methyl-3-(pentyloxy)benzoate

[0690] Group 3

[0691] Example 1.

[0692]

[0693] (Z)-2-Methyl-4-(pent-2-en-1-yloxy)benzoic acid

[0694] Example 2.

[0695]

[0696] (Z)-2,6-Dimethoxy-4-(pent-2-en-1-yloxy)benzoic acid

[0697] Example 3.

[0698]

[0699] (Z)-2,6-Dimethyl-4-(pent-2-en-1-yloxy)benzoic acid

[0700] Group 4

[0701] Example 1.

[0702]

[0703] 5-Hexanoyl-2-methylbenzoic acid

[0704] Example 2.

[0705]

[0706] (Z)-2-Methyl-5-(pent-2-en-1-yloxy)benzoic acid

[0707] Example 3.

[0708]

[0709] 4-(Pentyloxy)-[1,1'-biphenyl]-2-carboxylic acid

[0710] Example 4.

[0711]

[0712] 2,6 - Dimethyl - 3 - (pentyloxy)benzoic acid

[0713] Example 5.

[0714]

[0715] (Z)-2,6 - Dimethoxy - 3-(pent - 2 - en - 1 - yloxy)benzoic acid

[0716] Group 5

[0717] Example 1.

[0718]

[0719] 2 - Methyl - 3,5 - bis(pentyloxy)benzoic acid

[0720] Example 2.

[0721]

[0722] 2,6 - Dimethyl - 3,5 - bis(pentyloxy)benzoic acid

[0723] Example 3.

[0724]

[0725] 2,6 - Dimethoxy - 3,5 - dipentylbenzoic acid

[0726] General Synthetic Methods of the Compounds Described herein

[0727] Generally, all compounds of the present invention can be prepared by conventional methods using readily available and / or conventionally preparable starting materials, reagents, and conventional synthetic methods. Key synthetic steps may include cross - coupling reactions, ether - forming reactions (such as Mitsunobu - type reactions), Friedel - Craft reactions, aromatic nucleophilic substitution reactions, and functional group interconversion (FGI) reactions. It should also be understood that in certain reactions, it may be necessary / required to protect any sensitive groups in the compound. Suitable protecting groups and methods for protecting and de - protecting 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 the parent compound containing an acidic moiety by conventional chemical methods. The salts can be prepared in situ or in a separate step.

[0728] The compounds of general formula (I) can be prepared by the following general methods:

[0729] Method I:

[0730]

[0731] The compounds of formulas (II) and (III) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The leaving group (LG) present in the compound of formula (II) can be, for example, a mesylate, a tosylate 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: R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I) and each optionally comprises a protecting group. One skilled in the art will be able to select a suitable protecting group based on the desired results.

[0732] Using Method I, in the presence of a base, such as a metal hydride, such as NaH, a metal hydroxide, such as NaOH, an alkoxide of a metal, such as NaOEt, a metal carbanion, such as n-butyllithium, or a metal carbonate, such as K2CO3, in a suitable solvent or solvent system, the alcohol of formula (III) can undergo a substitution reaction with the compound of formula (II). Suitable solvent systems can include a two-phase mixture optionally in the presence of additional heat and the use of a phase transfer catalyst. Method I can also include optional steps of adding and removing protecting groups. For example, removing a protecting group can include converting an ester group to a carboxylic acid. Some embodiments of Method I can include using a catalyst and / or heating to provide the compound of formula (IV).

[0733] In some embodiments, the compound of formula (III) can be described by any one of formulas (IIIA)-(IIIE):

[0734]

[0735] wherein the substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I).

[0736] In some embodiments, the compound of formula (IV) can comprise any one of formulas (IV-A)-(IV-E):

[0737]

[0738] wherein the substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise any one of the foregoing embodiments of formula (I); and wherein R is an optionally substituted group selected from alkyl, alkenyl and alkynyl groups.

[0739] Method II:

[0740]

[0741] Compounds of formula (II) and (V) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The leaving group (LG) present in the compound of formula (II) can, for example, be a mesylate, a tosylate 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 phenyl ring comprising four substituents selected from the following: R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X comprise any one of the aforementioned embodiments of formula (I), and each optionally comprises a protecting group.

[0742] 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, a thiol of formula (V) can be substituted with a compound of formula (II) to form a compound of formula (VI) (step 1). 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 II may also include the optional steps of adding and removing a protecting group. For example, removing a protecting group may include converting an ester group into a carboxylic acid. Some embodiments of method II may include using a catalyst and / or heating to provide a compound of formula (VII).

[0743] The corresponding sulfoxide and sulfone of compound (VI) can be prepared by oxidation of thioether with a suitable oxidant (step 2). Examples of oxidants are meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide (H2O2) and oxone (potassium peroxymonosulfonate). By using 1 equivalent or less of the oxidant, the main product is usually sulfoxide (n = 1). By using an excess of the oxidant, the main product is usually sulfone (n = 2).

[0744] In some embodiments, the compound of formula (V) can be described by any one of formulas (VA)-(VE):

[0745]

[0746] wherein the substituents R1, R2, R3, R4, R5, R6, R7 and X each comprise a group according to any one of the preceding embodiments of formula (I).

[0747] In some embodiments, the compound of formula (VI) may comprise any one of formulas (VI-A)-(VI-E):

[0748]

[0749]

[0750] Wherein the substituents R1, R2, R3, R4, R5, R6, R7 and X each independently comprise any one of the foregoing embodiments of formula (I); and wherein R is an optionally 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 formulae (VII-A)-(VII-E):

[0752]

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

[0754] Method III:

[0755]

[0756] The compounds of formula (VIII) and (IX) are commercially available, or they are known in the literature, or they 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. Ar is a benzene ring containing four substituents selected from: R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X comprise any one 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 the 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 a protecting group 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 the compound of formula (X).

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

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

[0760] Method IV:

[0761]

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

[0763] Method IV represents various cross-coupling reactions, wherein fragments (XI) and (XII) are linked together to form a carbon-carbon bond between the fragments by means of a metal catalyst, for example based on a complex of palladium, copper, iron, cobalt or nickel. These cross-coupling reactions can be carried out under classical or non-classical Heck, Kumada, Negishi, Sonogashira, Stille or Suzuki conditions using methods familiar to those skilled in the art. The technician will be able to select suitable leaving groups (LG 'and E), catalysts and reaction conditions according to the desired result. Method IV may also include the optional step of adding and removing protecting groups. For example, removing protecting groups may include converting ester groups into carboxylic acids. Some embodiments of method IV may include using catalysts and / or heating to provide compounds of formula (XIII).

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

[0765]

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

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

[0768]

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

[0770] Method V:

[0771]

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

[0773] Method V represents a cross-coupling reaction, in which the fragments (XIV) and (XV) are joined 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. The skilled person will be able to select suitable leaving groups (LG and E), catalysts and reaction conditions based on the desired outcome. Method V may also include optional steps of adding and removing protecting groups. For example, removal of a protecting group may include converting an ester group to a carboxylic acid. Some embodiments of Method V may include the use of a catalyst and / or heating to provide the 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) is reacted with a compound of formula R-LG, the compound of formula (XVI) can also be formed, wherein the LG-group can be, for example, trifluoromethanesulfonate or a halogen, such as bromine, chlorine or iodine.

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

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

[0777]

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

[0779] Method VI:

[0780]

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

[0782] Method VI represents a cross-coupling reaction in which two fragments (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 under classical or non-classical Buchwald–Hartwig amination or Chan-Lam coupling conditions using methods familiar to those skilled in the art. The technician will be able to select a suitable leaving group (LG), catalyst, and reaction conditions based on the desired result. Method VI may also include the 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, the compound of formula (XVIII) can be described by the compound of formula (XV), (XV-A), (XV-B), (XV-C), (XV-D), or (XV-E) above.

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

[0785]

[0786] wherein the substituents R1, R2, R3, R4, R5, R6, R7 and X each independently comprise any one of the foregoing embodiments of formula (I); and wherein the R and R'-groups present in the compounds of formula (XVII) can be the same or different and can be, for example, 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 can be the same as R and R', except for H atoms or -COR groups.

[0787] Method VII:

[0788]

[0789] The compounds of formulae (XX) and (XXI) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The R-group present in the compounds of formula (XX) can 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 compounds of formula (XXI) can be, for example, O-trifluoromethanesulfonate (OTf) or a suitable halogen, such as chlorine, bromine or iodine or boric acid. Ar is a benzene ring containing four substituents selected from: R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X comprise any one 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 fragments (XX) and (XXI) are joined 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 the conditions of classical or non-classical Buchwald–Hartwig reactions, Ullman condensations or Chan-Lam couplings. The skilled person will be able to select a suitable leaving group (E), catalyst and reaction conditions based on the desired outcome. Method VII may also include optional steps of adding and removing protecting groups. For example, removal of the protecting group can include converting an ester group to a carboxylic acid. Some embodiments of Method VII may include the use of a catalyst and / or heating to provide the compound of formula (XXII).

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

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

[0793]

[0794]

[0795] Wherein the 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 optionally substituted group selected from alkyl, alkenyl and alkynyl groups.

[0796] Method VIII

[0797]

[0798] The compounds of formulae (XXIII) and (XXIV) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The LG-group present in the compounds of formula (XXIII) can be, for example, a halogen, such as chlorine, or an RCOO-group. R is allyl, alkenyl or aryl. Ar is a benzene ring containing four substituents selected from: R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X comprise any one of the foregoing embodiments of formula (I) and each optionally comprises a protecting group.

[0799] Method VIII represents an electrophilic aromatic substitution reaction in which the fragments (XXIII) and (XXIV) are joined 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 under classical or non-classical Friedel Crafts acylation coupling conditions using methods familiar to those skilled in the art. The skilled person will be able to select a suitable leaving group (LG), catalyst and reaction conditions based on the desired outcome. Method VIII may also include optional steps of adding and removing protecting groups. For example, removal of the protecting group can include converting an ester group to a carboxylic acid. Some embodiments of Method VIII may include the use of a catalyst and / or heating to provide the compound of formula (XXV).

[0800] In some embodiments, the compounds of formula (XXIV) can be described by any one of formulae (XXIV-A)-(XXIV-E):

[0801]

[0802]

[0803] In some embodiments, the compound of formula (XXV) can be described by the compound of formula (XVI), (XVI-A), (XVI-B), (XVI-C), (XVI-D), or (XVI-E) above.

[0804] Method IX

[0805]

[0806] Compounds of formula (XXVI) and (XXVII) are commercially available, or they are known in the literature, or they are prepared by standard methods known in the art. The LG-group present in the compound of formula (XXIII) may, for example, be a halogen, such as chlorine. R is an allyl, alkenyl or aryl. Ar is a phenyl ring comprising four substituents selected from the group consisting of R1, R2, R3, R4 and R5. The substituents R1, R2, R3, R4, R5, R6, R7 and X comprise any one of the aforementioned embodiments of formula (I), and each optionally comprises a protecting group.

[0807] Method IX represents an electrophilic aromatic substitution reaction, wherein fragments (XXIII) and (XXIV) are linked together by means of Lewis acids, for example based on complexes of aluminum, iron, zinc, boron or titanium. These reactions can be carried out under classical or non-classical Friedel Crafts alkylation coupling conditions using methods familiar to those skilled in the art. The technician will be able to select suitable leaving groups (LG), catalysts and reaction conditions based on the desired results. Method IX may also include the optional steps of adding and removing protecting groups. For example, removing protecting groups may include converting an ester group into a carboxylic acid. Some embodiments of method IX may include using a catalyst and / or heating to provide a compound of formula (XXVIII).

[0808] In some embodiments, the compound of formula (XXVII) can be described by the compound of formula (XXIV), (XXIV-A), (XXIV-B), (XXIV-C), (XXIV-D) or (XXIV-E) above.

[0809] In some embodiments, the compound of formula (XXVIII) can be described by the compound of formula (XVI), (XVI-A), (XVI-B), (XVI-C), (XVI-D), or (XVI-E) described above.

[0810] The example section below provides a general scheme and specific but non-limiting examples of the compounds of formula I.

[0811] Synthetic Examples

[0812] The present disclosure may be further described by the following non-limiting examples, where standard techniques known to those skilled in the art and techniques similar to those described in these examples may be used where appropriate. It should be understood that additional embodiments consistent with the disclosure provided herein will be envisioned by those skilled in the art.

[0813] Unless otherwise stated, reactions were carried out at room temperature, typically in the range of 18 - 25 °C, under anhydrous conditions with HPLC grade solvents. Evaporation was carried out by rotary evaporation in vacuo. Column chromatography was carried out on silica gel by a flash procedure. Nuclear magnetic resonance (NMR) shift values were recorded on a Bruker Avance DPX 200 or 300 or on an AVII 400 instrument with the following peak multiplicities as described: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; p, pentuplet; m, multiplet; br, broad. Mass spectra were recorded using a Gl956A mass spectrometer (electrospray, 3000 V) switching between positive and negative ionization modes. The reported yields are illustrative and do not necessarily represent the maximum yields obtainable.

[0814] Example 1: Preparation of 3-butoxy-2-methylbenzoic acid:

[0815]

[0816] Step 1:

[0817] To a solution of 3-hydroxy-2-methylbenzoic acid (0.913 g, 6 mmol) in DMF (30 ml) was added potassium carbonate (3.32 g, 24.00 mmol) and 1-iodobutane (2.05 ml, 18.01 mmol), 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 in vacuo to give 3-butoxy-2-methylbenzoic acid butyl ester (1.55 g, 5.86 mmol, 98% yield) as a solid. MS (electrospray): 287.0 [M+Na]+.

[0818] Step 2:

[0819] To a solution of butyl 3-butoxy-2-methylbenzoate (1.6 g, 6.0 mmol) in THF (10 ml) was added a solution of LiOH·H2O (1.0 g, 23.8 mmol) in H2O (5 ml). 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 1 M HCl. The mixture was extracted with EtOAc (100 ml), the organic phase was washed with brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc w / 5% HCOOH 90 / 10) gave 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 [M - H]-.

[0820] Example 2: Preparation of 3-(hexyloxy)-2-methylbenzoic acid:

[0821]

[0822] Step 1:

[0823] To a solution of 3-hydroxy-2-methylbenzoic acid (0.913 g, 6.00 mmol) in DMF (10 ml) was added K2CO3 (2.49 g, 18.02 mmol) 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 in vacuo to give hexyl 3-(hexyloxy)-2-methylbenzoate (1.92 g, 5.99 mmol, 100% yield).

[0824] Step 2:

[0825] To a solution of hexyl 3-(hexyloxy)-2-methylbenzoate (1.92 g, 5.99 mmol) in THF (20 ml) was added LiOH·H2O (2.1 g, 50.0 mmol) in water (10 ml). The mixture was stirred at room temperature for 2 nights and then at 50 °C for 1 night. The reaction was incomplete. The mixture was concentrated in vacuo, dissolved in dioxane (20.00 ml) and water (20.00 ml), and refluxed for 3 hours. The mixture was cooled, acidified with 6 M HCl (15 ml) and extracted with Et2O (2 x 50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (silica gel, heptane∶EtOAc - 0∶100, 10∶90) gave 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 [M-H]-.

[0826] Example 3: Preparation of 2-methyl-3-octylbenzoic acid:

[0827]

[0828] Step 1:

[0829] At room temperature and under N2 atmosphere, 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bis(1,3,2-dioxaborolane) (5.3 g, 21 mmol), AcOK (6.17 g, 62.9 mmol) and Pd(dppf)Cl2 ([1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloride) (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 at 120 °C overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (300 ml), filtered through a pad of diatomaceous earth 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 in vacuo. Flash chromatography (heptane / EtOAc 98 / 2 - 95 / 5) afforded methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.3 g, 8.3 mmol, 40% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.88 - 7.75 (m, 2H), 7.19 (t, 1H), 3.86 (s, 3H), 2.72 (s, 3H), 1.34 (s, 12H).

[0830] Step 2:

[0831] Under N2 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-dioxaborolan-2-yl)benzoate (0.537 g, 1.943 mmol) in DMF (25 ml). The mixture was stirred at 60 °C overnight and cooled to room temperature. The mixture was diluted with Et2O (150 ml), filtered through a pad of silica which was washed with EtOAc (150 ml). The filtrate was concentrated and flash chromatographed (heptane / EtOAc 99 / 1, 98 / 2) to give methyl 2-methyl-3-octylbenzoate (320 mg, 1.22 mmol, 62.8% yield) as an oil. 1H NMR (400 MHz, CDCl3) 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).

[0832] Step 3:

[0833] Under N2 atmosphere, a solution of LiOH·H2O (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). The mixture was heated at 70 °C for 2 h. The mixture was cooled to room temperature, acidified to pH 1 - 2 with 1 M HCl(aq), and extracted with EtOAc (2 x 50 ml), washed with brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc / HCOOH 90 / 10 / 0.1 - 88 / 12 / 0.1) afforded 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 [M-H]-.

[0834] Example 4: Preparation of (Z)-2-methyl-3-(oct-5-en-1-yl)benzoic acid:

[0835]

[0836] Step 1:

[0837] Under a N2 atmosphere at 0 °C, 4-methylbenzenesulfonyl 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), and then TEA (7.89 g, 78 mmol) was added. The reaction mixture was stirred at 0 °C for 3 h, poured onto ice water (100 ml), and extracted with CH2Cl2 (2 x 100 ml). The combined organic phases were concentrated in vacuo. Pyridine (13 ml) and water (10 ml) were added to the residue, and the mixture was stirred at room temperature for 30 min. Heptane (200 ml) was added, and the organic layer was washed with water (100 ml), 1 M HCl (aq, 100 ml), brine (100 ml), dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (heptane / EtOAc 90 / 10) afforded (Z)-oct-5-en-1-ol 4-methylbenzenesulfonate (8.6 g, 30.5 mmol, 78% yield) as an oil. 1H NMR (300 MHz, CDCl3) 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]+.

[0838] Step 2:

[0839] 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 2 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 in vacuo to give (Z)-8-iodooct-3-ene (1.1 g, 4.6 mmol, 65.2% yield) as an oil. 1H NMR (400 MHz, CDCl3) 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).

[0840] Step 3:

[0841] Under a N2 atmosphere, lithium tert-butoxide (0.464 g, 5.79 mmol), copper(I) iodide (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-dioxaborolan-2-yl)benzoate (0.8 g, 2.9 mmol) in DMF (40 ml). The mixture was stirred at 60 °C overnight 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 flash chromatography (heptane / EtOAc 99 / 1, 98 / 2) to afford methyl (Z)-2-methyl-3-(oct-5-en-1-yl)benzoate (0.3 g, 1.2 mmol, 40% yield) as an oil. MS (electrospray): 283.1 [M+Na]+.

[0842] Step 4:

[0843] Under a N2 atmosphere, a solution of lithium hydroxide monohydrate (366 mg, 8.73 mmol) in water (5 ml) was added to a solution of methyl (Z)-2-methyl-3-(oct-5-en-1-yl)benzoate (284 mg, 1.09 mmol) in EtOH (10 ml). 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), and extracted with EtOAc (2 x 50 ml), washed with brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc / HCOOH 80 / 10 / 0.1), followed by preparative HPLC gave (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 [M-H]-.

[0844] Example 5: Preparation of (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoic acid:

[0845]

[0846] Step 1:

[0847] Under a N2 atmosphere at 0 °C, 4-methylbenzene-1-sulfonyl chloride (19.0 g, 100 mmol) was added to a solution of (Z)-hex-3-en-1-ol (5.0 g, 50 mmol) in CH2Cl2 (50 ml), and then TEA (10.1 g, 100 mmol) was added. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was poured onto ice water (100 ml) and extracted with CH2Cl2 (2 x 100 ml). The combined organic phases were concentrated in vacuo. Pyridine (13 ml) and water (10 ml) were added to the residue, and the mixture was stirred at room temperature for 30 min. 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 in vacuo. Flash chromatography (heptane / EtOAc 90 / 10) afforded (Z)-hex-3-en-1-ol 4-methylbenzenesulfonate (10.8 g, 42.5 mmol, 85% yield) as an oil. 1H NMR (400 MHz, CDCl3) 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): 277.0 [M+Na]+.

[0848] Step 2:

[0849] Under a N2 atmosphere, lithium tert-butoxide (0.298 g, 3.72 mmol), CuI (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-dioxaborolan-2-yl)benzoate (0.77 g, 2.79 mmol) in DMF (35 ml). The reaction mixture was stirred at 60 °C overnight 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 flash chromatography (heptane / EtOAc 100 / 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 1H NMR).

[0850] Step 3:

[0851] Under a N2 atmosphere, a solution of LiOH·H2O (0.472 g, 11.28 mmol) in water (10 ml) was added to a solution of methyl (Z)-3-(hex-3-en-1-yloxy)-2-methylbenzoate (0.35 g, 1.41 mmol) (impure) in ethanol (20 ml). The mixture was stirred at 40 °C overnight. The mixture was cooled to room temperature, acidified to pH ~1 - 2 with 2 M HCl (aq, 3 ml), and extracted with Et2O (2 x 50 ml). Flash chromatography (heptane / EtOAc w / 5% HCOOH 95 / 5 - 90 / 10) gave 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 [M - H]-.

[0852] Example 6: Preparation of (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoic acid:

[0853]

[0854] Step 1:

[0855] 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), and then TEA (7.89 g, 78.0 mmol) was added. 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).

[0856] The combined organic phase was concentrated in vacuo. 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 (aqueous solution, 100 ml), brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc 90 / 10) afforded (Z)-oct-5-en-1-yl 4-methylbenzenesulfonate (8.6 g, 30.5 mmol, 78% yield) as an oil. 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), 3.95 (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]+.

[0857] Step 2:

[0858] Under an N2 atmosphere, LiOtBu (0.290 g, 3.62 mmol), Cul (0.069 g, 0.362 mmol) and (Z)-oct-5-en-1-yl 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-dioxaborolan-2-yl)benzoate (0.75 g, 2.72 mmol) in DMF (30 ml). The reaction mixture was stirred at 60 °C overnight 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 flash chromatography (heptane / EtOAc 100 / 1) to afford 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).

[0859] Step 3:

[0860] Under N2 atmosphere, a solution of LiOH·H2O (267 mg, 6.37 mmol) in water (10 ml) was added to a solution of methyl (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoate (220 mg, 0.796 mmol) in EtOH (25 ml). The mixture was stirred at 40 °C overnight. The mixture was cooled to room temperature, acidified to pH 1 - 2 with 3M HCl (aq, 1 ml), extracted with Et2O (2 x 20 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc w / 5% HCOOH 95 / 5 - 90 / 10) afforded 150 mg of the product. Purification by preparative HPLC gave (Z)-2-methyl-3-(oct-5-en-1-yloxy)benzoic acid (60 mg, 0.228 mmol, 28.6% yield) as 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 [M - H]-.

[0861] Example 7: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (“Compound B”):

[0862]

[0863] Step 1:

[0864] Under a N2 atmosphere at 0 °C, diisopropyl azodicarboxylate (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 minutes, and then 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) was added dropwise. The cooling was removed, and the reaction mixture was stirred overnight at ambient temperature and concentrated in vacuo. Flash chromatography (heptane / EtOAc 97 / 3) afforded 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).

[0865] Step 2:

[0866] Under a N2 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). 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), and extracted with EtOAc (2 x 300 ml), washed with brine (300 ml), dried (Na2SO4), filtered, and concentrated in vacuo to give 14.5 g of a crude product. The crude product was recrystallized from heptane / EtOAc (ca. 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 [M-H]-.

[0867] Example 8: Preparation of 2-methyl-3-(pentyloxy)benzoic acid (“Compound A”):

[0868]

[0869] Step 1:

[0870] Under a N2 atmosphere at 0 °C, diisopropyl azodicarboxylate (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, and then a solution of 1-pentanol (4.9 ml, 45 mmol) and ethyl 3-hydroxy-2-methylbenzoate (8.1 g, 45 mmol) in THF (50 ml) was added dropwise. The cooling was removed, and the reaction mixture was stirred overnight at ambient temperature and concentrated in vacuo. Flash chromatography (heptane / EtOAc - 98 / 2) afforded 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]+.

[0871] Step 2:

[0872] Under a N2 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). The mixture was stirred overnight at room temperature. The mixture was acidified to pH ~ 1 - 2 with 3M HCl(aq) and extracted with EtOAc (2 x 300 ml), washed with water (300 ml) and brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-3-(pentyloxy)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 [M-H]-.

[0873] Example 9: Preparation of (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoic acid:

[0874]

[0875] Step 1:

[0876] Under a N2 atmosphere at 0 °C, diisopropyl azodicarboxylate (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, and then 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) was added dropwise. The cooling was removed, and the yellow reaction mixture was stirred overnight at ambient temperature and concentrated in vacuo. Flash chromatography (heptane / EtOAc 98 / 2 - 95 / 5) afforded ethyl (Z)-2-methyl-4-(pent-2-en-1-yloxy)benzoate (9.5 g, 38.3 mmol, 82% yield) as an oil.

[0877] Step 2:

[0878] Under a N2 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). The mixture was stirred at room temperature for 2 hours. The mixture was acidified to pH ~1 - 2 with 3M HCl(aq) and extracted with EtOAc (2 x 150 ml), washed with water (100 ml) and brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (heptane / EtOAc / HCOOH 90 / 10 / 0.5 - 85 / 15 / 0.5) afforded (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 [M-H]-.

[0879] Example 10: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzamide (“Compound C”):

[0880]

[0881] 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) was added HBTU (4.13 g, 10.90 mmol) and then 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 in vacuo. Flash chromatography (heptane / EtOAc / HCOOH - 65 / 35 / 0.5) afforded (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]+.

[0882] Example 11: Preparation of (Z)-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)methanol:

[0883]

[0884] Under an N2-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 ethyl (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 h. 40 ml of water was added dropwise, and then 1 M HCl (80 ml) was added. The cooling bath was removed, and the reaction mixture was stirred for 5 min. 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. Flash chromatography on silica gel (80 g) eluting with heptane - heptane:EtOAc (90:10) afforded (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]+.

[0885] Example 12: Preparation of (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid:

[0886]

[0887] Step 1:

[0888] 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 stirred under reflux for 60 h. 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 flash chromatography on silica gel (500 g) eluting with heptane - heptane:EtOAc (80:20) afforded methyl 2-(3-hydroxy-2-methylphenyl)acetate (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).

[0889] Step 2:

[0890] Diisopropyl azodicarboxylate (5 ml, 25.4 mmol) was added dropwise to a solution of triphenylphosphine (6.41 g, 24.44 mmol) in dry THF (125 ml) under a N2 atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 35 min, then a solution of methyl 2-(3-hydroxy-2-methylphenyl)acetate (4 g, 22.2 mmol) and cis-4-hept-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. Flash chromatography on silica gel (200 g) eluting with heptane - heptane:EtOAc (98:2) afforded methyl (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]+.

[0891] Step 3:

[0892] To a solution of methyl (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetate (4.15 g, 15.02 mmol) in ethanol (55 mL) was added a solution of lithium hydroxide monohydrate (5.04 g, 120 mmol) in water (55 mL). The reaction mixture was purged with argon and stirred at room temperature for 20 h. 6M HCl was added to pH 1. The mixture was extracted with EtOAc (200 mL x 2), dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography on silica gel (80 g) eluting with heptane - heptane:EtOAc (80:20) afforded (Z)-2-(3-(hept-4-en-1-yloxy)-2-methylphenyl)acetic acid (3.69 g, 13.22 mmol, 88% yield) as an oil which solidified on standing. 1H NMR (300 MHz, CDCl3) δ7.08 (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).

[0893] Example 13: Preparation of (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetic acid:

[0894]

[0895] Step 1:

[0896] Under a nitrogen atmosphere at 0 °C, diisopropyl (E)-azodicarboxylate (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 minutes, and then a solution 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) was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 67.5 hours. The reaction mixture was concentrated under reduced pressure. Flash chromatography on silica gel (80 g) eluting with heptane - heptane:EtOAc (98:2) gave methyl (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetate (3.67 g, 14.78 mmol, 66.6% yield) 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): 271.2 [M+Na]+.

[0897] Step 2:

[0898] A solution of lithium hydroxide monohydrate (4.96 g, 118 mmol) in water (55 ml) was added to a solution of methyl (Z)-2-(2-methyl-3-(pent-2-en-1-yloxy)phenyl)acetate (3.67 g, 14.78 mmol) in ethanol (55 ml). The reaction mixture was flushed with argon and stirred at room temperature for 20 hours. 6M HCl was added to pH 1. The mixture was extracted with MTBE (200 ml x 2), dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography on silica gel (80 g) eluting with heptane - heptane:EtOAc (80:20) gave (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).

[0899] Example 14: Preparation of 2-methyl-3-(pent-2-yn-1-yloxy)benzoic acid:

[0900]

[0901] Step 1:

[0902] Under nitrogen at room temperature, a mixture of 3-hydroxy-2-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) in 5 ml of dimethylformamide was stirred overnight. After transfer 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. After evaporation of the solvent from the pure fractions, 0.33 g of pent-2-yn-1-yl 2-methyl-3-(pent-2-yn-1-yloxy)benzoate was obtained 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]+.

[0903] Step 2:

[0904] To a solution of pent-2-yn-1-yl 2-methyl-3-(pent-2-yn-1-yloxy)benzoate (0.32 g, 1.13 mmol) in 40 ml of 1:1 tetrahydrofuran / water was added lithium hydroxide monohydrate (2.02 g, 48 mmol), 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, then washed with saturated NaCl(aq.) and dried over MgSO4. The solvent was filtered off and removed to give a solid, which was purified by recrystallization from 50 ml of 1:1 methanol / water. The product was filtered off and dried in vacuo 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 [M-H]-.

[0905] Example 15: Preparation of 2-methyl-3-(pentylamino)benzoic acid:

[0906]

[0907] Step 1:

[0908] 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 h, 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, followed by filtration and removal of the solvent under reduced pressure, the crude product was purified on a silica gel column, eluting with 5% ethyl acetate in n-heptane. The pure fractions were combined and the solvent was evaporated under reduced pressure to give 0.31 g of methyl 2-methyl-3-(pentylamino)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]+.

[0909] Step 2:

[0910] Lithium hydroxide monohydrate (1.92 g, 46 mmol) was added to a solution of methyl 2-methyl-3-(pentylamino)benzoate (0.30 g, 1.27 mmol) in 40 ml of 1:1 tetrahydrofuran / water. The mixture was stirred at 60 °C for two days. Due to the slow progress of the reaction, the temperature was raised 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, washed subsequently with saturated NaCl(aq.), and dried over MgSO4. The solvent was removed by filtration and evaporation to give the crude product, which was purified on a silica gel column eluting 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 [M-H]-.

[0911] Example 16: Preparation of 3-(dipentylamino)-2-methylbenzoic acid:

[0912]

[0913] Step 1:

[0914] 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 time, more 1-iodopentane (0.9 ml, 6.9 mmol) was added and the mixture was stirred for an additional 3 h at 100 °C. The mixture was transferred to a separatory funnel with 100 ml of water and extracted with 2 x 100 ml of diethyl ether. The combined organic phases were washed with 50 ml of water and then with 50 ml of saturated NaCl(aq.) twice. After drying over MgSO4, 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-(dipentylamino)-2-methylbenzoate as an 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]+.

[0915] Step 2:

[0916] Lithium hydroxide monohydrate (2.23 g, 53 mmol) was added to a solution of methyl 3-(dipentylamino)-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, washed subsequently with saturated NaCl(aq.), and dried over MgSO4. The solvent was removed by filtration and evaporation to give the crude product, which was purified on a silica gel column eluting with a gradient of 5% to 10% ethyl acetate in n-heptane. The solvent was removed under reduced pressure from the combined pure fractions to give 0.33 g of the title compound as an oil that solidified on 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 [M-H]-.

[0917] Example 17: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid:

[0918]

[0919] Step 1:

[0920] To a solution of 2-ethyl-3-hydroxybenzoic acid (166 mg, 1.0 mmol) in DMF (10 ml) was added potassium carbonate (0.55 g, 4.0 mmol), and then (Z)-1-bromopent-2-ene (0.59 g, 4.0 mmol) was added. The reaction mixture was heated at 90 °C for 1 h. 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-yl 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]+.

[0921] Step 2:

[0922] To a solution of (Z)-pent-2-en-1-yl 2-ethyl-3-(((Z)-pent-2-en-1-yl)oxy)benzoate (300 mg, 0.92 mmol) in ethanol (10 ml) was added 10 M NaOH (10 ml), 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), and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Dry column vacuum chromatography (heptane:EtOAc - 80:20) afforded 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 [M-H]-.

[0923] Example 18: Preparation of (Z)-2,6-dimethyl-4-(pent-2-en-1-yloxy)benzoic acid:

[0924]

[0925] Step 1:

[0926] To a solution of methyl 4-hydroxy-2,6-dimethylbenzoate (100 mg, 0.55 mmol) in DMF (5 ml) was added potassium carbonate (167 mg, 1.22 mmol), and then (Z)-1-bromopent-2-ene (182 mg, 1.22 mmol) was added. The reaction mixture was heated at 90 °C for 1 h. 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.

[0927] Step 2:

[0928] To a solution of methyl (Z)-2,6-dimethyl-4-(pent-2-en-1-yloxy)benzoate (130 mg, 0.52 mmol) in ethanol (10 ml) was added 10 M NaOH (10 ml), 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), and 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 [M-H]-.

[0929] Example 19: Preparation of 2-methyl-6-(pentyloxy)benzoic acid:

[0930]

[0931] Step 1:

[0932] To a solution of ethyl 6-methylsalicylate (0.73 g, 4.05 mmol) in DMF (10 ml) was added potassium carbonate (1.12 g, 8.10 mmol), and then 1-iodopentane (1.0 ml, 8.10 mmol). The reaction mixture was heated at 90 °C overnight. 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-(pentyloxy)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]+.

[0933] Step 2:

[0934] To a solution of ethyl 2-methyl-6-(pentyloxy)benzoate (1.00 g, 3.99 mmol) in THF (10 ml) and water (10 ml) was added LiOH.H2O (0.83 g, 20 mmol), and the reaction mixture was stirred at room temperature. TLC showed no conversion. 5M 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 on a rotary evaporator, 1M 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 0.154 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 [M-H]-.

[0935] Example 20: Preparation of 2-methoxy-6-(pentyloxy)benzoic acid:

[0936]

[0937] Step 1:

[0938] To a solution of methyl 2-hydroxy-6-methoxybenzoate (0.74 g, 4.05 mmol) in DMF (10 ml) was added potassium carbonate (1.12 g, 8.10 mmol) and then 1-iodopentane (1.0 ml, 8.10 mmol). The reaction mixture was heated at 90 °C overnight. 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-(pentyloxy)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]+.

[0939] Step 2:

[0940] To a solution of methyl 2-methoxy-6-(pentyloxy)benzoate (1.00 g, 3.96 mmol) in THF (10 ml) and water (10 ml) was added LiOH.H2O (0.83 g, 20 mmol) and the reaction mixture was stirred at room temperature. TLC showed no conversion. 5M 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 on a rotary evaporator, 1M 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 [M-H]-.

[0941] Example 21: Preparation of 2-methyl-3-(methyl(pentyl)amino)benzoic acid:

[0942]

[0943] Step 1:

[0944] To a solution of methyl 3-amino-2-methylbenzoate (1.00 g, 6.02 mmol) in DMF (16 ml) was added DIPEA (2.3 ml, 13.2 mmol) and methyl iodide (0.83 ml, 13.3 mmol). The reaction mixture was heated at 70 °C for 6.5 h in a sealed vessel and 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. Flash chromatography (heptane:EtOAc 85:15) afforded 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]+.

[0945] Step 2:

[0946] To a solution of methyl 2-methyl-3-(methylamino)benzoate (0.51 g, 2.85 mmol) in DMF (5 ml) was added potassium carbonate (0.47 g, 3.41 mmol), then 1-iodopentane (0.74 ml, 5.7 mmol) was added. The reaction mixture was heated at 100 °C overnight. The reaction was slow. To this end, a fresh batch of 1-iodopentane (0.7 ml and 1 ml) was added over two hours and heating was continued for 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 in ethanol (10 ml) and 5 M NaOH (10 ml) at 100 °C for 1 h. After removal of ethanol, 1 M 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) afforded 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 [M-H]-.

[0947] Example 22: Preparation of potassium 2-methyl-3-(pentyloxy)benzoate:

[0948]

[0949] Under sonication, potassium hydroxide (0.33 g, 5 mmol) was dissolved in ethanol (abs. 30 ml). 2-Methyl-3-(pentyloxy)benzoic acid (1.11 g, 5 mmol) was added to the solution, and the resulting solution was stirred for 2 h and then evaporated to dryness. The product potassium salt was redissolved in water (10 ml) and lyophilized 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). 13C NMR (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.

[0950] Example 23: Preparation of sodium 2-methyl-3-(pentyloxy)benzoate:

[0951]

[0952] Under sonication, sodium hydroxide (0.20 g, 5 mmol) was dissolved in ethanol (abs. 20 ml). 2-Methyl-3-(pentyloxy)benzoic acid (1.11 g, 5 mmol) was added to the solution, and the resulting solution was stirred for 2 h and then evaporated to dryness. The product sodium salt was suspended in water (10 ml) and lyophilized 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.

[0953] Example 24: Preparation of 3-((5-hydroxypentyl)oxy)-2-methylbenzoic acid:

[0954]

[0955] To a solution of 3-hydroxy-2-methylbenzoic acid (1.52 g, 10.0 mmol) in DMF (20 ml) was added potassium carbonate (3.00 g, 22.0 mmol) and potassium iodide (1.6 g, 10 mmol). Then 5-bromoamyl acetate (4.60 g, 22.0 mmol) was added. The reaction mixture was heated at 100 °C overnight. 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 in ethanol (10 ml) and 5 M NaOH (10 ml) at 100 °C for 1.5 h. Flash 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 [M-H]-.

[0956] Example 25: Preparation of 3-(pentyloxy)-2-(trifluoromethyl)benzoic acid:

[0957]

[0958] Step 1:

[0959] Under a nitrogen atmosphere, boron tribromide (2 ml, 21 mmol) was added to a cold suspension of 3-methoxy-(2-trifluoromethyl)benzoic acid (0.51 g, 2.3 mmol) in 10 ml of dichloromethane. After reacting for 2 hours, the reaction was carefully quenched by dropwise addition of 5 ml of water. The mixture was transferred to a separatory funnel with 50 ml of water, and the acidic intermediate was extracted twice with 50 ml of ethyl acetate. Subsequently, the combined organic phases were washed with 50 ml of saturated NaCl(aq.), dried over magnesium sulfate. After filtration and removal of the solvent under reduced pressure, the crude acid intermediate was dissolved in 10 ml of dimethylformamide, and then potassium carbonate (1.06 g, 7.67 mmol) and 1-iodopentane (0.71 ml, 5.4 mmol) were added. The formation of the product was observed by TLC at room temperature for 1 hour, and complete conversion was achieved by slowly heating to 50 °C for an additional 1 hour. The reaction mixture was transferred to a separatory funnel with 100 ml of water and extracted twice with ether. The combined organic phases were washed twice with 50 ml of water and then 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, eluted with 95:5 n-heptane / ethyl acetate, and after removal of the solvent, 0.40 g of pentyl 3-(pentyloxy)-2-(trifluoromethyl)benzoate (50% over two steps) was obtained. 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 (“base peak”).

[0960] Step 2:

[0961] To a solution of pentyl 3-(pentyloxy)-2-(trifluoromethyl)benzoate (0.20 g, 0.58 mmol) in 10 ml of abs. ethanol was added 10 ml of 10 M potassium hydroxide (aq.). After refluxing for 2.5 h, 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 then dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure to give the crude product as a solid. Purification on a silica gel column with 40:60 n-heptane / ethyl acetate gradient elution gave 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 [M-H]-.

[0962] Example 26: Preparation of magnesium 2-methyl-3-(pentyloxy)benzoate:

[0963]

[0964] To a solution of 2-methyl-3-(pentyloxy)benzoic acid (111 mg, 0.50 mmol) in ethanol (abs. 50 ml) and water (50 ml) was added magnesium hydroxide (15 mg, 0.25 mmol). 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.

[0965] Example 27: Preparation of 2-Methyl-3-valeramidobenzoic Acid:

[0966]

[0967] Step 1:

[0968] 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), and then valeryl chloride (0.37 ml, 3.15 mmol) was added. The reaction mixture was then stirred at room temperature overnight, 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-valeramidobenzoate 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]+.

[0969] Step 2:

[0970] To a solution of methyl 2-methyl-3-valeramidobenzoate (0.41 g, 1.64 mmol) in ethanol (20 ml) was added 2.5 M NaOH (20 ml), and the reaction mixture was stirred at 95 °C for 30 minutes. After cooling to room temperature, ethanol was removed on a rotary evaporator, 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 [M-H]-.

[0971] Example 28: Preparation of 3-(2-Ethoxyethoxy)-2-methylbenzoic Acid:

[0972]

[0973] Step 1:

[0974] In the presence of 0.5 ml of H2SO4, 3-hydroxy-2-methylbenzoic acid (3.0 g, 19.7 mmol) in methanol (30 ml) was heated at 90 °C overnight. After cooling to room temperature, the methanol was removed on a rotary evaporator 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).

[0975] Step 2:

[0976] To a solution of methyl 3-hydroxy-2-methylbenzoate (0.83 g, 5.00 mmol) in DMF (10 ml) was added potassium carbonate (1.38 g, 10.0 mmol) and potassium iodide (0.83 g, 5.00 mmol) and then 2-bromoethyl ethyl ether (0.7 ml, 6.00 mmol). The reaction mixture was heated at 100 °C with stirring. After 30 minutes, 2-bromoethyl ethyl ether (0.5 ml, 4.3 mmol) was added again and heating was continued for 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) afforded 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]+.

[0977] Step 3:

[0978] To a solution of methyl 3-(2-ethoxyethoxy)-2-methylbenzoate (0.85 g, 3.57 mmol) in ethanol (25 ml) was added 2.5 M NaOH (25 ml), and the reaction mixture was stirred at 95 °C for 15 minutes. After cooling to room temperature, the ethanol was removed on a rotary evaporator, 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 0.73 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 [M-H]-.

[0979] Example 29: Preparation of 2-methyl-3-((5,5,5-trifluoropentyl)oxy)benzoic acid:

[0980]

[0981] Step 1:

[0982] To a solution of methyl 3-hydroxy-2-methylbenzoate (0.50 g, 3.00 mmol) in DMF (10 ml) was added potassium carbonate (0.83 g, 6.00 mmol) and potassium iodide (0.50 g, 3.00 mmol), and then 5-bromo-1,1,1-trifluoropentane (1.00 g, 4.80 mmol) was added. The reaction mixture was heated at 100 °C for 1.5 hours 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) gave 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]+.

[0983] Step 2:

[0984] To a solution of methyl 2-methyl-3-((5,5,5-trifluoropentyl)oxy)benzoate (0.66 g, 2.27 mmol) in ethanol (25 ml) was added 2.5 M NaOH (25 ml), and the reaction mixture was stirred at 95 °C for 30 minutes. After cooling to room temperature, the ethanol was removed on a rotary evaporator, 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 (400 MHz, 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 [M-H]-.

[0985] Example 30: Preparation of magnesium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0986]

[0987] 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 hour 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).

[0988] Example 31: Preparation of (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzyl acetate:

[0989]

[0990] At 0 °C, 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), and then acetyl chloride (85 μl, 1.2 mmol) was added. The ice bath was removed and the reaction mixture was stirred for 1 h. 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]+.

[0991] Example 32: Preparation of calcium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0992]

[0993] 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.

[0994] Example 33: Preparation of potassium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0995]

[0996] Under sonication, potassium hydroxide (0.33 g, 5 mmol) was dissolved in ethanol (abs. 30 ml). To this solution was added (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (1.10 g, 5 mmol), and the mixture was sonicated until completely dissolved. The reaction mixture was stirred for two hours and then evaporated to dryness. The product potassium salt was redissolved in water (10 ml) and freeze-dried overnight to afford 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.

[0997] Example 34: Preparation of sodium (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoate:

[0998]

[0999] Under sonication, sodium hydroxide (0.20 g, 5 mmol) was dissolved in ethanol (abs. 20 ml). To this solution was added (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid (1.10 g, 5 mmol), and the mixture was sonicated until completely dissolved. The reaction mixture was stirred for two hours and then evaporated to dryness. The product sodium salt was redissolved in water (10 ml) and freeze-dried overnight to afford 1.20 g (99% yield) of the title compound as a solid. 1H NMR (400 MHz, 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.

[1000] Example 35: Preparation of 2-methyl-3-(pentylthio)benzoic acid:

[1001]

[1002] Step 1:

[1003] 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 with stirring for 2.5 h. 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 [M-H]-.

[1004] Step 2:

[1005] 3-Amino-2-methylbenzoic acid (0.60 g, 3.96 mmol) was placed in a reaction flask with 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 ethylxanthate (0.63 g, 3.96 mmol) were dissolved in water (2.7 g) and the suspension was heated to 70 °C. Then the pre-formed diazo solution was carefully added and heating was continued for one hour, then sodium hydroxide (0.63 g, 15.8 mmol) in water (1.62 g) was added. The reaction mixture was heated for two hours, cooled and acidified with hydrochloric acid. The precipitated product 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 [M-H]-.

[1006] Step 3:

[1007] At 0 °C, 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), and then iodo-pentane (0.50 ml, 4.00 mmol) was added. The ice bath was removed and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. Flash 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 [M-H]-.

[1008] Example 36: Preparation of 2-methyl-3-(pentylsulfinyl)benzoic acid:

[1009]

[1010] 2-Methyl-3-(pentylthio)benzoic acid (119.1 mg, 0.500 mmol) was dissolved in 10 ml of methanol and cooled in 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, then the ice bath was 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.), then dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by gradient elution on a silica gel column using 75%-100% ethyl acetate in n-heptane. After removal of the solvent from the pure fractions, the title compound was obtained as an oil which solidified on 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 [M-H]-.

[1011] Example 37: Preparation of 2-Methyl-3-(phenylsulfonyl)benzoic Acid:

[1012]

[1013] 2-Methyl-3-(pentylthio)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 in an ice bath, dilute H2SO4(aq.) was added to pH ~ 2, and solid NaHSO3 was added to quench the permanganate. The mixture was transferred to a separatory funnel with an additional 50 ml of water and extracted with 3 x 50 ml of ethyl acetate, acidifying 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 using a silica gel column with a gradient elution of ethyl acetate (50%-100%) in n-heptane. The solvent was removed from the desired fractions 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 (approx. 2 resonances), 17.66, 13.88. MS (ESI, negative ion mode) m / z 269.0 [M-H]-.

[1014] Example 38: Preparation of Calcium 2-Methyl-3-(pentyloxy)benzoate:

[1015]

[1016] Calcium hydroxide (19 mg, 0.25 mmol) was added to a solution of 2-methyl-3-(pentyloxy)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 (101 MHz, 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 not identified due to excessive signal broadening).

[1017] Example 39: Preparation of (Z)-2-methyl-5-(pent-2-en-1-yloxy)benzoic acid:

[1018]

[1019] Step 1:

[1020] 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), and then (Z)-1-bromopent-2-ene (1.93 g, 13.0 mmol) was added. The reaction mixture was heated at 90 °C overnight. 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-yl ester as an oil. MS (ESI, positive ion mode) m / z 311.1 [M+Na]+.

[1021] Step 2:

[1022] To a solution of (Z)-pent-2-en-1-yl 2-methyl-5-(((Z)-pent-2-en-1-yl)oxy)benzoate (500 mg, 1.73 mmol) in ethanol (25 ml) was added 2.5 M NaOH (10 ml) and the reaction mixture was stirred at 95 °C for 40 minutes. 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. Flash chromatography (heptane:EtOAc 70:30) afforded 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 part of the product is in the (E)-configuration). MS (ESI, negative ion mode) m / z 219.1 [M-H]-.

[1023] Example 40: Preparation of 2-methyl-3,5-bis(pentyloxy)benzoic acid:

[1024]

[1025] Step 1:

[1026] 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 - 25 °C by occasional cooling with an ice bath. Stirring was continued for 30 minutes. A solution of 3,5-dihydroxybenzoic acid (10 g, 65.0 mmol) in 38% aq. EtOH (23 ml) was prepared in another flask. 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. This compound (2 g, 7.96 mmol) in MeOH (20 ml), water (1.5 ml) and piperidine (1 ml) was hydrogenated overnight (balloon) 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.

[1027] Step 2:

[1028] To a solution of 3,5-dihydroxy-2-methylbenzoic acid (360 mg, 2.14 mmol) in DMF (10 ml) was added potassium carbonate (1.38 g, 10.0 mmol), and then 1-iodopentane (1.3 ml, 10.5 mmol) was added. The reaction mixture was heated at 90 °C for 9 h. 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 pentyl 2-methyl-3,5-bis(pentyloxy)benzoate as an oil. This compound was dissolved in ethanol (20 ml) and heated with 20 ml of 2.5 M NaOH for 4 h. After cooling to room temperature, the ethanol was removed and 1 M HCl was added. The aqueous phase was extracted with EtOAc (x3), the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography (heptane:EtOAc 70:30) afforded 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 [M-H]-.

[1029] Example 41: Preparation of 5-hexanoyl-2-methylbenzoic acid:

[1030]

[1031] To a solution of 5-bromo-2-methylbenzoic acid (215 mg, 1.00 mmol) in dry THF (10 ml) at -78 °C was added BuLi (2.5 M in hexanes, 0.84 ml, 2.10 mmol). After 5 min, 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 min. 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 flash 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 [M-H]-.

[1032] Biological Examples

[1033] Evaluate the effects of Compound B and Compound A on blood lipids in APOE*3Leiden mice fed a high-fat diet.

[1034] In addition to human apolipoprotein C1 (APOC1), APOE*3Leiden mice also express a variant of human apolipoprotein E3 (APOE3), APOE*3Leiden. APOE*3Leiden mice exhibit elevated plasma cholesterol and triglyceride levels, mainly limited to the VLDL / LDL-sized lipoprotein fraction.

[1035] The study was conducted in APOE*3Leiden mice (13 - 15 weeks old) fed a semi-synthetic high-fat diet (24% fat w / w) and 0.25% cholesterol w / w. After a 4-week acclimation period, the mice were subdivided into groups of 5 mice each and started receiving Compound A, Compound B, or vehicle alone. Compounds B and A were administered at a dose of 0.3 mmol / kg body weight / day via the diet. Sunflower oil (10 ml v / w) was used as the vehicle to facilitate mixing. After 4 weeks of treatment, the mice were euthanized by CO2 asphyxiation and commercially available kits were used to measure plasma cholesterol and triglycerides.

[1036] In a further study as described above, the effects of Compound A, Compound B, and Compound C on triglyceride levels were compared with those of reference compound 1 ((Z)-3-(pent-2-en-1-yloxy)benzoic acid) and reference compound 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.

[1037]

[1038] Evaluate the effects of Compound B and Compound A on blood glucose control and hepatic target gene expression in ob / ob A MLN mice

[1039] When cholesterol (2%) and 40% fat (containing 18% trans fatty acids) and 20% fructose are added to a high-calorie diet (i.e., A MLN diet), ob / ob mice consistently have a tendency to develop fibrosis (liver). Compared with wild-type C57BL / 6 mice (A MLN mice) fed the same diet, ob / ob mice (referred to as "ob / ob A MLN mice") fed the A MLN diet develop steatohepatitis and fibrosis within a shorter time frame (≤12 weeks). ob / ob A MLN mice provide an obesity diet-induced model of NASH that can also be used to study the effects on blood glucose control.

[1040] Thirty male ob / ob mice (5 weeks old) were fed an AMLN diet for 15 weeks and then randomly divided into three groups of 10 mice / group to receive compound B or compound A (both at 0.3 mmol / kg body weight per day) or no treatment (vehicle) for an additional 4 weeks. Hepatic expression of key genes regulating plasma lipid concentration (LDLr), liver fibrosis (col1A1), bile acid transport / re-uptake (Slc51b and Slc10a2), and inflammation (CD68) was evaluated by RNA sequencing at 4 weeks. To evaluate the effects of compound B and compound A on glycemic control, an oral glucose tolerance test (OGTT) was also performed at week 3. 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 effects on body weight.

[1041] Evaluate the effects of compound A and compound B on hepatic steatosis in C57BL / 6 mice fed an oral parenteral nutrition (PN) diet

[1042] Male C57BL / 6 mice, 6 to 8 weeks old at the start of the experiment, were used for all experimental groups. Mice were fed ad libitum a standard rodent chow (caloric composition: 26% protein, 14% fat, 60% carbohydrate) and water, or a parenteral nutrition (PN) solution mimicking the PN diet used in the neonatal intensive care unit. 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), which was administered in a single 50-ml bottle per cage and the mice drank ad libitum. It has been shown that ad libitum PN diet feeding results in hepatic steatosis (a precursor to more severe liver injury) in mice, which provides a model for PNALD. Prince et al., JPEN J Parenter Enteral Nutr., 2014; 38(5): 608-616.

[1043] In the initial experiment, only compound A was tested. The results of this experiment are described in Example 14.

[1044] At the start of the experiment, 6-week-old male C57BL / 6 mice were divided into three groups (10 mice per group). One group was fed ad libitum a standard rodent chow and water. The group fed the standard rodent chow received no additional treatment during the experiment and served as the negative control group. The other two groups were fed the above-described PN diet.

[1045] In two groups receiving PN diet, one group received medium-chain triglyceride oil (MCT) (Nestle TM HealthCare Nutrition, Florham Park, NJ) by gavage at a dose of 7.4 g fat / kg body weight every other day. For the other group, MCT was used as a vehicle for delivering compound A (0.3 mmol / kg body weight per day) by gavage.

[1046] After 19 days of treatment, the livers were obtained, fixed and frozen on dry ice, and then stored at -80 °C for Oil Red O analysis.

[1047] In subsequent experiments, both compound A and compound B were tested at two doses. The results of this experiment are described in Example 15.

[1048] Male C57BL / 6 mice, 6 to 8 weeks old at the start of the experiment, were used in all experimental groups. One group was fed ad libitum with standard rodent chow and water. The group fed with standard rodent chow received no additional treatment during the experiment and served as a negative control group. Another seven groups (ten mice per group) were fed ad libitum with the above PN solution.

[1049] Among the seven groups receiving PN diet, each group received one of the following gavage regimens, once every other day for 19 days:

[1050] (1) Saline: A saline solution administered in an equal volume to the group;

[1051] (2) MCT: Medium-chain triglyceride oil (MCT) (Nestle TM HealthCare Nutrition, Florham Park, NJ), at a dose of 7.4 g fat / kg body weight;

[1052] (3) (commercial fish oil lipid emulsion), at a dose of 2.4 g fat / kg body weight;

[1053] (4) Compound A LOW: Compound A, at a dose of 0.3 mmol / kg body weight per day (diluted in MCT to 0.0375 mmol / ml, resulting in administration of 7.4 g MCT / kg body weight);

[1054] (5) Compound A HI: Compound A, at a dose of 0.6 mmol / kg body weight per day (diluted in MCT to 0.075 mmol / ml, resulting in administration of 7.4 g MCT / kg body weight);

[1055] (6) Compound B LOW: Compound B, at a dose of 0.3 mmol / kg body weight per day (diluted in MCT to 0.0375 mmol / ml, resulting in administration at 7.4 g MCT / kg body weight); and

[1056] (7) Compound B HI: Compound B, at a dose of 0.6 mmol / kg body weight per day (diluted in MCT to 0.075 mmol / ml, resulting in administration at 7.4 g MCT / kg body weight).

[1057] After 19 days of treatment, the organs, including the liver, kidneys, and spleen, were collected and the relative weights between groups were analyzed. The liver was also fixed and frozen on dry ice and then stored at -80 °C for hematoxylin and eosin (H&E) staining analysis and oil red O analysis.

[1058] Evaluate the effect of Compound A on hepatic steatosis in C57BL / 6 mice administered intravenously with saline, or in

[1059] Male C57BL / 6 mice, 6 - 8 weeks old at the start of the experiment, were used for all experiments. One group was fed ad libitum with standard rodent chow and water. Another six groups (10 mice per group) were fed ad libitum with the above - mentioned parenteral nutrition (PN) solution.

[1060] The PN - fed groups received an intravenous injection of saline, or (commercial soy - based lipid emulsion) at a dose of 2.4 g / kg / day every other day via the tail vein and were treated by gavage (every other day) with 0.6 mmol / kg body weight of MCT or Compound A. The intravenous saline was of the same volume as the Intralipid group. The MCT gavage was of the same volume as the Compound A treatment (200 μl). The six experimental PN diet groups are listed below:

[1061] (1) Saline (intravenous) + PN + MCT (gavage)

[1062] (2) (intravenous) + PN + MCT (gavage)

[1063] (3) (intravenous) + PN + MCT (gavage)

[1064] (4) Saline (intravenous) + PN + Compound A (gavage)

[1065] (5) (intravenous) + PN + Compound A (gavage)

[1066] (6) (Intravenous) + PN + Compound A (Gavage)

[1067] Intravenous lipids are used in PN diets as a source of non - protein, non - carbohydrate calories. However, plant - based intravenous lipid emulsions, such as soy - based have been shown to cause parenteral nutrition - associated liver disease (PNALD). Javid et al., J. Pediatr. Surg., 2005; 40:1446 - 1453. Intravenous injection has been shown to reduce hepatic steatosis induced by PN diets in mice. Meisel et al., J. Pediatr. Surg., 2011; 46:666–667.

[1068] Example 1.

[1069] Effect of Compounds B and A (both at 0.3 mmol / kg body weight per day) on post - prandial blood glucose (AUC 0 - 240 minutes) in ob / ob AMLN mice: After 3 weeks of treatment, in response to an oral glucose load, both Compounds B and A significantly reduced total plasma glucose (area under the curve within 0 - 240 minutes) compared to vehicle ( Figure 1 ).

[1070] Example 2.

[1071] Effect of treatment with Compounds B and A (both at 0.3 mmol / kg body weight per day) for 4 weeks on post - prandial blood glucose in ob / ob AMLN mice: After 3 weeks of treatment, in response to an oral glucose load, both Compounds B and A significantly reduced plasma glucose at 30 minutes and 60 minutes compared to vehicle ( Figure 2 ).

[1072] Example 3.

[1073] Effect of treatment with Compounds B and A (both at 0.3 mmol / kg body weight per day) for 4 weeks on fasting insulin in ob / ob AMLN mice: After 4 weeks of treatment, both Compounds B and A (p < 0.05) reduced fasting plasma insulin (area under the curve within 0 - 240 minutes) compared to vehicle ( Figure 3 ).

[1074] Example 4.

[1075] Effect of treatment with Compounds B and A (both at 0.3 mmol / kg body weight per day) for 4 weeks on fasting blood glucose in ob / ob AMLN mice: After 4 weeks of treatment, both Compounds B and A significantly reduced fasting blood glucose (area under the curve within 0 - 240 minutes) compared to vehicle ( Figure 4 ).

[1076] Example 5.

[1077] Effect of 4-week treatment with Compound B and Compound A (both at 0.3 mmol / kg body weight per day) on hepatic collagen 1a1 gene expression in ob / ob AMLN mice: After 4 weeks of treatment, both Compound B and Compound A significantly decreased hepatic expression of Col1a1 (a key gene involved in liver fibrosis) compared to the vehicle ( Figure 5 ).

[1078] Example 6.

[1079] Effect of 4-week treatment with Compound B and Compound A (both at 0.3 mmol / kg body weight per day) on hepatic Slc10a2 gene expression in ob / ob AMLN mice: After 4 weeks of treatment, Compound A significantly decreased hepatic expression of Slc10a2 (encoding the apical sodium-dependent bile acid transporter [ASBT] that regulates the reabsorption of conjugated bile acids in the ileum) compared to the vehicle ( Figure 6 ).

[1080] Example 7.

[1081] Effect of 4-week treatment with Compound B and Compound A (both at 0.3 mmol / kg body weight per day) on hepatic Slc51b gene expression in ob / ob AMLN mice: After 4 weeks of treatment, Compound A significantly decreased hepatic expression of Slc51b (encoding the organic solute transporter β [OSTb] that regulates bile acid reabsorption) compared to the vehicle ( Figure 7 ).

[1082] Example 8.

[1083] Effect of 4-week treatment with Compound B and Compound A (both at 0.3 mmol / kg body weight per day) on hepatic ABCC2 gene expression in ob / ob AMLN mice: After 4 weeks of treatment, Compound A significantly increased hepatic expression of ABCC2 (encoding Mrp2 that regulates the canalicular export of bilirubin) compared to the vehicle ( Figure 8 ).

[1084] Example 9.

[1085] Effect of 4-week treatment with Compound B and Compound A (both at 0.3 mmol / kg body weight per day) on hepatic CYP7A1 gene expression in ob / ob AMLN mice: After 4 weeks of treatment, Compound A decreased hepatic expression of CYP7A1. CYP7A1 is the rate-limiting enzyme in hepatic bile acid synthesis ( Figure 9 ).

[1086] Example 10.

[1087] Effect of 4-week treatment with compound B and compound A (both at 0.3 mmol / kg body weight per day) on hepatic CD68 gene expression in ob / ob AMLN mice: After 4-week treatment, compared to the vehicle, compound A significantly decreased hepatic expression of CD68 (a marker of hepatic macrophages). Figure 10 )

[1088] Example 11.

[1089] Effect of 4-week treatment with compound B and compound A on plasma triglycerides (TG) and total cholesterol in APOE*3Leiden mice fed a high-fat, high-cholesterol diet: After 4-week treatment, compared to the response to the vehicle, both compound B (2 doses) and compound A significantly decreased total plasma cholesterol and TG (Table 1).

[1090] Table 1

[1091]

[1092] **P < 0.01 compared to control, ***P < 0.005 compared to control

[1093] Example 12.

[1094] Effect of 4-week treatment with compound B, compound A, and pioglitazone on relative body weight in ob / ob AMLN mice: After 4-week treatment, pioglitazone (30 mg / kg body weight per day) significantly increased body weight, while compound B had no effect and compound A significantly decreased body weight compared to the vehicle. Figure 11 )

[1095] Example 13.

[1096] Effect of 4-week treatment with compound B and compound A on hepatic low-density lipoprotein receptor (LDLr) gene expression in ob / ob AMLN mice: After 4-week treatment, both compound B and compound A significantly increased hepatic expression of LDLr (a key gene regulating hepatic uptake of plasma atherogenic lipoproteins) compared to the vehicle. Figure 12 )

[1097] Example 14.

[1098] Effect of 19-day oral PN diet in combination with medium-chain triglycerides (MCT) or compound A on hepatic steatosis in C57BL / 6 mice: In isolated liver sections, oil red O staining confirmed that compound A, but not MCT, prevented the development of steatosis induced by the oral PN diet. Figure 13 ) Normal hepatic architecture was observed in both fed and compound A-fed mice.

[1099] Example 15.

[1100] Effect of 19-day oral PN diet in combination with intragastric administration of saline, medium-chain triglyceride (MCT), compound A or compound B on hepatic steatosis in C57BL / 6 mice: In isolated liver sections, it was confirmed by H&E staining that compound A and compound B, but not MCT, prevented the development of steatosis induced by oral PN diet ( Figures 14 - 17 ). Normal hepatic architecture was observed in all mice. Arrows were used to indicate lipid accumulation.

[1101] Body weight, liver / body weight, and spleen / body weight were also analyzed in all groups ( Figure 18 ), which showed that there were no significant differences in body weight, liver / body weight, and spleen / body weight of mice treated with high and low doses of compound A and B compared with the saline group fed with chow or PN.

[1102] Example 16.

[1103] Effect of chow treatment compared with oral PN diet in combination with intravenous saline, or MCT or compound A administered by intragastric gavage on hepatic steatosis in C57BL / 6 mice: As confirmed by H&E staining in isolated liver sections, treatment with compound A prevented the development of steatosis induced by oral PN diet in all groups (intravenous saline, or ). Arrows were used to indicate lipid accumulation. Figures 22 - 25 )

[1104] Oil Red O staining in isolated liver sections also showed that treatment with compound A prevented the development of steatosis in all groups (intravenous saline, or ). Arrows were used to indicate lipid accumulation. Quantitative analysis of lipid accumulation confirmed that compound A prevented the development of steatosis compared with chow-fed controls ( Figures 26 - 29 ). Figure 30 )

[1105] Body weight was analyzed over 19 days ( Figures 19 - 21 ). Standardized body, liver, kidney, and spleen mass values were also analyzed, which showed that these values in mice treated with compound A were not significantly different from those in any other experimental group ( Figures 20 - 21 ).

[1106] Example 17.

[1107] Effect of Compound A on triglyceride levels in APOE*3Leiden mice within 4 weeks of treatment: Compound A significantly reduced triglyceride levels within 4 weeks ( Figure 31 ). Reference Compounds 1 and 2 did affect triglyceride levels.

Claims

1. A compound of formula (I): Wherein · R1 is methyl; · R2 is -O-(C5-C8) alkenyl having 1 double bond and the double bond at the ω-3 position; · R3, R4 and R5 are each a hydrogen atom; · n is 0 or 1; · R6 and R7 are the same or different and are independently selected from a hydrogen atom and methyl; and · X is COOH or when n is 0, X is a carboxamide having the formula C(O)NH2; Or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein · R1 is methyl; · R2 is -O-(C5-C8) alkenyl having 1 double bond and the double bond at the ω-3 position; · R3, R4 and R5 are each a hydrogen atom; · n is 0; and · X is COOH.

3. The compound according to claim 1, wherein X is COOH.

4. The compound according to claim 1, wherein n is 0 and X is COOH.

5. The compound according to claim 1, wherein the compound is · · (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid.

6. The compound according to claim 1, wherein the salt of the compound comprises a cation selected from Li + , Na + , K + , Mg 2+ and Ca 2+ .

7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof Wherein · R1 is methyl; · R2 is -O-(C4-C6) straight-chain alkyl or -O-(C5-C8) alkenyl having 1 double bond and the double bond at the ω-3 position; · R3, R4 and R5 are each a hydrogen atom; · n is 0 or 1; · R6 and R7 are the same or different and are independently selected from a hydrogen atom and methyl; and · X is COOH or when n is 0, X is a carboxamide having the formula C(O)NH2, and · wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient or diluent, or any combination thereof.

8. The pharmaceutical composition according to claim 7, wherein · R1 is methyl; · R2 is -O-(C4-C6) straight-chain alkyl or -O-(C5-C8) alkenyl having 1 double bond and the double bond at the ω-3 position; · R3, R4 and R5 are each a hydrogen atom; · n is 0; and · X is COOH.

9. The pharmaceutical composition according to claim 7, wherein X is COOH.

10. The pharmaceutical composition according to claim 7, wherein n is 0 and X is COOH.

11. The pharmaceutical composition according to claim 7, wherein the compound is (Z)-2-methyl-3-(pent-2-en-1-yloxy)benzoic acid.

12. The pharmaceutical composition according to claim 7, wherein the compound is 2-methyl-3-(pentyloxy)benzoic acid.

13. The pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable salt of the compound is selected from salts comprising a cation selected from Li + , Na + , K + , Mg 2+ , or Ca 2+ .

14. The pharmaceutically acceptable salts of the compound according to claim 7 are selected from: Sodium 2-methyl-3-(pentyloxy)benzoate; Potassium 2-methyl-3-(pentyloxy)benzoate; Magnesium 2-methyl-3-(pentyloxy)benzoate; and Calcium 2-methyl-3-(pentyloxy)benzoate.

15. The pharmaceutical composition according to any one of claims 7 to 14, which further comprises a pharmaceutically acceptable antioxidant.

16. The pharmaceutical composition according to any one of claims 7 to 14, wherein the composition is formulated for oral administration.

17. The pharmaceutical composition according to claim 16, wherein the composition is in the form of a gelatin capsule, a tablet or a sachet.

18. The pharmaceutical composition according to any one of claims 7 to 14, wherein the composition is formulated for parenteral administration.

19. The pharmaceutical composition according to claim 18, wherein the composition is formulated for intravenous administration.

20. The pharmaceutical composition according to any one of claims 7 to 14, which is used as a medicine.

21. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for reducing plasma triglycerides and / or total cholesterol in a subject in need thereof.

22. The use according to claim 21, wherein the subject in need thereof has elevated plasma triglycerides and / or total cholesterol.

23. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for treating a dyslipidemia disorder in a subject in need thereof.

24. The use according to claim 23, wherein the dyslipidemia disorder is hypertriglyceridemia.

25. The use according to claim 23, wherein the dyslipidemia disorder is hypercholesterolemia.

26. The use according to claim 23, wherein the treatment of the dyslipidemia disorder is prophylactic.

27. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for reducing plasma insulin levels in a subject in need thereof.

28. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for reducing fasting plasma insulin levels in a subject in need thereof.

29. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for enhancing glucose tolerance in a subject in need thereof.

30. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for reducing postprandial glucose levels in a subject in need thereof.

31. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for reducing fasting blood glucose levels in a subject in need thereof.

32. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for treating diabetes in a subject in need thereof.

33. The use according to claim 32, wherein the diabetes is type 2 diabetes.

34. The use according to claim 32, wherein the treatment of the diabetes is prophylactic.

35. Use of the pharmaceutical composition according to any one of claims 7 to 14 in the preparation of a medicament for alleviating or preventing weight gain in a subject in need thereof.

36. The use according to claim 35, wherein the subject is an obese or overweight individual.

37. The use according to claim 35, wherein the subject is an individual suffering from metabolic syndrome. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for treating non-alcoholic fatty liver disease in a subject in need thereof.

39. Use according to claim 38, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

40. Use according to claim 39, wherein the treatment of the non-alcoholic steatohepatitis is prophylactic.

41. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for reducing or prophylactically treating the development of liver fibrosis or reducing existing liver fibrosis in a subject in need thereof.

42. Use according to claim 38, wherein the medicament reduces or prophylactically treats the development of liver inflammation or reduces existing liver inflammation.

43. Use according to claim 38, wherein the medicament reduces or prophylactically treats the development of hepatic steatosis or reduces existing hepatic steatosis.

44. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for treating hepatobiliary disorders in a subject in need thereof.

45. Use according to claim 44, wherein the hepatobiliary disorder is sclerosing cholangitis or primary biliary cholangitis.

46. Use according to claim 44, wherein the treatment is prophylactic.

47. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for improving bile salt homeostasis in a subject in need thereof.

48. Use according to claim 44, wherein the medicament improves bile salt homeostasis.

49. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for reducing or prophylactically treating the development of liver inflammation or reducing existing liver inflammation in a hepatobiliary disorder of a subject in need thereof.

50. Use according to claim 49, wherein the hepatobiliary disorder is sclerosing cholangitis or primary biliary cholangitis.

51. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for treating parenteral nutrition-associated liver disease (PNALD) in a subject in need thereof.

52. Use according to claim 51, wherein the treatment is prophylactic.

53. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for improving bile salt homeostasis in PNALD in a subject in need thereof.

54. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for reducing or prophylactically treating the development of hepatic steatosis in PNALD or reducing existing hepatic steatosis in PNALD in a subject in need thereof.

55. Use of a pharmaceutical composition according to any one of claims 7 to 14 for the preparation of a medicament for reducing or prophylactically treating the development of liver inflammation in PNALD or reducing existing liver inflammation in PNALD in a subject in need thereof.

56. Use of a pharmaceutical composition according to any one of claims 7 to 14 in the manufacture of a medicament for reducing or prophylactically treating the development of liver fibrosis in PNALD or reducing existing liver fibrosis in PNALD in a subject in need thereof.

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