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WO2024206117A1 - Benzoic acid derivatives for use in methods of treating intestinal failure-associated liver disease in children - Google Patents

Benzoic acid derivatives for use in methods of treating intestinal failure-associated liver disease in children Download PDF

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Publication number
WO2024206117A1
WO2024206117A1 PCT/US2024/021090 US2024021090W WO2024206117A1 WO 2024206117 A1 WO2024206117 A1 WO 2024206117A1 US 2024021090 W US2024021090 W US 2024021090W WO 2024206117 A1 WO2024206117 A1 WO 2024206117A1
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WIPO (PCT)
Prior art keywords
group
atoms
subject
alkyl group
double bonds
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PCT/US2024/021090
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French (fr)
Inventor
David Alan Fraser
Hilde STEINEGER
Tore Skjaeret
Mark Puder
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Northsea Therapeutics BV
Boston Childrens Hospital
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Northsea Therapeutics BV
Boston Childrens Hospital
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Publication of WO2024206117A1 publication Critical patent/WO2024206117A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the human digestive system begins to form early in gestation, at around 3-4 weeks, but is slow to mature and a normal human diet of solid foods cannot be introduced prior to around 4-6 months of age. Infants therefore exclusively receive nutrition as either breastmilk or a synthetic breastmilk substitute up to this point. However, certain infants are unable to receive adequate nutrition orally. This may be, for example, because of prematurity, illness (such as infection by Group B streptococcus or sepsis), or physical problems such as high or cleft palate that prevent swallowing. In older children that might be normally expected to eat solid foods, oral nutrition may not be tolerated because of illness. Children may also exhibit extreme “picky eating,” which may be caused by sensory issues.
  • PN Parenteral Nutrition
  • Premature neonates are also at high risk from additional conditions such as sepsis and surgical gastrointestinal conditions such as necrotizing enterocolitis (Christensen, R. D. et al, J Perinatol 27, 284– 290 (2007)).
  • the effects of parenteral nutrition are not only significant, but can also be long-lasting.
  • There Attorney Reference: 14622.0007-00304 have been reports of persistent abnormal liver fibrosis and steatosis many years after weaning from PN has been completed (Mutanen A et al., Hepatology, 58(2); 729-738 (2013)).
  • cirrhosis may progress to end-stage liver disease, with death from sepsis or portal hypertension (Nandivada et al op. cit.).
  • the current strategies to treat IFALD include lipid restriction, which carries the risk of essential fatty acid deficiency, or transition to a fish oil lipid emulsion, which has been demonstrated to rescue acute hepatic injury and attenuate the progression of liver disease (Gura et al., Pediatr.; 230: 46-54.e2 (2021); Secor et al., Expert Opin. Drug Saf.; 20: 307-320 (2021)).
  • Intralipid® a lipid emulsion which contains soybean oil.
  • a fish oil (FO) lipid emulsion, Omegaven® has recently been approved by the United States Food and Drug Administration (FDA) for use in children to treat IFALD.
  • Omegaven® is administered in an amount of 1g/kg/day, with a concentration of Omegaven® of 1 g/10 mL. For an average newborn infant weighing 3-4 kg, this results in a volume to be administered of around 30-40 mL per day. It has further been reported that a significant percentage of patients fail therapy; in a study of 182 patients treated with Omegaven®, 14% failed therapy (Nandivada et al.).
  • the present invention relates to methods of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) Attorney Reference: 14622.0007-00304 wherein the subject is a human child. In some embodiments, the child is receiving or has previously received parenteral nutrition.
  • IFAD intestinal failure-associated liver disease
  • the present invention also relates to methods of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a human infant. is receiving or has previously received parenteral nutrition. In some was born less than 140 days prior to initial administration.
  • IFAD intestinal failure-associated liver disease
  • the present invention further relates to methods of treating IFALD in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a pre-term than 37 weeks gestation).
  • the infant is receiving or has received parenteral nutrition.
  • the human pre-term infant was born less than 140 days prior to initial administration.
  • the present invention also relates to methods of treating cholestasis in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof Attorney Reference: 14622.0007-00304 (I) wherein the subject is a human child. In receiving or has previously received parenteral nutrition. In some embodiments, the child is a pre- term infant. Description of the Figures Fig.1. Nutritional outcomes of pre-term piglet model. Piglets in the MCT and Compound A groups received similar amounts of PN (Fig. 1A) and gained similar weight (Fig. 1B).
  • Immunohistochemical staining (DAB, brown) of formalin-fixed paraffin-embedded liver sections was performed for ⁇ SMA (G, H) and cytokeratin 7 (I, J). MCT piglets demonstrate extensive bile pigment (A, arrows) and bile duct proliferation (I), steatosis (A, asterisks; C), and fibrosis indicated by bridging portal-portal and portal-central vein fibrosis (C, arrows). ⁇ SMA staining (G) indicates hepatic stellate cell activation.
  • Compound A piglets demonstrate mild bile pigment (B, arrows), mild bile duct proliferation (B, asterisks; J), minimal fibrotic portal expansion (D, arrows), and minimal ⁇ SMA staining (H).
  • B mild bile pigment
  • B mild bile duct proliferation
  • D minimal fibrotic portal expansion
  • H minimal ⁇ SMA staining
  • ⁇ SMA sections have 1mm reference bars.
  • Cytokeratin 7 sections have 200nm reference bars.
  • MCT piglets compared to Compound A piglets, demonstrated increased oil red O staining and liver triglyceride content consistent with hepatosteatosis (A, B), increased ⁇ SMA (C) and cytokeratin 7 staining (D) consistent with hepatic stellate cell activation and bile duct proliferation, and increased Ishak fibrosis score (E) assessed by a masked pathologist.
  • Attorney Reference: 14622.0007-00304 Ishak fibrosis scores are shown as boxplots for each group with individual scores represented as empty circles. The mean score is presented as a diamond.
  • IFAD intestinal failure-associated liver disease
  • the present invention also relates to methods of treating cholestasis in children, particularly infants, including pre-term infants, by administering a compound of formula (I).
  • the children are receiving parenteral nutrition (PN).
  • the children have previously received parenteral nutrition and have elevated liver biomarkers.
  • Intestinal failure (IF) is defined as decreased gut function to a level less than the minimum necessary for macronutrient and/or water or electrolyte absorption that results in the need for intravenous supplementation (IVS) to maintain health and/or growth.
  • Patients with IF may also have a spectrum of liver diseases, collectively termed IFALD, that includes cholestasis (the reduction or stoppage of bile flow resulting in impaired bile salt homeostasis) with or without progression to cirrhosis, hepatic steatosis, hepatic fibrosis, and gallbladder disease in the setting of prolonged PN use in the absence of other obvious causes.
  • IFALD liver diseases
  • IFALD iFALD-associated liver disease
  • the methods of the invention reduce cholestasis in a subject defined herein.
  • the methods of the invention reduce hepatic steatosis in a subject defined herein.
  • the methods of the invention reduce hepatic fibrosis in a subject defined herein.
  • the methods of the invention reduce cirrhosis in a subject defined herein.
  • the methods of the invention reduce gallbaldder disease in a subject defined herein. In some embodiments, the methods of the invention reduces plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce direct plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce total plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce gamma glutamyl transferase (GGT) levels in a subject defined herein. The methods of the invention may also reduce plasma levels of ALT and/or AST in a subject defined herein. Nutrition markers may also be improved by the methods described herein.
  • the methods of the invention result in weight gain in a subject defined herein.
  • the methods of the invention result in elevated serum albumin levels in a subject defined herein.
  • the methods of the invention result in elevated plasma total protein levels in a subject defined herein.
  • the method is prophylactic.
  • the methods of the invention prophylactically treat the development of cholestasis in a subject defined herein.
  • the methods of the invention prophylactically treat the development of hepatic steatosis in a subject defined herein.
  • the methods of the invention prophylactically treat the development of hepatic fibrosis in a subject defined herein.
  • the methods of the invention prophylactically treat the development of cirrhosis in a subject defined herein. In some embodiments, the methods of the invention prophylactically treat the development of gallbladder disease in a subject defined herein. In some embodiments, the method is therapeutic. Thus, in some embodiments the methods of the invention therapeutically treat cholestasis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat hepatic steatosis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat the development of hepatic fibrosis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat cirrhosis in a subject defined herein.
  • the methods of the invention therapeutically treat gallbladder disease in a subject defined herein.
  • the compounds of formula (I) defined herein are believed to act as anti-inflammatory, anticholestatic and anti-fibrotic agents, and thereby therapeutically and/or prophylactically treat IFALD.
  • Premature neonatal IFALD is characterized by an inflammatory and cholestatic phenotype.
  • the immature liver is poorly able to handle the numerous inflammatory insults in this population including pro-inflammatory lipids and phytosterols, bacterial products from translocation across disrupted intestinal epithelium, and sepsis from necrotizing enterocolitis or central line-associated Attorney Reference: 14622.0007-00304 blood stream infections.
  • the subject is a human child, i.e., a human less than 18 years old.
  • the subject is a human child ranging from the ages of 1 and 18 years old, such as ranging from 2 and 16 years old, 2 and 14 years old, 3 and 12 years old, 2 and 4 years old, 4 and 6 years old, 6 and 8 years old, 8 and 10 years old, 10 and 12 years old.
  • the subject is a human child less than 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 years old. In some embodiments, the subject is a human child that is 1 to 2 years old, 3 to 4 years old, 5 to 6 years old, 7 to 10 years old, 11 to 14 years old, or 15 to 18 years old. In some embodiments, the subject is a human child that is 2 years old or less. In some embodiments, the subject is a human child age 2 to less than 12 years old. In some embodiments, the subject is a human child age 12 to less than 17 years. In some embodiments, the subject is a human infant, i.e., a human 1 year old or less.
  • the infant is 11 months old or less, 10 months old or less, 9 months old or less, 8 months old or less, 7 months old or less, 6 months old or less, 5 months old or less, 4 months old or less, 3 months old or less, 2 months old or less, or 1 month old or less. In some embodiments, the infant is less than 1 month old. In some embodiments, the subject is a human infant born less than about 140 days prior to initial administration of a compound of the invention. Thus, in some embodiments, the subject is a human infant born less than about 120 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 100 days prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than about 80 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 60 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 40 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 20 days prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9. 8, 7, 6, 5, 4, 3, 2, or 1 day prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than six weeks prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than five weeks prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than four weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than three weeks prior to initial Attorney Reference: 14622.0007-00304 administration of a compound of the invention. In some embodiments, the subject is a human infant born less than two weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than one week prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born 1 to 4 weeks, 1 to 3 weeks, 1 to 2 weeks, 2 to 4 weeks, 2 to 3 weeks, or 3 to 4 weeks prior to initial administration of a compound of the invention.
  • the subject is a human infant born less than 6 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 5 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 4 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 3 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 2 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 1 days prior to initial administration of a compound of the invention.
  • Pre-term is defined by the US Center for Disease Control and Prevention (CDC) as when a human infant is born prior to 37 weeks gestation.
  • the CDC further defines infants as children up to 1 year old.
  • child refers to a human less than 18 years old.
  • a fetus is not considered viable until 24 weeks gestation, however recent advances in neonatal care have resulted in successful birth occurring as early as 21 weeks, 1 day gestation.
  • the subject is a pre-term human infant (i.e., born prior to 37 weeks gestation).
  • the subject is a human infant born ranging from: 20 weeks to 36 weeks, 6 days gestation; 21 weeks to 36 weeks, 6 days gestation; 22 weeks to 36 weeks, 6 days gestation; 23 weeks to 36 weeks, 6 days gestation; 24 weeks to 36 weeks, 6 days gestation; 25 weeks to 36 weeks, 6 days gestation; 26 weeks to 36 weeks, 6 days gestation; 27 weeks to 36 weeks, 6 days gestation; 28 weeks to 36 weeks, 6 days gestation; 29 weeks to 36 weeks, 6 days gestation; 30 weeks to 36 weeks, 6 days gestation; 31 weeks to 36 weeks, 6 days gestation; 32 weeks to 36 weeks, 6 days gestation; 33 weeks to 36 weeks, 6 days gestation; 34 weeks to 36 weeks, 6 days gestation; 35 weeks to 36 weeks, 6 days gestation; or 36 weeks to 36 weeks, 6 days gestation.
  • the subject is a human infant born ranging from: 22 to 36 weeks gestation; 23 to 35 weeks gestation; 24 to 34 weeks gestation; 26 to 33 weeks gestation; or 28 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 24 to 33 weeks gestation. In some embodiments, the subject is a pre-term human infant born ranging from 26 to 32 weeks gestation. In some embodiments, the subject is a human infant born ranging from 28 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 29 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 29 to 30 weeks gestation.
  • the subject is a human infant born ranging from 30 to 32 weeks gestation. In some embodiments the subject is a human infant born ranging from 30 to 31 weeks gestation. In some embodiments the subject is a human infant born ranging from 31 to 32 weeks gestation. In some embodiments, the subject is a human infant born ranging from 32 to 33 weeks gestation.
  • Attorney Reference: 14622.0007-00304 the subject is a human child or infant that is receiving parenteral nutrition. In some embodiments, the child or infant received parenteral nutrition prior to administration of a compound of formula (I). In some embodiments, the child or infant receives parenteral nutrition coextensively with administration of a compound of formula (I).
  • the child or infant received parenteral nutrition for 4 weeks, 3 weeks, 2 weeks, or 1 week prior to administration of a compound of formula I. In some embodiments, the child or infant received parenteral nutrition for 6 days, 5 days, 4 day, 3 days, 2 days, or 1 day prior to administration of a compound of formula I. In some embodiments, the subject is a human child that previously received parenteral nutrition. In some embodiments, the subject is no longer receiving parenteral nutrition at the time of administration of a compound of formula (I). In some embodiments, the subject is a human child or infant that previously received parenteral nutrition and has elevated biomarkers of liver injury as compared to a child or infant that has not received parenteral nutrition.
  • GTT gamma glutamyl transferase
  • the child or infant received parenteral nutrition for up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, or up to 10 months. In some embodiments, the child or infant received parenteral nutrition for 1-10 months, 10-20 months, 20-30 months, 30-40 months, 40-60 months, 60-80 months, 80- 100 months, 100-120 montsh, 120-150 months, 150-200 months, or 200-250 months. In some embodiments, a compound of formula (I) is administered for about 1 to 5 weeks. In some embodiments, a compound of formula (I) is administered for 1 to 4 weeks, 1 to 3 weeks, or 1 to 2 weeks.
  • a compound of formula (I) is administered for about 2 to 4 weeks or about 3 to 4 weeks. In some embodiments, a compound of formula (I) is administered for less than 5 weeks, less than 4 weeks, less than 3 weeks, less than 2 weeks, or less than 1 week. In some embodiments, a compound of formula (I) is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks.
  • pharmaceutically acceptable refers to drugs, medicaments, inert ingredients etc., which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which a compound is administered.
  • the pharmaceutically acceptable vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • compositions 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, ethyl alcohol, 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.
  • 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, ethyl alcohol, polyethylene glyco
  • antibacterial and antifungal agents are parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • Isotonic agents may be included in a formulation.
  • isotonic agents include sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • the compounds of formula (I) may be formulated prior to administration into pharmaceutical compositions using available techniques and procedures.
  • the pharmaceutical compositions may be formulated in a manner suitable for administration by topical, oral, intravenous (iv), intramuscular (im), depo-im, subcutaneous (sc), depo-sc, sublingually, intranasal, intrathecal topical or rectal routes.
  • the compound(s) of formula (I) are formulated for sublingual administration.
  • the compound(s) of formula (I) are formulated as sublingual tablets.
  • the compound(s) of formula (I) are formulated as sublingual strips.
  • the compound(s) of formula (I) are formulated as sublingual drops.
  • the compound(s) of formula (I) are formulated as a sublingual spray.
  • the compound(s) of formula (I) can be orally administered or intravenously administered.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of the therapeutic agent in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the compounds of formula (I) and compositions comprising compounds of formula (I) may be formulated in conventional oral administration forms, e.g. tablets, coated tablets, capsules, powders, granulates, solutions, dispersions, suspensions, syrups, emulsions, sprays, etc., using conventional excipients, e.g.
  • antioxidants e.g. tocopherol
  • corn starch lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerol, sorbitol, polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof etc.
  • Conventional formulation techniques well known in the art, may be used.
  • Formulations suitable for oral administration may be in the form of capsules (e.g., hard or soft shell gelatin capsule), cachets, pills, tablets, lozenges, powders, granules, pellets, dragees, e.g., coated (e.g., enteric coated) or uncoated, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • capsules e.g., hard or soft shell gelatin capsule
  • cachets e.g., pills, tablets, lozenges
  • powders granules, pellets, dragees, e.g., coated (e.g., enteric coated) or uncoated, or as a solution or a suspension in
  • a compound of the present invention may also be administered as a bolus, electuary or paste, or incorporated directly into the subject's diet.
  • these pellets can be formulated to (a) provide for instant or rapid drug release (i.e., have no coating on them); (b) be coated, e.g., to provide for sustained drug release over time; or (c) be coated with an enteric coating for better gastrointestinal tolerability. Coating may be achieved by conventional methods, typically with pH or time- dependent coatings, such that the compound(s) of the invention is released in the vicinity of the desired location, or at various times to extend the desired action.
  • Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, and shellac.
  • a compound of the present invention may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Peroral compositions include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically acceptable vehicles suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include Attorney Reference: 14622.0007-00304 methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants.
  • Compounds of formula (I) are preferably administered intravenously for the methods of the invention.
  • Compounds of formula (I) may be admixed with a PN diet.
  • composition suitable for injectable use or for use by infusion may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • Dispersions may be prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Prolonged absorption of injectable compositions may be obtained by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Compositions for injection must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture 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 therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • Compounds according to the present invention may be administered parenterally, intraperitoneally, intraspinally, or intracerebrally.
  • the compound of the invention can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, this preparation may contain a preservative to prevent the growth of microorganisms.
  • Pharmaceutical formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of a compound of formula (I) or a plurality of solid particles of such compound(s). For instance, metal salts of the compounds of formula (I) are expected to have physical chemical properties amenable with the preparation of fine particles of active pharmaceutical ingredient (API) for administration by inhalation but not the free acid form of these compounds.
  • the desired formulation may be placed in a small chamber and nebulized.
  • Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the agents or salts.
  • the liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns.
  • the solid particles can be obtained by processing the solid agent of any Formula described herein, or a salt thereof, in any appropriate manner known in the art, such as by micronization.
  • the size of the solid particles or droplets will be, for example, from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose.
  • a pharmaceutical formulation suitable for administration as an aerosol may be in the form of a liquid, the formulation will comprise a water-soluble agent of a compound of formula (I) described herein, or a salt thereof, in a carrier which comprises water.
  • a surfactant may be present which lowers the surface tension of the formulation Attorney Reference: 14622.0007-00304 sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization.
  • the compositions comprising compounds of formula (I) may also be administered topically to a subject, e.g., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a “patch”.
  • compositions include, for example, lotions, creams, solutions, gels, emulsions and solids.
  • These topical compositions may comprise an effective amount, usually about 0.01% to about 10% (w/w), or from about 0.1% to about 5% (w/w), or from about 1% to about 5% (w/w), of a compound of formula (I).
  • Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of with dispersed or dissolved therein the therapeutic agent.
  • the carrier may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents and the like.
  • the carrier may include vernix.
  • Topical formulation includes one or more excipients such as, but not limited to, protectives, adsorbents, demulcents, emollients, preservatives, antioxidants, moisturizers, buffering agents, solubilizing agents, skin-penetration agents, and surfactants.
  • Suitable protectives and adsorbents include, but are not limited to, dusting powders, zinc sterate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide.
  • Suitable demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.
  • Suitable emollients include, but are not limited to, animal and vegetable fats and oils, myristyl alcohol, alum, and aluminum acetate.
  • Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.
  • quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride
  • mercurial agents such as phenylmercuric nitrate, phenyl
  • Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
  • Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol.
  • Suitable buffering agents for use with the invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers.
  • Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
  • Suitable skin-penetration agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N- decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate); and N-methylpyrrolidone.
  • compositions useful for attaining systemic delivery of the subject agents may include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents may also be included.
  • a suitable daily dosage of the compound of formula (I) may range from about 5 mg to about 2 g per kg of body weight, such as from about 25 mg to about 1 g per kg of body weight.
  • the daily dose ranges from about 10 mg to about 1 g per kg of body weight, from about 25 mg to about 750 mg per kg of body weight, from about 30 mg to about 600 mg per kg of body weight, from about 35 mg to about 500 mg per kg of body weight, from about 40 mg to about 300 mg per kg of body weight, from about 45 mg to about 250 mg per kg of body weight, from about 50 mg to about 200 mg per kg of body weight, from about 20 to about 100 mg per kg of body weight, or from about 25 to about 75 mg per kg of body weight.
  • the daily dose ranges from about 600 mg to 1.5 g, from about 700 mg to about 1.4 g, from about 800 mg to about 1.3 g, from about 900 mg to about 1.2 g, from about 700 mg to about 1.2 g, from about 800 mg to about 1.1 g, from about 900 mg to about 1 g, from about 700 mg to about 900 mg, from about 700 mg to about 800 mg, from about 800 mg to about 1 g, from about 800 mg to about 900 mg, from about 900 mg to about 1 g. In at least one embodiment, the daily dose ranges from about 30 mg to about 70 mg per kg of body weight.
  • 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, about 900 mg, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, or about 1.5 g per
  • the compound(s) may be administered, for example, once, twice, or three times per day.
  • the compound of formula (I) is administered as an infusion.
  • the compound of formula (I) is administered in an amount ranging from about 20 mg to about 300 mg per dose.
  • the compound of formula (I) is administered in an amount ranging from about 25 mg to about 100 mg per kg of body weight.
  • the compound of formula (I) is administered once per day.
  • the dose may be provided in one dose per day or in multiple doses per day. For example, a daily dosage may be provided in two doses per day, three doses per day, or four doses per day.
  • a daily dosage is provided in a single dose per day.
  • Attorney Reference: 14622.0007-00304 the dose may not be administered every day.
  • the dose may be administered every other day, every three days, every four days, twice per week, or once per week.
  • the compound of formula (I) is administered intravenously at a dose of 30 mg per kg of body weight per day.
  • the compound of formula (I) is administered intravenously at a dose of 40 mg per kg of body weight.
  • the compound of formula (I) is administered intravenously at a dose of 50 mg per kg of body weight per day.
  • the compound of formula (I) is administered intravenously at a dose of 75 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 150 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 250 mg per kg of body weight per day.
  • the compound of formula (I) is administered intravenously at a dose of 300 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 800 mg per kg of body weight per day.
  • the compound of formula (I) is administered intravenously at a dose of 900 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.3 g per kg of body weight per day.
  • the compound of formula (I) is administered intravenously at a dose of 1.4 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.5 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 30 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 40 mg per kg of body weight. In some embodiments, the compound of formula (I) is administered orally at a dose of 50 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 75 mg per kg of body weight per day.
  • the compound of formula (I) is administered orally once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 150 mg per kg Attorney Reference: 14622.0007-00304 of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 250 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 300 mg per kg of body weight per day.
  • the compound of formula (I) is administered orally at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 800 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 900 mg per kg of body weight per day.
  • the compound of formula (I) is administered orally at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.3 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.4 g per kg of body weight per day.
  • the compound of formula (I) is administered orally at a dose of 1.5 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 30 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 40 mg per kg of body weight. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 50 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 75 mg per kg of body weight per day.
  • the compound of formula (I) is administered sublingually once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 150 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 250 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 300 mg per kg of body weight per day.
  • the compound of formula (I) is administered sublingually at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is Attorney Reference: 14622.0007-00304 administered sublingually at a dose of 800 mg per kg of body weight per day.
  • the compound of formula (I) is administered orally at a dose of 900 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.3 g per kg of body weight per day.
  • the compound of formula (I) is administered sublingually at a dose of 1.4 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.5 g per kg of body weight per day. D.
  • 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group; • R2 is a C4-C12 alkyl group, a C1-C12 hydroxyalkyl group, a C1-C12 haloalkyl
  • 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 is a heteroatom, or a phenyl group.
  • R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms of which 1 - 2 are heteroatoms, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalken
  • R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group. In some embodiments, R1 is chosen from a methyl group, an ethyl group, an isopropyl group, a -CF3 group, a -(CH2)3OH group, and a phenyl group.
  • R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalken
  • R1 is a C1-C3 alkyl group or a C1-C3 hydroxyalkyl group.
  • R2 is a C4-C9 alkyl 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, an -O-(C3-C8) alkyl group, O-(C3-C8) Attorney Reference: 14622.0007-00304 hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8
  • R1 is a C1-C2 alkyl group or a C1-C2 hydroxyalkyl group.
  • R2 is a C4-C9 alkyl 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, an -O-(C3-C8) alkyl group, O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1
  • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an - O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position.
  • R1 is a C1-C2 alkyl group or a C1-C2 hydroxyalkyl group and R2 is a C5- C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an -O-(C4-C6) alkyl group, an -O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O-heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) alkenyl group having 1 double bond.
  • R1 is a methyl group or an ethyl group and R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an -O-(C4-C6) straight chain alkyl group, an - O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O-heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) alkenyl group having 1 double bond.
  • R1 is a methyl group or an ethyl group and R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an - O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond.
  • R1 is a methyl group and R2 is a C5-C8 straight chain alkyl group, a C6- C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ - 3 position.
  • the double bond is in the Z configuration.
  • Attorney Reference: 14622.0007-00304 In some embodiments, R1 is a methyl group.
  • R2 is an -O-(C3-C8) alkyl group and may have the formula -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17.
  • R2 is a -S-(C3-C8) alkyl group and may have the formula -SC3H7, -SC4H9, -SC5H11, - SC6H13, -SC7H15, or -SC8H17.
  • R3, R4, and R5 are each a hydrogen atom.
  • R5 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 atom is a heteroatom.
  • one or more of R3, R4, and R5 is a halogen atom.
  • one or more of R2, R3, and R4 is a fluorine atom.
  • R3 and R5 are each a hydrogen atom and R4 is a fluorine atom.
  • m is 0. In other embodiments, m is 1.
  • 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 chosen 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 0. In some embodiments X is a carboxylic acid, a carboxamide, a hydroxymethyl, or a carboxylic ester such as an acetate group.
  • 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. 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 chosen 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.
  • n is 1 or 2 and X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, or a carboxylic ester such as an acetate group.
  • n is 1 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C2 alkyl group.
  • n is 1 and R6 and R7 are both hydrogen atoms.
  • n is 1 and R6 and R7 are both methyl groups.
  • R6 is a methyl group and R7 is a hydrogen.
  • n is 1, R6 and R7 are both hydrogen atoms
  • X is a carboxylic acid.
  • n is 1, R6 and R7 are both methyl groups, and X is a carboxylic acid.
  • X may be chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group.
  • R1 is a methyl group or an ethyl group
  • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ -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 independently chosen from a hydrogen atom and a methyl group
  • • and X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group.
  • R1 is a methyl group
  • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position
  • • R3, R4, and R5 are each a hydrogen atom
  • • n is 0
  • • and X is a carboxylic acid.
  • R1 is a methyl group
  • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position
  • • R3, R4, and R5 are each a hydrogen atom
  • • n is 1
  • • R6 and R7 are each a hydrogen atom • and X is carboxylic acid.
  • compounds of formula (I) described by group (2) are described by formulas (IB-1), (IB-2), (IB-3), or (IB-4): Attorney Reference: 14622.0007-00304 3), wherein (2); and • X1 is a halogen atom; • a is 0 or 1; • Z’ is H or a C1-C4 alkyl group; • R1 is a C1-C4 alkyl group; • R1 is a methyl group or an ethyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ⁇ -3 position; • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C
  • R1 is a C1-C2 alkyl group or an -O-(C1-C2) alkyl group.
  • R5 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an - O-(C4-C6) alkyl group, an -O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O- heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) Attorney Reference: 14622.0007-00304 alkenyl group having 1 double bond.
  • the double bond is in the ⁇ -3 position. In some embodiments the double bond is in Z configuration. In some embodiments, Z’ is H. In some embodiments Z’ is a methyl or ethyl group.
  • R6 and R7 are the same or different and are independently chosen 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.
  • R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalken
  • the compounds of formula (I) may be used in the present methods in pharmaceutically acceptable salt form.
  • Such salts may be represented by wherein X is COO-, and Z+ K+, Mg2+, or Ca2+; a protonated primary amine such as tert-butyl ammonium, (3S,5S,7S)-adamantan-1-ammonium, 1,3-dihydroxy-2- (hydroxymethyl)propan-2-ammonium, a protonated aminopyridine (e.g., pyridine-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- ium, a quaternary amine such as 2-hydroxy-N,N,N-trimethylethan-1-aminium and a protonated
  • X COO-
  • diamine such as ethane-1,2- diammonium or piperazine-
  • pharmaceutically acceptable salts are also described, for example, in Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor).
  • Certain compounds of formula (I) may exist in Zwitterionic form and the present invention includes Zwitterionic forms of these compounds and mixtures thereof.
  • the present methods may also utilize prodrugs of the compound of formula (I).
  • produgs includes the pharmaceutically acceptable esters or amides obtained upon reaction of alcohols or amines, including amino acids, with the free acids defined by formula I.
  • the compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof. Hence, compounds of formula (I) that exist as diastereomers, racemates, and enantiomers are included within the scope of the present disclosure. It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that methods of the invention may utilize all such solvated forms which possess biological activity.
  • the alkyl group may be chosen 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.
  • Alkenyl refers to a straight chain or branched chain alkenyl group.
  • the alkenyl group may be chosen from allyl, 2-butenyl, 3-hexenyl, 4-heptenyl, 5-octenyl, and 6-nonenyl.
  • the alkenyl group has 1 double bond.
  • the alkenyl group has 2 double bonds.
  • the alkenyl group has 3 double bonds.
  • the alkenyl group has an ⁇ -3 double bond.
  • the alkenyl group has 1 double bond and it is in the ⁇ -3 position.
  • the alkenyl group is a C4-C9 straight chain alkenyl group having 1 double bond at the ⁇ -3 position.
  • the double bond is in Z configuration.
  • the alkenyl group has 1-3 double bonds and each double bond is in Z configuration.
  • the alkenyl group is a C5-C9 straight chain alkenyl group having 1 double bond in the ⁇ -3 position and it is in Z configuration.
  • the alkenyl group is a C5 straight chain alkenyl group having 1 double bond at the ⁇ -3 position.
  • the alkenyl group is a C6 straight chain alkenyl group having 1 double bond at the ⁇ -3 position.
  • the alkenyl group is a C7 straight chain alkenyl Attorney Reference: 14622.0007-00304 group having 1 double bond at the ⁇ -3 position.
  • the alkenyl group is a C8 straight chain alkenyl group having 1 double bond at the ⁇ -3 position.
  • the double bond is in Z configuration.
  • Alkynyl refers to a straight chain or branched chain alkynyl group.
  • the alkynyl group may be chosen from a C4-C12 alkynyl group having 1-3 triple bonds.
  • the alkynyl group has 1 triple bond.
  • the alkynyl group may be chosen from a C5- C10 alkynyl group having 1 triple bond.
  • the triple bond is in the ⁇ -3 position.
  • Hydroxyalkyl refers to a hydroxy derivative of a straight chain or branched chain alkyl group.
  • the hydroxyalkyl group may be chosen from a C1-C12 hydroxyalkyl group, a C2-C11 hydroxyalkyl group, a C1-C6 hydroxyalkyl group, or a C1-C4 hydroxyalkyl group.
  • the hydroxyalkyl group may be chosen from a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, or a hydroxybutyl group.
  • Heteroalkyl' refers to a straight chain or branched chain alkyl group, containing one or more heteroatoms selected from S, O and N, where the alkyl chain optionally may contain one or more hydroxy groups, one or more halogen atoms and/or a carbonyl group.
  • a heteroalkyl group cannot contain a heteroatom in the first position of the chain with respect to the aromatic ring.
  • a group with the formula -OC6H13 is not a heteroalkyl group under this definition.
  • a hydroxyalkyl group is not considered a heteroalkyl group under this definition.
  • a group with the formula -C6H12OH is not a heteroalkyl group under this definition.
  • a group with the formula -C4H8OC2H4OH is considered a heteroalkyl group having 7 atoms, of which 1 is a heteroatom (oxygen), and further containing a hydroxy group.
  • the heteroalkyl group has 3-12 atoms.
  • the heteroalkyl group has 3-9 atoms.
  • the heteroalkyl group has 4-8 atoms.
  • the heteroalkyl group has 5 or 6 atoms.
  • the heteroalkyl group has 1-3 heteroatoms.
  • the heteroalkyl group has 3-9 atoms of which 1-3 are heteroatoms.
  • the heteroalkyl group has 4-8 atoms of which 1 is a heteroatom. In some embodiments, the heteroatom is in the second position of the heteroalkyl group. In some embodiments, the heteroatom is in the third position of the heteroalkyl group. In some embodiments, the heteroatom is in the fourth position of the heteroalkyl group. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulphur.
  • the formula of the heteroalkyl group may be chosen from -CH2OC4H9, -C2H4OC3H7, -C2H4OC2H3, -C3H6OCH3, -CH2OC5H11, -CH2OC3H7, -C2H4OC3H7, -C3H6OC2H7.
  • An ‘alkyl-Y-’ group is a heteroalkyl group having 1 heteroatom in the ⁇ position with respect to the aromatic ring. Y may be chosen from an oxygen atom, a sulphur atom, and a NR12NR13 group, wherein R12 and R13 are independently chosen from a hydrogen group and C1-C4 group.
  • Y may be oxygen.
  • a C4 alkyl-Y- group has the formula -OC4H9 or - Attorney Reference: 14622.0007-00304 SC4H9.
  • a C5 alkyl-Y- group has the formula -OC5H11 or -SC5H11.
  • a C6 alkyl-Y-group has the formula -OC6H13 or -SC6H13.
  • Heteroalkenyl' refers to a straight chain or branched chain alkenyl group, containing one or more heteroatoms selected from S, O and N in the main chain, where the alkenyl chain optionally may contain hydroxy groups, halogen atoms and/or a carbonyl group.
  • the heteroatom is a sulphur.
  • the heteroatom is an oxygen.
  • the alkenyl group has 2 double bonds.
  • the alkenyl group has 3 double bonds.
  • the alkenyl group has an ⁇ -3 double bond.
  • the alkenyl group has 1 double bond and it is in the ⁇ -3 position.
  • the heteroalkenyl group has 3-9 atoms of which 1 atom is a heteroatom and 1 double bond. In some embodiments, the heteroalkenyl group has 6-9 atoms of which 1 atom is a heteroatom and 1 double bond, wherein the heteroatom is an oxygen, and wherein the double bond is in the ⁇ -3 position. In some embodiments, the double bond is in Z configuration.
  • the heteroatom cannot be in the first or last position of the heteroalkenyl group.
  • a heteroalkenyl group cannot contain a heteroatom in the first position of the chain with respect to the aromatic ring.
  • Haloalkyl refers to a straight chain or branched chain alkyl group, in which one or more hydrogen atoms have been substituted by a halogen atom.
  • the halogen atom may be chosen from fluorine, chlorine, bromine, and iodine.
  • the halogen atom is F.
  • the haloalkyl group contains a -CF3 group.
  • a haloalkyl group may also be a heteroalkyl group.
  • the haloalkyl may be a heteroalkyl group having 6-9 atoms of which 1-3 atoms are heteroatoms.
  • the haloalkyl group is a heteroalkyl group having 1 heteroatom.
  • the heteroatom is an oxygen atom.
  • the halogen atom is fluorine.
  • Haloalkenyl refers to a straight chain or branched chain alkenyl group, in which one or more hydrogen atoms have been substituted by a halogen atom.
  • the halogen atom may be chosen from fluorine, chlorine, bromine, and iodine.
  • a haloalkenyl group may also be a heteroalkenyl group.
  • X is a carboxylic acid.
  • X is a carboxylic acid derivative.
  • X may be chosen from a carboxylate, a glyceride, an anhydride, a carboxamide, and a phospholipid.
  • X is a carboxylate such as a carboxylic ester.
  • X is a carboxylic ester such as an acetate group.
  • X is a glyceride and, in some embodiments, the glyceride may be in the form of a triglyceride, a 1,2-diglyceride, a 1,3 diglyceride, a 1-monoglyceride, or a 2-monoglyceride.
  • X is an anhydride.
  • X is a carboxamide and, in some embodiments, the carboxamide may be chosen from N- methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide and N,N-diethyl carboxamide.
  • X is a phospholipid Attorney Reference: 14622.0007-00304
  • n is 0.
  • X is a carboxylic acid, a carboxamide, or a hydroxymethyl.
  • n is 0 and X is a carboxylic acid.
  • n is 0 and X is a carboxamide having the formula -C(O)NH2.
  • n is 0 and X is a hydroxymethyl. 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 chosen 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 chosen from a hydroxymethyl group, a carboxylic acid, a carboxylic ester, or a carboxamide.
  • n is 1 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C2 alkyl group. In some embodiments, n is 1 and R6 and R7 are both hydrogen atoms. In some embodiments, n is 1 and R6 and R7 are both methyl groups. In some embodiments, R6 is a methyl group and R7 is a hydrogen. In some embodiments, n is 1, R6 and R7 are both hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1, R6 and R7 are both methyl groups, and X is a carboxylic acid.
  • n is 1, R6 and R7 are both hydrogen atoms, and X is an acetate group.
  • X may be chosen from a hydroxymethyl group, a carboxylic acid, a carboxylic ester, and a carboxamide.
  • a “pharmaceutically active amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e. an amount of the combination product which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the combination product is within the skill of the art.
  • the dosage regimen for treating a condition with the combination product of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient.
  • “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 may be therapeutic in respect to an existing condition or it may be prophylactic, i.e., preventative. As used herein, “pre-term” or “premature” refers to a human infant born prior to 37 weeks gestation.
  • Preterm Yorkshire piglets were delivered, central venous catheters were placed, and parenteral nutrition was provided for 14 days. Animals were treated with either medium chain triglycerides (MCT) vehicle control or a compound of formula (I). Preparation and Monitoring of Animals The study protocol and procedures were approved by the Institutional Animal Care and Use Committee at Boston Children's Hospital, and the study was conducted in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals. Pregnant Yorkshire sows were obtained (Parsons Pig Farm, Hadley, MA) and piglets were delivered at four (Litter 1) or five (Litter 2) days preterm (112- or 111-days gestation respectively) via caesarean section.
  • MCT medium chain triglycerides
  • a femoral central venous catheter was inserted.500 ml of blood was collected into a blood bag containing citrate phosphate double dextrose (CP2D) solution (Haemonetics, Braintree, MA) and centrifuged to obtain plasma. Following this, a lower midline incision was made. One horn of the uterus was exteriorized and incised with electrocautery over the back of a piglet. The piglet was delivered from the uterus, oropharynx suctioned, umbilical cord ligated and divided, and handed off the surgical field for resuscitation. Subsequent piglets were delivered in this fashion.
  • C2D citrate phosphate double dextrose
  • piglets were dried, vigorously stimulated, warmed, and administered doxepram (0.2 ml), atropine (0.2 ml), and vitamin B12 (0.5 ml) via intramuscular injection. If necessary, ventilation and supplemental oxygen was provided via bag-valve mask. When necessary, additional doses were administered of epinephrine for bradycardia or doxepram for hypoventilation. Piglets were then placed in a warmed and humified incubator. After adequate resuscitation, piglets were induced and intubated. 3Fr central venous catheters were placed preferentially in the right external jugular vein.
  • Table 1 Total Parenteral Nutrition Composition (Per Litre) Component Quantity Amino Acids 64 g The volume of com p ys of life to the target volume of 125 ml/kg/day, see Fig. 1A and Table 2 below. Piglets were monitored for signs of TPN intolerance including hyperglycaemia, and evidence of dehydration such as lethargy. If there was concern for TPN intolerance, piglets were resuscitated with isotonic crystalloid and TPN rate was decreased for 24 hours before being readvanced. No other source of nutrition was provided. Table 2: Parenteral nutrition advancement scheme as a percentage of goal final volume.
  • Piglets were weighed daily. Baseline weight was defined as the birth weight obtained on day 1 of life. Daily weights were used for adjustment of TPN rate and study drug dose. Piglets were randomized to receive daily orogastric gavage of isovolumetric (3 ml/kg/d) medium chain triglyceride (MCT) vehicle or Compound A in medium chain triglyceride vehicle (Litter 1: 24 mg/kg/d; Litter 2: 48 mg/kg/d), see Table 3.
  • MCT medium chain triglyceride
  • Table 3 Summary of Treatment Groups Attorney Reference: 14622.0007-00304 Groups Treatment Control MCT vehicle Com ound A (Litter 1) 24 m /k /da once dail o pou In litter 1, all on DOL 1.
  • Four piglets were randomized to the MCT vehicle group, while the remaining seven were assigned to the Compound A group (24 mg/kg). Due to several piglets with infectious complications, all piglets in this cohort received broad-spectrum antibiotics (enrofloxacin) starting on DOL 10 and continuing until sacrifice. The study procedure underwent minor modifications for litter 2. The volume of PN fluid delivered was increased by 15 ml/kg/day (with no change in goal nutrition via addition of free water).
  • Piglets were also given cefazolin twice daily for the full length of the study to prevent infection. In litter 2, 14 of 15 piglets were successfully resuscitated and started TPN on DOL 1. Six piglets were randomized to the MCT group and eight to the Compound A group (48 mg/kg). Acute renal failure was noted in both MCT and Compound A piglets, and supplemental intravenous fluids were provided for resuscitation. Two piglets in each group required supplemental sodium bicarbonate (either intravenous or via oral gavage) for metabolic acidosis. No infectious complications were noted in this cohort. Collection and Analysis of Samples Blood Collection Blood was drawn on DOL 0, 8, and 15 (immediately prior to sacrifice). Complete blood count was performed using the VetScan HM5.
  • Hepatic steatosis was assessed via quantification of oil red O staining (CellProfiler, Boston, MA) as well as quantification of liver triglyceride content using a Attorney Reference: 14622.0007-00304 commercially available triglyceride assay according to the manufacturer’s instructions (Abcam ab65336, Cambridge, MA). Liver fibrosis was assessed by a masked pathologist using the Ishak fibrosis score. Outcomes and Statistical Analysis The primary outcome assessed was cholestasis (direct bilirubin).
  • piglets receiving Compound A demonstrated both lower plasma direct bilirubin and plasma GGT levels than the MCT animals.
  • Compound A at 24mg/kg and 48mg/kg decreased plasma total bilirubin at DOL 15 (litter 1: 1.4 vs.
  • Fig. 4 Representative histology is shown in Fig. 4.
  • MCT piglets demonstrated steatosis, bile duct proliferation, and bridging portal-portal and portal-central vein fibrosis.
  • compound A piglets demonstrated minimal steatosis, only mild bile duct proliferation, and minimal fibrotic portal expansion.
  • Bile duct proliferation was assessed using immunohistochemical staining for cytokeratin 7, a cholangiocyte marker.
  • Hepatic stellate cell activation a key step in fibrogenesis–was assessed using immunohistochemical staining for ⁇ smooth muscle actin ( ⁇ SMA).
  • ⁇ SMA ⁇ smooth muscle actin
  • a masked veterinary pathologist assessed liver fibrosis on formalin-fixed paraffin embedded liver tissue stained with Masson’s Trichrome (Fig.4C-D, Fig.5E).
  • the representative stains in Fig. 6, show that piglets receiving MCT demonstrated fibrous expansion of most portal areas with some portal-to-portal bridging (black arrows).
  • piglets receiving Compound A had significantly decreased fibrosis with fibrous expansion of some portal areas, but no portal-to-portal bridging as shown on the top right panel.
  • RNA-Seq was performed by Novogene Co. (Sacramento, CA, USA). RNA integrity was assessed with the RNA Nano 6000 Assay kit (Agilent Technologies, CA, USA). All samples had RIN> 4 and passed the established quality thresholds. mRNA was purified using poly-T oligo-attached magnetic beads and 150 bp paired-end reads were generated using the NovaSeq 6000 platform (Illumina, San Diego, CA).
  • IPA demonstrated the key upregulated canonical pathways included pathways involved in oxidative phosphorylation, eukaryotic initiation factor 2 (EIF2) signaling, fatty acid ⁇ -oxidation I, and glutathione redox reactions I. Both EIF2 phosphorylation and glutathione redox reactions are critical in mediating the antioxidant capacity in the liver and responding to oxidative stress (Choi et al., Nutr. Metab.; 14: 48 (2017)).
  • Key downregulated canonical pathways included the Sirtuin signaling pathway, Granzyme A signaling, and lipopolysaccharide/interleukin-1 (LPS/IL-1), and mediated inhibition of RXR function.
  • PPAR ⁇ /RXR activation was predicted with predicted increased fatty acid oxidation, fatty acid uptake, glucose homeostasis, lipoprotein metabolism, ⁇ -oxidation, and anti- inflammation. Consistent with this activation, investigation of the inhibited LPS/IL-1 Mediated Inhibition of RXR Function pathway demonstrates predicted activation of retinoid X receptor-mediated pathways including master regulators liver X receptor, farsenoid X receptor, retinoic acid receptor, pregnane X receptor, and PPARs. Notably, this includes genes involved in bile acid and organic ion transport, in addition to fatty acid metabolism.
  • NF- ⁇ B Nuclear factor kappa B
  • NF- ⁇ B Nuclear factor kappa B
  • STAT3 signal transducer and activator of transcription 3
  • Predicted upstream regulators are consistent with PPAR ⁇ and PPAR ⁇ agonism as the key mechanisms mediating the metabolic, anti-inflammatory, and anti-fibrotic effects of Compound A in this model.
  • Mode of Action Study GPR84 activation Attorney Reference: 14622.0007-00304
  • the activity of Compound A towards GPR84 was determined in vitro using a Hit Hunter® cAMP assay (Eurofins DiscoverX, CA, US) with Embelin acting as a positive control.
  • % Activity 100% x (mean relative luminescence units (RLU) of test sample - mean RLU of vehicle control) / (mean MAX control ligand-mean RLU of vehicle control).
  • PPAR ⁇ and PPAR ⁇ activation The activity of Compound A towards human PPAR ⁇ and PPAR ⁇ was determined in vitro using PathHunter NHR cell lines (Eurofins DiscoverX, CA, US) with GW7647 (2-[[4-[2- [[(Cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid) or troglitazone (5-[[4-[(6
  • NHR cell lines were expanded from freezer stocks according to standard procedure and seeded in a total volume of 20 ⁇ L into white walled, 384-well microplates and incubated at /5% CO 2 overnight prior to incubation with either Compound A or GW7647 or Troglitazone at 37°C/5% CO 2 or room temperature for 3-16 hours at 10-point concentration curve from 0.001 to 100 mM.
  • Compound activity was determined via chemiluminescence after the addition of PathHunter Detection reagent cocktail.
  • Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection.

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Abstract

Methods of treating intestinal failure-associated liver disease (IFALD) and cholestasis in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a human child.

Description

Attorney Reference: 14622.0007-00304 METHODS OF TREATING INTESTINAL FAILURE-ASSOCIATED LIVER DISEASE IN CHILDREN I. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application No.63/491,992, filed March 24, 2023, which is incorporated herein by reference in its entirety. II. Field of the invention The present invention relates to methods of treating intestinal failure-associated liver disease (IFLAD) and cholestasis in children, particularly infants, who have received or are receiving parenteral nutrition. III. Background Human infants are born in a relatively immature state compared with many other species. The human digestive system begins to form early in gestation, at around 3-4 weeks, but is slow to mature and a normal human diet of solid foods cannot be introduced prior to around 4-6 months of age. Infants therefore exclusively receive nutrition as either breastmilk or a synthetic breastmilk substitute up to this point. However, certain infants are unable to receive adequate nutrition orally. This may be, for example, because of prematurity, illness (such as infection by Group B streptococcus or sepsis), or physical problems such as high or cleft palate that prevent swallowing. In older children that might be normally expected to eat solid foods, oral nutrition may not be tolerated because of illness. Children may also exhibit extreme “picky eating,” which may be caused by sensory issues. This can cause a child to express a strong aversion to certain food flavours and/or textures. Because children have high nutritional needs to support growth and development, such children can become nutrient deficient through following a severely restricted diet. For such children, adequate nutrition must be administered via another route until oral nutrition can be tolerated. Parenteral Nutrition (PN) is thus a critical therapy for children who are unable to take in adequate nutrients orally. PN affords children who would otherwise become severely malnourished a chance to grow and develop. However, long-term PN treatment is limited by potentially serious complications, including liver disease. It has estimated that up to 75% of infants who require PN for 60 days develop intestinal failure- associated liver disease (IFALD). In the early 2000s, infants with IFALD followed for over 2 years had a 26% transplant and 27% mortality rate (Nandivada P et al., Am J Clin Nutr.104(3): 663–670 (2016)). Up to two-thirds of neonates, i.e., newborn infants and infants up to 4 weeks old, on long-term PN develop IFALD (Lauriti, G. et al., J Parenter Enteral Nutr; 38: 70–85 (2014)). Premature neonates are at particularly high risk due to an immature liver that is less capable of handling oxidative stress and inflammation than a mature liver. Premature neonates are also at high risk from additional conditions such as sepsis and surgical gastrointestinal conditions such as necrotizing enterocolitis (Christensen, R. D. et al, J Perinatol 27, 284– 290 (2007)). The effects of parenteral nutrition are not only significant, but can also be long-lasting. There Attorney Reference: 14622.0007-00304 have been reports of persistent abnormal liver fibrosis and steatosis many years after weaning from PN has been completed (Mutanen A et al., Hepatology, 58(2); 729-738 (2013)). Additionally, biomarkers of liver injury (e.g., elevated direct (conjugated) and total (plasma) bilirubin, gamma glutamyl transferase, alanine aminotransferase, and/or aspartate aminotransferase or reduced serum albumin levels) may remain even after weaning from PN. (Id.) IFALD is characterized initially by intrahepatic cholestasis, which can occur within 2 weeks of initiating PN, and then by progressive fibrosis and ultimately cirrhosis over the course of several months to years. Without transitioning to full enteral feedings, cirrhosis may progress to end-stage liver disease, with death from sepsis or portal hypertension (Nandivada et al op. cit.). The current strategies to treat IFALD include lipid restriction, which carries the risk of essential fatty acid deficiency, or transition to a fish oil lipid emulsion, which has been demonstrated to rescue acute hepatic injury and attenuate the progression of liver disease (Gura et al., Pediatr.; 230: 46-54.e2 (2021); Secor et al., Expert Opin. Drug Saf.; 20: 307-320 (2021)). The standard of care in the US at the present time is with Intralipid®, a lipid emulsion which contains soybean oil. A fish oil (FO) lipid emulsion, Omegaven®, has recently been approved by the United States Food and Drug Administration (FDA) for use in children to treat IFALD. Omegaven® is administered in an amount of 1g/kg/day, with a concentration of Omegaven® of 1 g/10 mL. For an average newborn infant weighing 3-4 kg, this results in a volume to be administered of around 30-40 mL per day. It has further been reported that a significant percentage of patients fail therapy; in a study of 182 patients treated with Omegaven®, 14% failed therapy (Nandivada et al.). Further, there is a population of patients who continue to develop IFALD despite having been weaned off PN (Mutanen A et al., Hepatology; 58: 729-738 (2013)). As such, there is a need for alternative methods of treating children who may benefit from lower dose enterally administered therapies, or potentially allowing a higher dose of lipid emulsion to be provided to support growth and development while minimizing hepatotoxicity. Summary of the Invention The present invention relates to methods of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I)
Figure imgf000003_0001
Attorney Reference: 14622.0007-00304 wherein the subject is a human child. In some embodiments, the child is receiving or has previously received parenteral nutrition. The present invention also relates to methods of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a human infant. is receiving or has previously received parenteral nutrition. In some
Figure imgf000004_0001
was born less than 140 days prior to initial administration. The present invention further relates to methods of treating IFALD in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a pre-term
Figure imgf000004_0002
than 37 weeks gestation). In some embodiments, the infant is receiving or has received parenteral nutrition. In some embodiments, the human pre-term infant was born less than 140 days prior to initial administration. The present invention also relates to methods of treating cholestasis in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I) as defined in the claims, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof Attorney Reference: 14622.0007-00304 (I) wherein the subject is a human child. In receiving or has previously received parenteral nutrition. In some
Figure imgf000005_0001
embodiments, the child is a pre- term infant. Description of the Figures Fig.1. Nutritional outcomes of pre-term piglet model. Piglets in the MCT and Compound A groups received similar amounts of PN (Fig. 1A) and gained similar weight (Fig. 1B). In both groups, plasma albumin increased from largely undetectable at birth through DOL 15, and was higher in Compound A group (Fig.1C). Fig. 2. Similar normalized organ weights at sacrifice. Preterm piglets on 14 days of parenteral nutrition treated with medium chain triglyceride (MCT) vehicle control or Compound A via daily orogastric gavage have similar normalized organ weights at sacrifice. Organ weights normalized to body weight at sacrifice. Mean ± SE. Comparisons within litters performed with Mann-Whitney U test. P > 0.05 for all comparisons. Fig.3. Effect of Compound A in a model of cholestasis in piglets as measured by direct bilirubin, total bilirubin, and gamma glutamyl transferase, compared with MCT control group. Data is expressed as mean±SEM; * P < 0.05. Fig. 4. Representative liver histology. Formalin-fixed paraffin-embedded liver sections were stained with hematoxylin & eosin (A, B) or Masson’s trichrome (C, D). Frozen liver sections were stained with oil red O (E, F). Immunohistochemical staining (DAB, brown) of formalin-fixed paraffin-embedded liver sections was performed for αSMA (G, H) and cytokeratin 7 (I, J). MCT piglets demonstrate extensive bile pigment (A, arrows) and bile duct proliferation (I), steatosis (A, asterisks; C), and fibrosis indicated by bridging portal-portal and portal-central vein fibrosis (C, arrows). αSMA staining (G) indicates hepatic stellate cell activation. Compound A piglets demonstrate mild bile pigment (B, arrows), mild bile duct proliferation (B, asterisks; J), minimal fibrotic portal expansion (D, arrows), and minimal αSMA staining (H). Magnification: A, B– 400X; C, D – 100X. Oil red O – 200x. αSMA sections have 1mm reference bars. Cytokeratin 7 sections have 200nm reference bars. Fig. 5. Quantification of liver steatosis, immunohistochemical staining, and Ishak fibrosis score. MCT piglets, compared to Compound A piglets, demonstrated increased oil red O staining and liver triglyceride content consistent with hepatosteatosis (A, B), increased αSMA (C) and cytokeratin 7 staining (D) consistent with hepatic stellate cell activation and bile duct proliferation, and increased Ishak fibrosis score (E) assessed by a masked pathologist. Mean ± SE. Comparisons (A-D) made with Wilcoxon rank-sum tests. Attorney Reference: 14622.0007-00304 Ishak fibrosis scores are shown as boxplots for each group with individual scores represented as empty circles. The mean score is presented as a diamond. Ishak fibrosis scores compared with Fisher’s exact test. * P < 0.05 ** P < 0.01. Fig. 6. Effect of Compound A (48 mg/kg/day) on hepatic steatosis representative frozen liver sections stained with oil red O are shown at 200x (left). Data on right panel shown as mean±SEM. Fig.7. Effect of Compound A on Hepatic Fibrosis. The top panel shows representative formalin- fixed paraffin-embedded liver tissue stained with Masson’s Trichrome at 100x. Lower panel shows box- whisker plots for Ishak fibrosis scores are shown. ** P < 0.01. Fig.8. Plasma bile acids (left) were elevated in MCT piglets at DOL 15 compared to Compound A (17.6 ± 12.4 vs.2.9 ± 3.5 umol/L, P = 0.03). Serum adiponectin (right) was assessed at DOL 15. Mean ± SE. Comparisons between MCT and Compound A piglets at DOL 1, 8, and 15 were performed with Wilcoxon Rank-Sum tests. *P < 0.05 ** P < 0.01. IV. Detailed Description of the Invention A. Methods of the invention The present invention relates to methods of treating intestinal failure-associated liver disease (IFALD) in children, particularly infants, including pre-term infants, by administering a compound of formula (I). The present invention also relates to methods of treating cholestasis in children, particularly infants, including pre-term infants, by administering a compound of formula (I). In some embodiments, the children are receiving parenteral nutrition (PN). In some embodiments, the children have previously received parenteral nutrition and have elevated liver biomarkers. Intestinal failure (IF) is defined as decreased gut function to a level less than the minimum necessary for macronutrient and/or water or electrolyte absorption that results in the need for intravenous supplementation (IVS) to maintain health and/or growth. Patients with IF may also have a spectrum of liver diseases, collectively termed IFALD, that includes cholestasis (the reduction or stoppage of bile flow resulting in impaired bile salt homeostasis) with or without progression to cirrhosis, hepatic steatosis, hepatic fibrosis, and gallbladder disease in the setting of prolonged PN use in the absence of other obvious causes. Drivers of IFALD are characterized into nutrient (e.g., lipid emulsion overfeeding, phytosterols) and non-nutrient dependent (e.g., small bowel overgrowth) causes, and liver dysfunction is typically detected by increased liver blood tests such as bilirubin, alkaline phosphatase (ALP), or transaminases such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). IFALD associated with long- term PN use may also be referred to as PN-associated liver disease (PNALD). Because IFALD is characterized by cholestatic liver disease, the development of IFALD can be monitored using typical biochemical and histologic biomarkers for cholestasis. These include elevated plasma biomarkers (direct bilirubin, total bilirubin, gamma glutamyl transferase, bile acids) and histologic liver injury with early progression to steatosis, bile duct proliferation, and fibrosis. Attorney Reference: 14622.0007-00304 Thus, in some embodiments, the methods of the invention reduce cholestasis in a subject defined herein. In some embodiments, the methods of the invention reduce hepatic steatosis in a subject defined herein. In some embodiments, the methods of the invention reduce hepatic fibrosis in a subject defined herein. In some embodiments, the methods of the invention reduce cirrhosis in a subject defined herein. In some embodiments, the methods of the invention reduce gallbaldder disease in a subject defined herein. In some embodiments, the methods of the invention reduces plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce direct plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce total plasma bilirubin levels in a subject defined herein. In some embodiments, the methods of the invention reduce gamma glutamyl transferase (GGT) levels in a subject defined herein. The methods of the invention may also reduce plasma levels of ALT and/or AST in a subject defined herein. Nutrition markers may also be improved by the methods described herein. Thus, in some embodiments, the methods of the invention result in weight gain in a subject defined herein. In some embodiments, the methods of the invention result in elevated serum albumin levels in a subject defined herein. In some embodiments, the methods of the invention result in elevated plasma total protein levels in a subject defined herein. In some embodiments, the method is prophylactic. Thus, in some embodiments the methods of the invention prophylactically treat the development of cholestasis in a subject defined herein. In some embodiments, the methods of the invention prophylactically treat the development of hepatic steatosis in a subject defined herein. In some embodiments, the methods of the invention prophylactically treat the development of hepatic fibrosis in a subject defined herein. In some embodiments, the methods of the invention prophylactically treat the development of cirrhosis in a subject defined herein. In some embodiments, the methods of the invention prophylactically treat the development of gallbladder disease in a subject defined herein. In some embodiments, the method is therapeutic. Thus, in some embodiments the methods of the invention therapeutically treat cholestasis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat hepatic steatosis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat the development of hepatic fibrosis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat cirrhosis in a subject defined herein. In some embodiments, the methods of the invention therapeutically treat gallbladder disease in a subject defined herein. Without wishing to be bound by theory, the compounds of formula (I) defined herein are believed to act as anti-inflammatory, anticholestatic and anti-fibrotic agents, and thereby therapeutically and/or prophylactically treat IFALD. Premature neonatal IFALD is characterized by an inflammatory and cholestatic phenotype. The immature liver is poorly able to handle the numerous inflammatory insults in this population including pro-inflammatory lipids and phytosterols, bacterial products from translocation across disrupted intestinal epithelium, and sepsis from necrotizing enterocolitis or central line-associated Attorney Reference: 14622.0007-00304 blood stream infections. The mode of action is still being elucidated but is understood to involve the GPR84, PPARα, and PPARγ pathways. The methods of the invention are thus intended for application to children, including infants and pre-term infants, who either are receiving parenteral nutrition or who have previously recevived parenteral nutrition. Thus, in some embodiments, the subject is a human child, i.e., a human less than 18 years old. In some embodiments, the subject is a human child ranging from the ages of 1 and 18 years old, such as ranging from 2 and 16 years old, 2 and 14 years old, 3 and 12 years old, 2 and 4 years old, 4 and 6 years old, 6 and 8 years old, 8 and 10 years old, 10 and 12 years old. In some embodiments, the subject is a human child less than 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 years old. In some embodiments, the subject is a human child that is 1 to 2 years old, 3 to 4 years old, 5 to 6 years old, 7 to 10 years old, 11 to 14 years old, or 15 to 18 years old. In some embodiments, the subject is a human child that is 2 years old or less. In some embodiments, the subject is a human child age 2 to less than 12 years old. In some embodiments, the subject is a human child age 12 to less than 17 years. In some embodiments, the subject is a human infant, i.e., a human 1 year old or less. In some embodiments, the infant is 11 months old or less, 10 months old or less, 9 months old or less, 8 months old or less, 7 months old or less, 6 months old or less, 5 months old or less, 4 months old or less, 3 months old or less, 2 months old or less, or 1 month old or less. In some embodiments, the infant is less than 1 month old. In some embodiments, the subject is a human infant born less than about 140 days prior to initial administration of a compound of the invention. Thus, in some embodiments, the subject is a human infant born less than about 120 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 100 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 80 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 60 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 40 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than about 20 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9. 8, 7, 6, 5, 4, 3, 2, or 1 day prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than six weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than five weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than four weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than three weeks prior to initial Attorney Reference: 14622.0007-00304 administration of a compound of the invention. In some embodiments, the subject is a human infant born less than two weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than one week prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born 1 to 4 weeks, 1 to 3 weeks, 1 to 2 weeks, 2 to 4 weeks, 2 to 3 weeks, or 3 to 4 weeks prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 6 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 5 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 4 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 3 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 2 days prior to initial administration of a compound of the invention. In some embodiments, the subject is a human infant born less than 1 days prior to initial administration of a compound of the invention. Pre-term is defined by the US Center for Disease Control and Prevention (CDC) as when a human infant is born prior to 37 weeks gestation. The CDC further defines infants as children up to 1 year old. As used herein, the term “child” refers to a human less than 18 years old. In general, a fetus is not considered viable until 24 weeks gestation, however recent advances in neonatal care have resulted in successful birth occurring as early as 21 weeks, 1 day gestation. Thus, in some embodiments, the subject is a pre-term human infant (i.e., born prior to 37 weeks gestation). In some embodiments, the subject is a human infant born ranging from: 20 weeks to 36 weeks, 6 days gestation; 21 weeks to 36 weeks, 6 days gestation; 22 weeks to 36 weeks, 6 days gestation; 23 weeks to 36 weeks, 6 days gestation; 24 weeks to 36 weeks, 6 days gestation; 25 weeks to 36 weeks, 6 days gestation; 26 weeks to 36 weeks, 6 days gestation; 27 weeks to 36 weeks, 6 days gestation; 28 weeks to 36 weeks, 6 days gestation; 29 weeks to 36 weeks, 6 days gestation; 30 weeks to 36 weeks, 6 days gestation; 31 weeks to 36 weeks, 6 days gestation; 32 weeks to 36 weeks, 6 days gestation; 33 weeks to 36 weeks, 6 days gestation; 34 weeks to 36 weeks, 6 days gestation; 35 weeks to 36 weeks, 6 days gestation; or 36 weeks to 36 weeks, 6 days gestation. In some embodiments, the subject is a human infant born ranging from: 22 to 36 weeks gestation; 23 to 35 weeks gestation; 24 to 34 weeks gestation; 26 to 33 weeks gestation; or 28 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 24 to 33 weeks gestation. In some embodiments, the subject is a pre-term human infant born ranging from 26 to 32 weeks gestation. In some embodiments, the subject is a human infant born ranging from 28 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 29 to 33 weeks gestation. In some embodiments, the subject is a human infant born ranging from 29 to 30 weeks gestation. In some embodiments, the subject is a human infant born ranging from 30 to 32 weeks gestation. In some embodiments the subject is a human infant born ranging from 30 to 31 weeks gestation. In some embodiments the subject is a human infant born ranging from 31 to 32 weeks gestation. In some embodiments, the subject is a human infant born ranging from 32 to 33 weeks gestation. Attorney Reference: 14622.0007-00304 In some embodiments, the subject is a human child or infant that is receiving parenteral nutrition. In some embodiments, the child or infant received parenteral nutrition prior to administration of a compound of formula (I). In some embodiments, the child or infant receives parenteral nutrition coextensively with administration of a compound of formula (I). In some embodiments, the child or infant received parenteral nutrition for 4 weeks, 3 weeks, 2 weeks, or 1 week prior to administration of a compound of formula I. In some embodiments, the child or infant received parenteral nutrition for 6 days, 5 days, 4 day, 3 days, 2 days, or 1 day prior to administration of a compound of formula I. In some embodiments, the subject is a human child that previously received parenteral nutrition. In some embodiments, the subject is no longer receiving parenteral nutrition at the time of administration of a compound of formula (I). In some embodiments, the subject is a human child or infant that previously received parenteral nutrition and has elevated biomarkers of liver injury as compared to a child or infant that has not received parenteral nutrition. Thus, in some embodiments, the child or infant previously received parenteral nutrition and has elevated plasma bilirubin levels. In some embodiments, the child or infant previously received parenteral nutrition and has elevated direct plasma bilirubin levels. In some embodiments, the child or infant previously received parenteral nutrition and hs elevated total plasma bilirubin levels. In some embodiments, the child or infant previously received parenteral nutrition and has elevated gamma glutamyl transferase (GGT) levels. In some embodiments, the child or infant previously received parenteral nutrition and has elevated alanine aminotransferase levels. In some embodiments, the child or infant previously received parenteral nutrition and has elevated aspartate aminotransferase levels. In some embodiments, the child or infant previously received parenteral nutrition and has reduced serum albumin levels. In some embodiments, the child or infant previously received parenteral nutrition and has hepatic steatosis and/or fibrosis. In some embodiments, the child or infant received parenteral nutrition for 4 weeks, 3 weeks, 2 weeks, or 1 week and said administration resulted in elevated liver biomarkers. In some embodiments, the child or infant received parenteral nutrition for 6 days, 5 days, 4 day, 3 days, 2 days, or 1 day and said administration resulted in elevated liver biomarkers. In some embodiments, the child or infant received parenteral nutrition for over 30 days. In some embodiments, the child or infant received parenteral nutrition for up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, or up to 10 months. In some embodiments, the child or infant received parenteral nutrition for 1-10 months, 10-20 months, 20-30 months, 30-40 months, 40-60 months, 60-80 months, 80- 100 months, 100-120 montsh, 120-150 months, 150-200 months, or 200-250 months. In some embodiments, a compound of formula (I) is administered for about 1 to 5 weeks. In some embodiments, a compound of formula (I) is administered for 1 to 4 weeks, 1 to 3 weeks, or 1 to 2 weeks. In some embodiments, a compound of formula (I) is administered for about 2 to 4 weeks or about 3 to 4 weeks. In some embodiments, a compound of formula (I) is administered for less than 5 weeks, less than 4 weeks, less than 3 weeks, less than 2 weeks, or less than 1 week. In some embodiments, a compound of formula (I) is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks. Attorney Reference: 14622.0007-00304 B. Formulations for use in the methods of the invention A “pharmaceutical composition” is a compound of formula (I) in any form suitable to be used for a medical purpose. The term "pharmaceutically acceptable" refers to drugs, medicaments, inert ingredients etc., which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which a compound is administered. The pharmaceutically acceptable vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Additional 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, ethyl alcohol, 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. Prevention of the action of microorganisms can be achieved by addition of antibacterial and antifungal agents. Examples of such agents are parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. Isotonic agents may be included in a formulation. Examples of isotonic agents include sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. The compounds of formula (I) may be formulated prior to administration into pharmaceutical compositions using available techniques and procedures. For instance, the pharmaceutical compositions may be formulated in a manner suitable for administration by topical, oral, intravenous (iv), intramuscular (im), depo-im, subcutaneous (sc), depo-sc, sublingually, intranasal, intrathecal topical or rectal routes. In some embodiments, the compound(s) of formula (I) are formulated for sublingual administration. In some embodiments, the compound(s) of formula (I) are formulated as sublingual tablets. In some embodiments, the compound(s) of formula (I) are formulated as sublingual strips. In some embodiments, the compound(s) of formula (I) are formulated as sublingual drops. In some embodiments, the compound(s) of formula (I) are formulated as a sublingual spray. In some embodiments, the compound(s) of formula (I) can be orally administered or intravenously administered. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of the therapeutic agent in such therapeutically useful compositions is such that a suitable dosage will be obtained. The compounds of formula (I) and compositions comprising compounds of formula (I) may be formulated in conventional oral administration forms, e.g. tablets, coated tablets, capsules, powders, granulates, solutions, dispersions, suspensions, syrups, emulsions, sprays, etc., using conventional excipients, e.g. solvents, diluents, binders, sweeteners, aromas, pH modifiers, viscosity modifiers, Attorney Reference: 14622.0007-00304 antioxidants (e.g. tocopherol), corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, ethanol, glycerol, sorbitol, polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof etc. Conventional formulation techniques, well known in the art, may be used. Formulations suitable for oral administration may be in the form of capsules (e.g., hard or soft shell gelatin capsule), cachets, pills, tablets, lozenges, powders, granules, pellets, dragees, e.g., coated (e.g., enteric coated) or uncoated, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste, or incorporated directly into the subject's diet. Moreover, in certain embodiments these pellets can be formulated to (a) provide for instant or rapid drug release (i.e., have no coating on them); (b) be coated, e.g., to provide for sustained drug release over time; or (c) be coated with an enteric coating for better gastrointestinal tolerability. Coating may be achieved by conventional methods, typically with pH or time- dependent coatings, such that the compound(s) of the invention is released in the vicinity of the desired location, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, and shellac. In solid dosage forms for oral administration a compound of the present invention may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. Peroral compositions include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically acceptable vehicles suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include Attorney Reference: 14622.0007-00304 methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants. Compounds of formula (I) are preferably administered intravenously for the methods of the invention. Compounds of formula (I) may be admixed with a PN diet. Pharmaceutical preparation suitable for injectable use or for use by infusion (e.g., via 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 may be prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof. Prolonged absorption of injectable compositions may be obtained by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. Compositions for injection must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture 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 therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Compounds according to the present invention may be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. For such compositions, the compound of the invention can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, this preparation may contain a preservative to prevent the growth of microorganisms. Pharmaceutical formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of a compound of formula (I) or a plurality of solid particles of such compound(s). For instance, metal salts of the compounds of formula (I) are expected to have physical chemical properties amenable with the preparation of fine particles of active pharmaceutical ingredient (API) for administration by inhalation but not the free acid form of these compounds. The desired formulation may be placed in a small chamber and nebulized. Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the agents or salts. The liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns. The solid particles can be obtained by processing the solid agent of any Formula described herein, or a salt thereof, in any appropriate manner known in the art, such as by micronization. The size of the solid particles or droplets will be, for example, from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose. A pharmaceutical formulation suitable for administration as an aerosol may be in the form of a liquid, the formulation will comprise a water-soluble agent of a compound of formula (I) described herein, or a salt thereof, in a carrier which comprises water. A surfactant may be present which lowers the surface tension of the formulation Attorney Reference: 14622.0007-00304 sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization. The compositions comprising compounds of formula (I) may also be administered topically to a subject, e.g., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a “patch”. Such compositions include, for example, lotions, creams, solutions, gels, emulsions and solids. These topical compositions may comprise an effective amount, usually about 0.01% to about 10% (w/w), or from about 0.1% to about 5% (w/w), or from about 1% to about 5% (w/w), of a compound of formula (I). Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of with dispersed or dissolved therein the therapeutic agent. The carrier may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents and the like. The carrier may include vernix. Topical formulation includes one or more excipients such as, but not limited to, protectives, adsorbents, demulcents, emollients, preservatives, antioxidants, moisturizers, buffering agents, solubilizing agents, skin-penetration agents, and surfactants. Suitable protectives and adsorbents include, but are not limited to, dusting powders, zinc sterate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide. Suitable demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol. Suitable emollients include, but are not limited to, animal and vegetable fats and oils, myristyl alcohol, alum, and aluminum acetate. Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents for use with the invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin-penetration agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N- decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate); and N-methylpyrrolidone. Attorney Reference: 14622.0007-00304 Other compositions useful for attaining systemic delivery of the subject agents may include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents may also be included. C. Dosing and Administration A suitable daily dosage of the compound of formula (I), may range from about 5 mg to about 2 g per kg of body weight, such as from about 25 mg to about 1 g per kg of body weight. For example, in some embodiments, the daily dose ranges from about 10 mg to about 1 g per kg of body weight, from about 25 mg to about 750 mg per kg of body weight, from about 30 mg to about 600 mg per kg of body weight, from about 35 mg to about 500 mg per kg of body weight, from about 40 mg to about 300 mg per kg of body weight, from about 45 mg to about 250 mg per kg of body weight, from about 50 mg to about 200 mg per kg of body weight, from about 20 to about 100 mg per kg of body weight, or from about 25 to about 75 mg per kg of body weight. In some embodiments, the daily dose ranges from about 600 mg to 1.5 g, from about 700 mg to about 1.4 g, from about 800 mg to about 1.3 g, from about 900 mg to about 1.2 g, from about 700 mg to about 1.2 g, from about 800 mg to about 1.1 g, from about 900 mg to about 1 g, from about 700 mg to about 900 mg, from about 700 mg to about 800 mg, from about 800 mg to about 1 g, from about 800 mg to about 900 mg, from about 900 mg to about 1 g. In at least one embodiment, the daily dose ranges from about 30 mg to about 70 mg per kg of body weight. 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, about 900 mg, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, or about 1.5 g per kg of body weight. The compound(s) may be administered, for example, once, twice, or three times per day. In some embodiments, the compound of formula (I) is administered as an infusion. In at least one embodiment, the compound of formula (I) is administered in an amount ranging from about 20 mg to about 300 mg per dose. In some embodiments, the compound of formula (I) is administered in an amount ranging from about 25 mg to about 100 mg per kg of body weight. In at least one embodiment, the compound of formula (I) is administered once per day. In some embodiments, the dose may be provided in one dose per day or in multiple doses per day. For example, a daily dosage may be provided in two doses per day, three doses per day, or four doses per day. In some embodiments, a daily dosage is provided in a single dose per day. Attorney Reference: 14622.0007-00304 In some embodiments, the dose may not be administered every day. In some embodiments, the dose may be administered every other day, every three days, every four days, twice per week, or once per week. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 30 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 40 mg per kg of body weight. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 50 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 75 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 150 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 250 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 300 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 800 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 900 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.3 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.4 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered intravenously at a dose of 1.5 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 30 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 40 mg per kg of body weight. In some embodiments, the compound of formula (I) is administered orally at a dose of 50 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 75 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 150 mg per kg Attorney Reference: 14622.0007-00304 of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 250 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 300 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 800 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 900 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.3 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.4 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 1.5 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 30 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 40 mg per kg of body weight. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 50 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 75 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually once per day at a dose of 100 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 150 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 200 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 250 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 300 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 400 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 500 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 600 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 700 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is Attorney Reference: 14622.0007-00304 administered sublingually at a dose of 800 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered orally at a dose of 900 mg per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.1 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.2 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.3 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.4 g per kg of body weight per day. In some embodiments, the compound of formula (I) is administered sublingually at a dose of 1.5 g per kg of body weight per day. D. Compounds of formula (I) The methods describe herein utilise aromatic compounds of the general formula (I): (I) wherein
Figure imgf000018_0001
• 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group; • 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, a OR10 group, a S(O)mR10 group, or a NR9R10 group; • R3, R4 are the same or different and may be chosen from a hydrogen atom or a halogen atom, • 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 Attorney Reference: 14622.0007-00304 double bond 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group;, • with the proviso that if R1 is a OR11 group and R5 is a hydrogen atom, a haloalkyl group, a C1- C4 alkyl group, a OR11 group, a SR11 group, or a NR12R13 group, then R2 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, C4-C6 alkynyl group, or a C4-C6 alkyl-Y- group; • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and an C1-C6 alkyl group, wherein R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; • 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; • R9 is a hydrogen atom or a C1-C11 alkyl group; • R10 is 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; • R11 is a C1-C4 alkyl group; • R12 and R13 are independently chosen from a hydrogen atom and a C1-C4 alkyl group; • X is a hydroxymethyl or a carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic ester, a glyceride, an anhydride, a carboxamide, or a phospholipid, or a prodrug thereof; • Y is an oxygen atom, a sulphur atom, or a NR12R13 group; • m is 0, 1, or 2; and • n is 0, 1, or 2. In some embodiments, 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 is a heteroatom, or a phenyl group. In some embodiments, R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl, an -O-heteroalkyl group having 4-8 atoms of which 1 - 2 are heteroatoms, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C3-C8) haloalkenyl group having 1- Attorney Reference: 14622.0007-00304 2 double bonds, an -O-(C3-C8) alkynyl group having 1-2 triple bonds, a -S-(C3-C8) alkyl group, a -S-(C3- C8) hydroxyalkyl group, a -S-(C3-C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5- 8 atoms of which 1 is heteroatom and 1 double bond, a -S-(C3-C8) alkynyl group having 1-2 triple bonds, a -S-(C3-C8) haloalkenyl group having 1-2 double bonds, a -S-(C3-C8) alkynyl group having 1-2 triple bonds, a -C(O)-(C3-C8) alkyl group, a -C(O)-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, -C(O)-(C3-C8) alkenyl group having 1-2 double bonds, a -S(O)-(C3-C8) alkyl group, a -S(O)- heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S(O)-(C3-C8) alkenyl group having 1-2 double bonds, a -S(O)-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, a -S(O)2-(C3-C8) alkyl group, -S(O)2-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S(O)2-(C3-C8) alkenyl group having 1-2 double bonds, a -S(O)2-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms; an amine group having a hydrogen atom and a C3-C8 alkyl group; an amine group having a hydrogen atom and a heteroalkyl group having 4-8 atoms of which 1-2 are heteroatoms; an amine group having a hydrogen atom and a ketone group; an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group; an amine group having a C1-C9 alkyl group and a heteroalkyl group having 4-8 atoms of which 1 is a heteroatom, or an amine group having a C1-C9 alkyl group and a C3-C8 alkenyl group having 1-2 double bonds. In some embodiments, R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group. In some embodiments, R1 is chosen from a methyl group, an ethyl group, an isopropyl group, a -CF3 group, a -(CH2)3OH group, and a phenyl group. In some embodiments, R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 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, a -S-(C3-C8) alkyl group, a -S-(C3- C8) hydroxyalkyl group, a -S-(C3-C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5- 8 atoms of which 1 is heteroatom and 1 double bond, a -C(O)-(C3-C8) alkyl group, a -S(O)-(C3-C8) alkyl group, a -S(O)2-(C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group, or an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. In some embodiments, R1 is a C1-C3 alkyl group or a C1-C3 hydroxyalkyl group. In some embodiments, R2 is a C4-C9 alkyl 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, an -O-(C3-C8) alkyl group, O-(C3-C8) Attorney Reference: 14622.0007-00304 hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C4-C8) haloalkenyl group having 1- 2 double bonds, a -S-(C3-C8) alkyl group, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C4-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond; a -C(O)-(C3-C8) alkyl group, a -S(O)-(C3-C8) alkyl group, a -S(O)2-(C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group; an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. In some embodiments, R1 is a C1-C2 alkyl group or a C1-C2 hydroxyalkyl group. In some embodiments, R2 is a C4-C9 alkyl 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, an -O-(C3-C8) alkyl group, O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C4-C8) haloalkenyl group having 1- 2 double bonds, a -S-(C3-C8) alkyl group, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C4-C8) alkenyl group having 1-2 double bonds, or a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond. In some embodiments, R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an - O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position. In some embodiments, R1 is a C1-C2 alkyl group or a C1-C2 hydroxyalkyl group and R2 is a C5- C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an -O-(C4-C6) alkyl group, an -O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O-heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) alkenyl group having 1 double bond. In some embodiments, R1 is a methyl group or an ethyl group and R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an -O-(C4-C6) straight chain alkyl group, an - O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O-heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) alkenyl group having 1 double bond. In some embodiments, R1 is a methyl group or an ethyl group and R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an - O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond. In some embodiments, R1 is a methyl group and R2 is a C5-C8 straight chain alkyl group, a C6- C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group 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. Attorney Reference: 14622.0007-00304 In some embodiments, R1 is a methyl group. In some embodiments, R2 is an -O-(C3-C8) alkyl group and may have the formula -OC3H7, -OC4H9, -OC5H11, -OC6H13, -OC7H15, or -OC8H17. In some embodiments, R2 is a -S-(C3-C8) alkyl group and may have the formula -SC3H7, -SC4H9, -SC5H11, - SC6H13, -SC7H15, or -SC8H17. In some embodiments, R2 is an -O-(C3-C8) alkenyl group having 1-2 double bonds and may have the formula -OCH2CH=CHCH2CH3, -O(CH2)2CH=CHCH2CH3, - O(CH2)3CH=CHCH2CH3, or -O(CH2)4CH=CHCH2CH3. In some embodiments, R2 is a -S-(C3-C8) alkenyl group having 1-2 double bonds and may have the formula -SCH2CH=CHCH2CH3, - S(CH2)2CH=CHCH2CH3, -S(CH2)3CH=CHCH2CH3, or -S(CH2)4CH=CHCH2CH3. In some embodiments, R3, R4, and R5 are each a hydrogen atom. In some embodiments, R5 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 atom is a heteroatom. In some embodiments, one or more of R3, R4, and R5 is a halogen atom. In some embodiments, one or more of R2, R3, and R4 is a fluorine atom. In some embodiments, R3 and R5 are each a hydrogen atom and R4 is a fluorine atom. In some embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2. 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 chosen 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 0. In some embodiments X is a carboxylic acid, a carboxamide, a hydroxymethyl, or a carboxylic 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. 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 chosen 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 chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, or a carboxylic ester such as an acetate group. In some embodiments, n is 1 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C2 alkyl group. In some embodiments, n is 1 and R6 and R7 are both hydrogen atoms. In some embodiments, n is 1 and R6 and R7 are both methyl groups. In some embodiments, R6 is a methyl group and R7 is a hydrogen. In some embodiments, n is 1, R6 and R7 are both hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1, R6 and R7 are both methyl groups, and X is a carboxylic acid. In some embodiments, X may be chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group. In some embodiments: • R1 is a methyl group or an ethyl group; Attorney Reference: 14622.0007-00304 • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in 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 independently chosen from a hydrogen atom and a methyl group; • and X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group. In some embodiments: • R1 is a methyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R3, R4, and R5 are each a hydrogen atom; • n is 0; • and X is a carboxylic acid. In some embodiments: • R1 is a methyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R3, R4, and R5 are each a hydrogen atom; • n is 1; • R6 and R7 are each a hydrogen atom • and X is carboxylic acid. In some embodiments, compounds of formula (I) described by group (2) are described by formulas (IB-1), (IB-2), (IB-3), or (IB-4): Attorney Reference: 14622.0007-00304 3), wherein (2); and
Figure imgf000024_0001
• X1 is a halogen atom; • a is 0 or 1; • Z’ is H or a C1-C4 alkyl group; • R1 is a C1-C4 alkyl group; • R1 is a methyl group or an ethyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1- C6 alkyl group; • Z1 is -O-, -S(O)m-, or -N(R14)-; • R14 is 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 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; • R15 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, a OR14 group, a S(O)mR14 group, or a NR9R14 group; • R9 is a hydrogen atom or a C1-C11 alkyl group; and • m is 0, 1, or 2. In some embodiments R1 is a C1-C2 alkyl group or an -O-(C1-C2) alkyl group. In some embodiments, R5 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond, an - O-(C4-C6) alkyl group, an -O-(C4-C6) hydroxyalkyl group, an -O-(C4-C6) haloalkyl group, an -O- heteroalkyl group having 4-6 atoms of which 1 are heteroatoms and the heteroatom is an O, an -O-(C5-C8) Attorney Reference: 14622.0007-00304 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 Z configuration. In some embodiments, Z’ is H. In some embodiments Z’ is a methyl or ethyl group. In some embodiments, R6 and R7 are the same or different and are independently chosen 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, R2 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, an -O-(C3-C8) alkyl group, an -O-(C3- C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 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, a -S-(C3-C8) alkyl group, a -S-(C3- C8) hydroxyalkyl group, a -S-(C3-C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5- 8 atoms of which 1 is heteroatom and 1 double bond, a -C(O)-(C3-C8) alkyl group, a -S(O)-(C3-C8) alkyl group, a -S(O)2-(C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group, or an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. The compounds of formula (I) may be used in the present methods in pharmaceutically acceptable salt form. Such salts may be represented by wherein X is COO-, and Z+
Figure imgf000025_0001
K+, Mg2+, or Ca2+; a protonated primary amine such as tert-butyl ammonium, (3S,5S,7S)-adamantan-1-ammonium, 1,3-dihydroxy-2- (hydroxymethyl)propan-2-ammonium, a protonated aminopyridine (e.g., pyridine-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- ium, a quaternary amine such as 2-hydroxy-N,N,N-trimethylethan-1-aminium and a protonated guanidine such as amino((4-amino-4-carboxybutyl)amino)methaniminium or a protonated heterocycle such as 1H- Attorney Reference: 14622.0007-00304 imidazol-3-ium. Additional examples of suitable salts include salts of a diprotonated diamine such as ethane-1,2-diammonium or piperazine-1,4-diium. or by wherein X = COO-, and diamine such as ethane-1,2-
Figure imgf000026_0001
diammonium or piperazine- Examples of pharmaceutically acceptable salts are also described, for example, in Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor). Certain compounds of formula (I) may exist in Zwitterionic form and the present invention includes Zwitterionic forms of these compounds and mixtures thereof. The present methods may also utilize prodrugs of the compound of formula (I). Examples of such produgs includes the pharmaceutically acceptable esters or amides obtained upon reaction of alcohols or amines, including amino acids, with the free acids defined by formula I. The compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof. Hence, compounds of formula (I) that exist as diastereomers, racemates, and enantiomers are included within the scope of the present disclosure. It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that methods of the invention may utilize all such solvated forms which possess biological activity. Exemplified compounds of formula (I) Example 1.
Figure imgf000026_0002
acid Example 2. Attorney Reference: 14622.0007-00304 acid
Figure imgf000027_0001
Example 3. acid
Figure imgf000027_0002
Example 4. acid
Figure imgf000027_0003
Example 5. 5-en-1-yl)benzoic acid
Figure imgf000027_0004
Example 6.
Figure imgf000027_0005
-2-methylbenzoic acid Example 7.
Figure imgf000027_0006
en-1-yloxy)benzoic acid Example 8.
Figure imgf000027_0007
yl)-2-methylbenzoic acid Example 9.
Figure imgf000027_0008
2-en-1-yloxy)benzoic acid (“Compound B”) Attorney Reference: 14622.0007-00304 Example 10. benzoic acid (“Compound A”)
Figure imgf000028_0001
Example 11. en-1-yloxy)benzamide (“Compound C”) en-1-yloxy)phenyl)methanol -2-methylphenyl)acetic acid 2-en-1-yloxy)phenyl)acetic acid 1-yloxy)benzoic acid
Figure imgf000028_0002
acid Example 17. Attorney Reference: 14622.0007-00304 -2-methylbenzoic acid
Figure imgf000029_0001
Example 18. 2-yn-1-yloxy)benzoic acid
Figure imgf000029_0002
Example 19. oxy)-2-methylbenzoic acid
Figure imgf000029_0003
Example 20. trifluoropentyl)oxy)benzoic acid
Figure imgf000029_0004
Example 21.
Figure imgf000029_0005
benzoic acid Example 22.
Figure imgf000029_0006
biphenyl]-2-carboxylic acid Example 23.
Figure imgf000029_0007
benzoic acid Example 24. Attorney Reference: 14622.0007-00304 -3-(pentyloxy)benzoic acid
Figure imgf000030_0001
Example 25. 3-(pentyloxy)benzoic acid
Figure imgf000030_0002
Example 26. benzoic acid
Figure imgf000030_0003
Example 27. benzoic acid
Figure imgf000030_0004
Example 28.
Figure imgf000030_0005
benzoic acid Example 29.
Figure imgf000030_0006
benzoic acid Example 30.
Figure imgf000030_0007
-2-methylbenzoic acid Attorney Reference: 14622.0007-00304 Example 31. (pentyl)amino)benzoic acid
Figure imgf000031_0001
Example 32. H O N OH O acid
Figure imgf000031_0002
Example 33. 2-en-1-yloxy)benzyl acetate
Figure imgf000031_0003
Example 34. 3-(pentyloxy)benzoic acid
Figure imgf000031_0004
Example 35. (pentyloxy)phenyl)propanoic acid
Figure imgf000031_0005
benzoic acid Example 37.
Figure imgf000031_0006
benzoate Attorney Reference: 14622.0007-00304 Example 38. benzoate
Figure imgf000032_0001
Example 39. benzoate
Figure imgf000032_0002
Example 40. benzoate
Figure imgf000032_0003
compounds of formula (I) are provided in WO 2020/074964 A1, incorporated herein by reference. E. Definitions ‘Alkyl’ refers to a straight chain, a branched chain or a cyclic alkyl group. In at least some embodiments, the alkyl group may be chosen 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. ‘Alkenyl’ refers to a straight chain or branched chain alkenyl group. In at least some embodiments, the alkenyl group may be chosen 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 embodiment, the alkenyl group has an ω-3 double bond. In some embodiments, the alkenyl group has 1 double bond and it is in the ω-3 position. In some embodiments, the alkenyl group is a C4-C9 straight chain alkenyl group having 1 double bond at the ω-3 position. In some embodiments, the double bond is in Z configuration. In some embodiments the alkenyl group has 1-3 double bonds and each double bond is in 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 it is in Z configuration. In some embodiments, the alkenyl group is a C5 straight chain alkenyl group having 1 double bond at the ω-3 position. In some embodiments, the alkenyl group is a C6 straight chain alkenyl group having 1 double bond at the ω-3 position. In some embodiments, the alkenyl group is a C7 straight chain alkenyl Attorney Reference: 14622.0007-00304 group having 1 double bond at the ω-3 position. In some embodiments, the alkenyl group is a C8 straight chain alkenyl group having 1 double bond at the ω-3 position. In some embodiments, the double bond is in Z configuration. ‘Alkynyl’ refers to a straight chain or branched chain alkynyl group. In some embodiments, the alkynyl group may be chosen from a C4-C12 alkynyl group having 1-3 triple bonds. In some embodiments, the alkynyl group has 1 triple bond. In some embodiments, the alkynyl group may be chosen from a C5- C10 alkynyl group having 1 triple bond. In some embodiments, the triple bond is in the ω-3 position. ‘Hydroxyalkyl’ refers to a hydroxy derivative of a straight chain or branched chain alkyl group. In some embodiments, the hydroxyalkyl group may be chosen from a C1-C12 hydroxyalkyl group, a C2-C11 hydroxyalkyl group, a C1-C6 hydroxyalkyl group, or a C1-C4 hydroxyalkyl group. In some embodiments, the hydroxyalkyl group may be chosen from a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, or a hydroxybutyl group. 'Heteroalkyl' refers to a straight chain or branched chain alkyl group, containing one or more heteroatoms selected from S, O and N, where the alkyl chain optionally may contain one or more hydroxy groups, one or more halogen atoms and/or a carbonyl group. A heteroalkyl group cannot contain a heteroatom in the first position of the chain with respect to the aromatic ring. For example, a group with the formula -OC6H13 is not a heteroalkyl group under this definition. A hydroxyalkyl group is not considered a heteroalkyl group under this definition. For example, a group with the formula -C6H12OH is not a heteroalkyl group under this definition. A group with the formula -C4H8OC2H4OH is considered a heteroalkyl group having 7 atoms, of which 1 is a heteroatom (oxygen), and further containing a hydroxy group. In some embodiments, the heteroalkyl group has 3-12 atoms. In some embodiments, the heteroalkyl group has 3-9 atoms. In some embodiments, the heteroalkyl group has 4-8 atoms. In some embodiments, the heteroalkyl group has 5 or 6 atoms. In some embodiments, the heteroalkyl group has 1-3 heteroatoms. In some embodiments, the heteroalkyl group has 3-9 atoms of which 1-3 are heteroatoms. In some embodiments, the heteroalkyl group has 4-8 atoms of which 1 is a heteroatom. In some embodiments, the heteroatom is in the second position of the heteroalkyl group. In some embodiments, the heteroatom is in the third position of the heteroalkyl group. In some embodiments, the heteroatom is in the fourth position of the heteroalkyl group. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulphur. In some embodiments, the formula of the heteroalkyl group may be chosen from -CH2OC4H9, -C2H4OC3H7, -C2H4OC2H3, -C3H6OCH3, -CH2OC5H11, -CH2OC3H7, -C2H4OC3H7, -C3H6OC2H7. An ‘alkyl-Y-’ group is a heteroalkyl group having 1 heteroatom in the α position with respect to the aromatic ring. Y may be chosen from an oxygen atom, a sulphur atom, and a NR12NR13 group, wherein R12 and R13 are independently chosen from a hydrogen group and C1-C4 group. For example, in some embodiments, Y may be oxygen. In some embodiments, a C4 alkyl-Y- group has the formula -OC4H9 or - Attorney Reference: 14622.0007-00304 SC4H9. In some embodiments, a C5 alkyl-Y- group has the formula -OC5H11 or -SC5H11. In some embodiments, a C6 alkyl-Y-group has the formula -OC6H13 or -SC6H13. 'Heteroalkenyl' refers to a straight chain or branched chain alkenyl group, containing one or more heteroatoms selected from S, O and N in the main chain, where the alkenyl chain optionally may contain hydroxy groups, halogen atoms and/or a carbonyl group. In some embodiments, the heteroatom is a sulphur. In some embodiments, the heteroatom is an oxygen. In some embodiments, the alkenyl group has 2 double bonds. In some embodiments, the alkenyl group has 3 double bonds. In some embodiment, the alkenyl group has an ω-3 double bond. In some embodiments, the alkenyl group has 1 double bond and it is in the ω-3 position. In some embodiments, the heteroalkenyl group has 3-9 atoms of which 1 atom is a heteroatom and 1 double bond. In some embodiments, the heteroalkenyl group has 6-9 atoms of which 1 atom is a heteroatom and 1 double bond, wherein the heteroatom is an oxygen, and wherein the double bond is in the ω-3 position. In some embodiments, the double bond is in Z configuration. The heteroatom cannot be in the first or last position of the heteroalkenyl group. For example, a heteroalkenyl group cannot contain a heteroatom in the first position of the chain with respect to the aromatic ring. For example, a group with the formula -OCH2CH=CHCH2CH3 is not a heteroalkyl group under this definition. ‘Haloalkyl’ refers to a straight chain or branched chain alkyl group, in which one or more hydrogen atoms have been substituted by a halogen atom. For example, the halogen atom may be chosen from fluorine, chlorine, bromine, and iodine. In some embodiments, the halogen atom is F. In some embodiments, the haloalkyl group contains a -CF3 group. In some embodiments, a haloalkyl group may also be a heteroalkyl group. In some embodiments, the haloalkyl may be a heteroalkyl group having 6-9 atoms of which 1-3 atoms are heteroatoms. In some embodiments, the haloalkyl group is a heteroalkyl group having 1 heteroatom. In some embodiments, the heteroatom is an oxygen atom. In some embodiments, the halogen atom is fluorine. ‘Haloalkenyl’ refers to a straight chain or branched chain alkenyl group, in which one or more hydrogen atoms have been substituted by a halogen atom. For example, the halogen atom may be chosen from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkenyl group may also be a heteroalkenyl group. In some embodiments, X is a carboxylic acid. In some embodiments, X is a carboxylic acid derivative. In some embodiments, X may be chosen from a carboxylate, a glyceride, an anhydride, a carboxamide, and a phospholipid. In some embodiments, X is a carboxylate such as a carboxylic ester. In some embodiments, X is a carboxylic 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, a 1,2-diglyceride, a 1,3 diglyceride, a 1-monoglyceride, or a 2-monoglyceride. In some embodiments, X is an anhydride. In some embodiments, X is a carboxamide and, in some embodiments, the carboxamide may be chosen from N- methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide and N,N-diethyl carboxamide. In some embodiments, X is a phospholipid Attorney Reference: 14622.0007-00304 In some embodiments, n is 0. In some embodiments X is a carboxylic acid, a carboxamide, or a 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 a hydroxymethyl. 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 chosen 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 chosen from a hydroxymethyl group, a carboxylic acid, a carboxylic ester, or a carboxamide. In some embodiments, n is 1 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C2 alkyl group. In some embodiments, n is 1 and R6 and R7 are both hydrogen atoms. In some embodiments, n is 1 and R6 and R7 are both methyl groups. In some embodiments, R6 is a methyl group and R7 is a hydrogen. In some embodiments, n is 1, R6 and R7 are both hydrogen atoms, and X is a carboxylic acid. In some embodiments, n is 1, R6 and R7 are both methyl groups, and X is a carboxylic acid. In some embodiments, n is 1, R6 and R7 are both hydrogen atoms, and X is an acetate group. In some embodiments, X may be chosen from a hydroxymethyl group, a carboxylic acid, a carboxylic ester, and a carboxamide. A “pharmaceutically active amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e. an amount of the combination product which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the combination product is within the skill of the art. Generally, the dosage regimen for treating a condition with the combination product of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient. “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 may be therapeutic in respect to an existing condition or it may be prophylactic, i.e., preventative. As used herein, “pre-term” or “premature” refers to a human infant born prior to 37 weeks gestation. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, and so forth 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 at least 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 the present specification and attached claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and such. Attorney Reference: 14622.0007-00304 The present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the inventions. The disclosed inventions are further illustrated by the following examples, which should not be construed as limiting the inventions. F. Examples Described herein is a preterm piglet model of intestinal failure-associated liver disease that reflects the biochemical and histologic disease of human neonates. Preterm Yorkshire piglets were delivered, central venous catheters were placed, and parenteral nutrition was provided for 14 days. Animals were treated with either medium chain triglycerides (MCT) vehicle control or a compound of formula (I). Preparation and Monitoring of Animals The study protocol and procedures were approved by the Institutional Animal Care and Use Committee at Boston Children's Hospital, and the study was conducted in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals. Pregnant Yorkshire sows were obtained (Parsons Pig Farm, Hadley, MA) and piglets were delivered at four (Litter 1) or five (Litter 2) days preterm (112- or 111-days gestation respectively) via caesarean section. Briefly, the sow was induced, and a femoral central venous catheter was inserted.500 ml of blood was collected into a blood bag containing citrate phosphate double dextrose (CP2D) solution (Haemonetics, Braintree, MA) and centrifuged to obtain plasma. Following this, a lower midline incision was made. One horn of the uterus was exteriorized and incised with electrocautery over the back of a piglet. The piglet was delivered from the uterus, oropharynx suctioned, umbilical cord ligated and divided, and handed off the surgical field for resuscitation. Subsequent piglets were delivered in this fashion. After delivery, piglets were dried, vigorously stimulated, warmed, and administered doxepram (0.2 ml), atropine (0.2 ml), and vitamin B12 (0.5 ml) via intramuscular injection. If necessary, ventilation and supplemental oxygen was provided via bag-valve mask. When necessary, additional doses were administered of epinephrine for bradycardia or doxepram for hypoventilation. Piglets were then placed in a warmed and humified incubator. After adequate resuscitation, piglets were induced and intubated. 3Fr central venous catheters were placed preferentially in the right external jugular vein. If unsuccessful, either the right internal jugular vein, the left internal jugular, or the left external jugular veins were used. Intravenous cefazolin (20 mg/kg), banamine (1 mg/kg), buprenorphine (0.01 mg/kg), cerenia (1 mg/kg), and intramuscular iron were administered. The piglets were returned to incubators and cohoused for a total of two piglets per incubator bay. Maternal plasma was provided over the first 24 hours of life for passive immunity (15 ml/kg over three doses). Cefazolin was provided for central line-associated bloodstream infection prophylaxis. In Litter Attorney Reference: 14622.0007-00304 1, cefazolin (20 mg/kg) was provided routinely twice daily on day of life (DOL) 1-4 and 8-11, with additional cefazolin and/or enrofloxacin given for signs of infection. In Litter 2, cefazolin was provided twice daily throughout the experiment. Daily intravenous famotidine (1 mg/kg) was administered to both litters for gastric prophylaxis. Total Parenteral Nutrition (TPN) Total parenteral nutrition with a target Intralipid dose of 5 g/kg/day was initiated on day of life (DOL) 1 and continued until sacrifice on day 15. The composition of the parenteral nutrition formulation is shown in Table 1. Table 1: Total Parenteral Nutrition Composition (Per Litre) Component Quantity Amino Acids 64 g The volume of com
Figure imgf000037_0001
p ys of life to the target volume of 125 ml/kg/day, see Fig. 1A and Table 2 below. Piglets were monitored for signs of TPN intolerance including hyperglycaemia, and evidence of dehydration such as lethargy. If there was concern for TPN intolerance, piglets were resuscitated with isotonic crystalloid and TPN rate was decreased for 24 hours before being readvanced. No other source of nutrition was provided. Table 2: Parenteral nutrition advancement scheme as a percentage of goal final volume. Day 1 Day 2 Day 3 Day 4 Days 5-14
Figure imgf000037_0002
In-Study Monitoring and Treatment Piglets were weighed daily. Baseline weight was defined as the birth weight obtained on day 1 of life. Daily weights were used for adjustment of TPN rate and study drug dose. Piglets were randomized to receive daily orogastric gavage of isovolumetric (3 ml/kg/d) medium chain triglyceride (MCT) vehicle or Compound A in medium chain triglyceride vehicle (Litter 1: 24 mg/kg/d; Litter 2: 48 mg/kg/d), see Table 3. Table 3: Summary of Treatment Groups Attorney Reference: 14622.0007-00304 Groups Treatment Control MCT vehicle Com ound A (Litter 1) 24 m /k /da once dail
Figure imgf000038_0002
o pou In litter 1, all
Figure imgf000038_0001
on DOL 1. Four piglets were randomized to the MCT vehicle group, while the remaining seven were assigned to the Compound A group (24 mg/kg). Due to several piglets with infectious complications, all piglets in this cohort received broad-spectrum antibiotics (enrofloxacin) starting on DOL 10 and continuing until sacrifice. The study procedure underwent minor modifications for litter 2. The volume of PN fluid delivered was increased by 15 ml/kg/day (with no change in goal nutrition via addition of free water). Piglets were also given cefazolin twice daily for the full length of the study to prevent infection. In litter 2, 14 of 15 piglets were successfully resuscitated and started TPN on DOL 1. Six piglets were randomized to the MCT group and eight to the Compound A group (48 mg/kg). Acute renal failure was noted in both MCT and Compound A piglets, and supplemental intravenous fluids were provided for resuscitation. Two piglets in each group required supplemental sodium bicarbonate (either intravenous or via oral gavage) for metabolic acidosis. No infectious complications were noted in this cohort. Collection and Analysis of Samples Blood Collection Blood was drawn on DOL 0, 8, and 15 (immediately prior to sacrifice). Complete blood count was performed using the VetScan HM5. Complete metabolic panel and mammalian liver profiles were performed using the VetScan VS2 (Zoetis, Parsippany, NJ). Analysis of plasma total bilirubin, direct bilirubin, and triglycerides were performed by the Boston Children’s Hospital clinical laboratory. Histology and Tissue Analysis Formalin-fixed paraffin embedded liver tissue was stained for haematoxylin & eosin (H&E) and Masson’s Trichrome. Frozen liver tissue embedded in Tissue-Tek optimal cutting temperature compound (Torrance, CA) was stained with oil red O. Hepatic steatosis was assessed via quantification of oil red O staining (CellProfiler, Boston, MA) as well as quantification of liver triglyceride content using a Attorney Reference: 14622.0007-00304 commercially available triglyceride assay according to the manufacturer’s instructions (Abcam ab65336, Cambridge, MA). Liver fibrosis was assessed by a masked pathologist using the Ishak fibrosis score. Outcomes and Statistical Analysis The primary outcome assessed was cholestasis (direct bilirubin). Secondary outcomes included other markers of cholestasis (total bilirubin, GGT), nutrition markers (weight gain, albumin, total protein), hepatic steatosis, and hepatic fibrosis. Due to methodological differences between litter 1 and litter 2, all statistical comparisons were made within litter. Continuous outcomes were assessed using nonparametric methods as the central limit theorem could not be relied upon due to the small sample size. At prespecified time points, comparison between two groups was performed with the Wilcoxon rank-sum test. Mean change in continuous outcomes, adjusted for baseline labs, was performed using the rank-based analysis of covariance (rANCOVA). The distribution of each outcome was assessed by Shapiro-Wilk (S-W) test. To judge the robustness of the results, parametric tests were used (t-test and ANCOVA) and in all cases the interpretation of the result was consistent for both tests. Assessment of parenteral nutrition volume delivered was performed via area under the curve calculated using the trapezoidal method as AUC = 0.5 ^ Σ [(Ti+1 - Ti)*(Yi+1 + Yi)]. When divided by the number of observation days, this could be interpreted as a weighted average of the outcome. This was similarly assessed via the Wilcoxon rank-sum test. Assessment of the categorical outcome of Ishak fibrosis score was performed using the Fisher exact test. All tests of significance are two-sided with P<0.05 considered statistically significant. Results In litter 1, all 12 piglets were successfully resuscitated and started parenteral nutrition on DOL 1. Four piglets were randomized to the MCT vehicle group, while the remaining seven were assigned to the Compound A group (24 mg/kg). Two MCT piglets survived to the end of the study at DOL 15, while a third survived until DOL 14 and is included in the analysis. Acute renal failure was noted in one MCT piglet. Five of seven Compound A piglets survived until DOL 15. Mortality in this cohort was primarily due to sepsis. Several piglets with infectious complications were noted. In litter 2, 14 of 15 piglets were successfully resuscitated and started parenteral nutrition on DOL 1. All six MCT piglets survived to DOL 15. Five of eight Compound A piglets survived until DOL 15. Mortality in Litter 2 was primarily due to acute renal failure in the days after birth, attributed to hypovolemia in the setting of delayed central venous catheter placement and slow initiation of TPN. No infectious complications were noted in this cohort. A summary table of Necropsy findings and final diagnoses for piglets are presented in Table 4 below. Table 4: Necropsy findings and final diagnoses for piglets determined by necropsy and in consultation with the large animal veterinarian. Attorney Reference: 14622.0007-00304 Litter Treatment Day of Life Necropsy Findings / Final Diagnosis Group o o s ss ss
Figure imgf000040_0002
the preliminary biochemical endpoints in Figs.1-3 and 5. In each litter, piglets in the MCT and Compound A groups each received a similar total volume of parenteral nutrition (Litter 1: 114 vs.110 ml/kg/day, P=0.77; Litter 2: 134 vs.131 ml/kg/day, P=0.33), see Fig.1A. Piglets in both litters 1 and 2 gained a similar amount of weight following treatment with MCT or Compound A (0.5 ± 0.1 vs.0.6 ± 0.1 kg, P = 0.15), see Fig.1B and Table 5. Table 5: Comparison of body weight over time Litter 1 MCT Compound A (n=3) (24 mg/kg) (n=5) Weight (kg), unadjusted, mean ± SD PS-W Pt-test Prank-sum DOL 1 1.4 ± 0.1 1.3 ± 0.1 0.22
Figure imgf000040_0001
DOL 14 1.8 ± 0.3 1.6 ± 0.2 0.28 0.30 0.39 DOL 15 (n=2, 5) 1.8 ± 0.0 1.5 ± 0.2 0.37 0.14 0.38 ANCOVA change in weight, mean ± PS-W PANCOVA PrANCOVA SE DOL 1 – 14, adjusted for DOL 1 0.4 ± 0.1 0.3 ± 0.1 0.14 0.51 0.51 DOL 1 – 15, adjusted for DOL 1 (n=7) 0.4 ± 0.1 0.2 ± 0.1 0.03 0.20 0.25 Attorney Reference: 14622.0007-00304 Litter 2 MCT Compound A (n=6) (48 mg/kg) (n=5) Weight (kg), unadjusted, mean ± SD PS-W Pt-test Prank-sum DOL 1 1.1 ± 0.3 1.2 ± 0.1
Figure imgf000041_0001
DOL 14 1.6 ± 0.3 1.8 ± 0.1 DOL 15 1.6 ± 0.3 1.8 ± 0.1 0.23 0.30 0.36 ANCOVA change in weight, mean ± PS-W PANCOVA PrANCOVA SE DOL 1 – 14, adjusted for DOL 1 0.55 ± 0.65 ± 0.06 0.41 0.28 0.06 0.06 DOL 1 – 15, adjusted for DOL 1 0.50 ± 0.60 ± 0.06 0.99 0.24 0.15 0.05 Weight-normalized liver, right kidney, and spleen weights were similar between the MCT and Compound A groups in each litter, see Fig.2. Plasma albumin was assessed as a biochemical marker of nutritional status and liver synthetic function. In both groups, plasma albumin increased from largely undetectable at birth through DOL 15. Compared to the MCT group, piglets receiving Compound A had higher plasma albumin at DOL 8 and 15 (DOL 8: 1.3 ± 0.4 vs. 1.9 ± 0.1 g/dL, P = 0.004; DOL 15: 2.7 ± 0.6 vs. 3.6 ± 0.3 g/dL, P =0.02), see Fig. 1C and Table 6 below. Similarly, plasma total protein was also assessed as a biochemical marker of nutritional status. Compared to MCT animals, total protein at DOL 15 trended higher in both Compound A groups (Litter 1: 4.1 vs.4.9 g/dL, P=0.10; Litter 2: 3.9 vs.4.4, P=0.06). Table 6: Compound A increased plasma albumin compared to MCT Litter 1 MCT Compound (n=3) A (24 mg/kg) (n=5) ALB (g/dL), unadjusted, mean±SD PS-W Pt-test Prank-sum DOL 1 0.1 ± 0.1 0.2 ± 0.2 0.01
Figure imgf000041_0002
DOL 8 1.7 ± 0.4 2.1 ± 0.2 0.12 0.12 0.21 DOL 15 2.2 ± 0.5 3.5 ± 0.4 0.18 0.006 0.04 ANCOVA change in ALB, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15 (no adjustment for DOL 1) 2.1 ± 0.5 3.4 ± 0.4 0.15 0.008 0.05 Attorney Reference: 14622.0007-00304 Litter 2 MCT Compound A (n=6) (48 mg/kg) (n=5) ALB (g/dL), unadjusted, mean±SD PS-W Pt-test Prank- sum DOL 1 (n=4, 5) 0.5 for all 0.5 for all --
Figure imgf000042_0001
DOL 8 1.3 ± 0.4 1.9 ± 0.1 0.21 0.009 0.004 DOL 15 2.7 ± 0.6 3.6 ± 0.3 0.59 0.01 0.02 ANCOVA change in ALB, mean ± SE PS-W Pt-test Prank- sum DOL 1 – 15 (no adjustment for DOL 1) (n=9) 2.4 ± 0.5 3.6 ± 0.3 0.57
Figure imgf000042_0002
Direct and total bilirubin levels were monitored to assess cholestasis, and cholestatic liver injury was assessed with plasma gamma glutamyl transferase (GGT) levels, see Table 7 (direct bilirubin), Table 8 (total bilirubin), and Table 9 (GGT levels) below. As shown in Fig. 3, piglets receiving Compound A demonstrated both lower plasma direct bilirubin and plasma GGT levels than the MCT animals. In litter 1, compared to MCT animals, the Compound A (24 mg/kg) piglets demonstrated lower plasma direct bilirubin at DOL 15 (0.8 vs. 0.2 mg/dL, P=0.02). Similarly, in litter 2 the Compound A (48 mg/kg) piglets demonstrated lower plasma direct bilirubin at DOL 15 (1.6 vs.0.2 mg/dL, P=0.01). Similarly, in both litter 1 and litter 2 compared to MCT, Compound A at 24mg/kg and 48mg/kg decreased plasma total bilirubin at DOL 15 (litter 1: 1.4 vs. 0.4 mg/dL, P=0.02; litter 2: 2.6 vs. 0.6 mg/dL, P=0.02). Compared to MCT, Compound A decreased GGT at DOL 15 (Litter 1: 161 vs.46 mg/dL, P=0.04; Litter 2: 155 vs.29 mg/dL, P=0.01). With each output, the reduction of cholestatic liver injury in animals treated with either dose of Compound A was clearly demonstrated with statistical significance. Table 7: Compound A decreased direct bilirubin compared to MCT Litter 1 MCT Compound A (n=3) (24 mg/kg) (n=5) Direct bilirubin (mg/dL), unadjusted, PS-W Pt-test Prank- mean±SD
Figure imgf000042_0003
DOL 1 0.1 for all 0.1 for all -- -- -- DOL 8 0.8 ± 1.2 0.1 ± 0.0 <0.0001 0.42 0.38 DOL 15 0.8 ± 0.6 0.2 ± 0.1 0.004 0.19 0.02 Attorney Reference: 14622.0007-00304 ANCOVA change in DB, mean ± SE PS-W Pt-test Prank- sum DOL 1 – 15 (no adjustment for DOL 1) 2.8 ± 0.6 1.3 ± 1.2 0.04 0.10 0.02 Litter 2 MCT Compound A (n=6) (48 mg/kg) (n=5) Direct bilirubin (mg/dL), unadjusted, PS-W Pt-test Prank- mean±SD sum DOL 1 0.1 for all 0.1 for all -- -- -- DOL 8 0.2 ± 0.2 0.1 ± 0.0 <0.00 0.22 0.45 01 DOL 15 1.6 ± 1.0 0.2 ± 0.2 0.009 0.02 0.01 ANCOVA change in DB, mean ± SE PS-W Pt-test Prank- sum DOL 1 – 15 (no adjustment for DOL 1) 3.6 ± 1.0 0.5 ± 1.1 0.05 0.001 0.01 In litter 1, direct bilirubin was below the detectable limit (<0.2) and recoded to 0.1mg/dL for 17/24 observations (56% MCT, 80% Compound A @ 24 mg/kg). In litter 2, direct bilirubin was recoded for 24/33 (73%) observations (56% MCT, 93% Compound A @ 48 mg/kg). Table 8: Compound A decreased total bilirubin compared to MCT Litter 1 MCT Compound A (n=3) (24 mg/kg) (n=5) Total bilirubin (mg/dL), unadjusted, PS-W Pt-test Prank-sum mean±SD DOL 1 0.1 ± 0.1 0.2 ± 0.0 0.0005 0.24 0.46 DOL 8 1.0 ± 1.3 0.2 ± 0.1 <0.0001 0.39 0.18 DOL 15 1.4 ± 1.1 0.4 ± 0.2 0.004 0.24 0.02 ANCOVA change in TB, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15, adjusted for DOL 1 1.8 ± 0.7 0.7 ± 0.5 0.63 0.30 0.09 Litter 2 MCT Compound A (n=6) (48 mg/kg) (n=5) Attorney Reference: 14622.0007-00304 Total bilirubin (mg/dL), unadjusted, PS-W Pt-test Prank-sum mean±SD DOL 1 0.1 ± 0.1 0.2 ± 0.1 0.002
Figure imgf000044_0001
DOL 8 0.3 ± 0.3 0.1 ± 0.0 <0.0001 0.19 0.45 DOL 15 2.6 ± 1.6 0.6 ± 0.4 0.02 0.03 0.02 ANCOVA change in TB, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15, adjusted for DOL 1 3.4 ± 0.6 1.8 ± 0.6 0.20 0.12 0.15 In litter 1, total bilirubin <0.2 was below the detectable limit and recoded to 0.1 mg/dL for 6/24 (25%) observations (22% MCT, 27% Compound A @ 24 mg/kg). In litter 2, total bilirubin was recoded for 15/33 (45%) observations (44% MCT, 47% Compound A @ 48 mg/kg). Table 9: Compound A decreased gamma glutamyl transferase compared to MCT Litter 1 MCT Compound (n=3) A (24 mg/kg) (n=5) GGT (mg/dL), unadjusted, mean±SD PS-W Pt-test Prank-sum DOL 1 46 ± 3 45 ± 26
Figure imgf000044_0002
DOL 8 99 ± 89 32 ± 12 0.0002 0.33 0.07 DOL 15 161 ± 118 46 ± 16 0.0016 0.23 0.04 ANCOVA change in GGT, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15, adjusted for DOL 1 115 ± 44 1 ± 34 0.004 0.09 0.04 Litter 2 MCT Compound A (n=6) (48 mg/kg) (n=5) GGT (mg/dL), unadjusted, mean±SD PS-W Pt-test Prank-sum DOL 1 38 ± 8 33 ± 3 0.82
Figure imgf000044_0003
DOL 8 78 ± 72 29 ± 2 <0.0001 0.16 0.08 DOL 15 189 ± 131 34 ± 7 0.003 0.03 0.01 ANCOVA change in GGT, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15, adjusted for DOL 1 155 ± 28 29 ± 24 0.003 0.02 0.05 Attorney Reference: 14622.0007-00304 Secondary outcomes included histologic biomarkers of progressive and/or chronic IFALD. Representative histology is shown in Fig. 4. MCT piglets demonstrated steatosis, bile duct proliferation, and bridging portal-portal and portal-central vein fibrosis. In contrast, compound A piglets demonstrated minimal steatosis, only mild bile duct proliferation, and minimal fibrotic portal expansion. Steatosis was quantified first by staining frozen liver sections with oil red O; MCT piglets demonstrated increased oil red O staining compared to Compound A piglets (Fig.4E-F, Fig.5A; 5.0 ± 3.2 vs.0.7 ± 1.1 % area stained, P = 0.017). Compared to MCT animals, Compound A piglets trended towards a lower mean % liver area stained with oil red O (10.0 vs.2.1, P=0.08). In the liver triglyceride assay, Compound A piglets (48 mg/kg, litter 2) had lower liver triglyceride content, consistent with decreased hepatic steatosis (41.2 vs.15.6 mg triglycerides / g liver tissue, P=0.009), see Fig.6. Liver triglyceride content was also substantially higher in the MCT piglets compared to Compound A piglets (Fig.5B; 41.2 ± 15.5 vs.15.6 ± 3.4 mg triglycerides / g liver tissue, P = 0.0087). Bile duct proliferation was assessed using immunohistochemical staining for cytokeratin 7, a cholangiocyte marker. MCT piglets demonstrated increased cytokeratin 7 staining compared to Compound A piglets, consistent with increased bile duct proliferation (Fig.4I-J, Fig.5D; 1.6 ± 0.5 vs.0.6 ± 0.3 % area stained, P = 0.0087). Hepatic stellate cell activation–a key step in fibrogenesis–was assessed using immunohistochemical staining for α smooth muscle actin (αSMA). MCT piglets demonstrated increased αSMA staining compared to Compound A piglets, consistent with increased αSMA activation (Fig.4G-H, Fig.5C; 3.4 ± 0.9 vs.1.9 ± 0.5 % area stained, P = 0.0043). A masked veterinary pathologist assessed liver fibrosis on formalin-fixed paraffin embedded liver tissue stained with Masson’s Trichrome (Fig.4C-D, Fig.5E). MCT piglets had more severe fibrosis than Compound A piglets with a median Ishak fibrosis score of 3 (fibrous expansion of most portal areas with occasional portal-portal bridging) versus median score of 1 (fibrous expansion of some portal areas ± short fibrous septa) (P = 0.007). The representative stains in Fig. 6, show that piglets receiving MCT demonstrated fibrous expansion of most portal areas with some portal-to-portal bridging (black arrows). However, piglets receiving Compound A had significantly decreased fibrosis with fibrous expansion of some portal areas, but no portal-to-portal bridging as shown on the top right panel. These findings indicate that Compound A (48 mg/kg) treated piglets demonstrated decreased fibrosis of the liver (median 3 vs.1, P=0.007) as compared to the MCT treated group. The box-whisker plots for Ishak fibrosis scores also show this outcome (lower panel in Fig.7). Plasma bile acids and serum adiponectin were assessed for litter 2 animals, see Fig.8 and Table 10 below. Compared to MCT, Compound A (48 mg/kg) decreased plasma bile acids at DOL 15 (17.6 vs.2.9 µmol/L, P=0.03). Table 10: Compound A (48mg/kg) decreased bile acids compared to MCT Litter 2 MCT Compound A (n=6) (n=5) Bile acids (μmol/L), unadjusted, PS-W Pt-test Prank-sum mean±SD Attorney Reference: 14622.0007-00304 DOL 1 (n=4, 5) 0.0 for all 0.0 for all -- -- -- DOL 8 5.3 ± 6.4 0.4 ± 0.2 <0.0 0.12 0.12 001 DOL 15 17.6 ± 12.4 2.9 ± 3.5 0.04 0.03 0.03 ANCOVA change in BA, mean ± SE PS-W PANCOVA PrANCOVA DOL 1 – 15 (no adjustment for DOL 1) 20.5 ± 11.7 1.6 ± 4.1 0.07 0.01 0.02 (n=9)
Figure imgf000046_0001
Serum adiponectin, a sensitive and specific marker of PPARγ activation, was elevated in the Compound A piglets at DOL 15 compared to the MCT piglets (18.7 ± 17.6 vs. 214.2 ± 122.7 ng/ml, P = 0.0043), see Fig.8. This suggests that Compound A is a PPARγ agonist. Analysis of functional pathways Liver tissue was collected at necropsy, flash frozen in liquid nitrogen, and stored at -80o C until analysis. mRNA-Seq was performed by Novogene Co. (Sacramento, CA, USA). RNA integrity was assessed with the RNA Nano 6000 Assay kit (Agilent Technologies, CA, USA). All samples had RIN> 4 and passed the established quality thresholds. mRNA was purified using poly-T oligo-attached magnetic beads and 150 bp paired-end reads were generated using the NovaSeq 6000 platform (Illumina, San Diego, CA). Raw data were cleaned with removal of low quality reads and then mapped to the Sscrofa11.1 pig genome using Hisat2 v2.0.5. Mapped reads were assembled using StringTie v1.3.3b.. Read numbers for each mapped gene were calculated with featureCounts v1.5.0-p3. Differentially expressed genes were determined using the DESeq2 R package 1.20.0. Adjusted P value < 0.05 using the Benjamini and Hochberg approach for multiple testing were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using clusterProfiler. Further functional pathway analysis and investigation of upstream regulators was performed using Ingenuity Pathway Analysis (Qiagen Inc.) using differentially expressed genes with adjusted P < 0.1 and log2foldchange > |0.5|. Gene expression analyses were performed to identify differences between the groups and pathways potentially mediating the hepatoproetctive effects of Compound A in the pre-term piglet model. mRNA- Seq was performed on liver tissue from all MCT and Compound A piglets. One-hundred and forty-seven differentially expressed genes (52 up, 95 down) were identified. Functional analysis was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity Pathway Analysis (IPA). Commonly enriched pathways across multiple functional analyses included fatty acid oxidation and metabolic processes (GO, KEGG, and IPA), retinol metabolism/retinoid X receptor (RXR) function (KEGG and IPA), and inflammation/cellular adhesion (GO and IPA). GO enrichment analysis demonstrated that the most enriched biological processes were fatty acid oxidation and lipid oxidation, while the most enriched cellular components were involved in cell adhesion. KEGG analysis found the most enriched pathways involved retinol metabolism, PPAR signaling, and fatty Attorney Reference: 14622.0007-00304 acid degradation. IPA demonstrated the key upregulated canonical pathways included pathways involved in oxidative phosphorylation, eukaryotic initiation factor 2 (EIF2) signaling, fatty acid β-oxidation I, and glutathione redox reactions I. Both EIF2 phosphorylation and glutathione redox reactions are critical in mediating the antioxidant capacity in the liver and responding to oxidative stress (Choi et al., Nutr. Metab.; 14: 48 (2017)). Key downregulated canonical pathways included the Sirtuin signaling pathway, Granzyme A signaling, and lipopolysaccharide/interleukin-1 (LPS/IL-1), and mediated inhibition of RXR function. Specific canonical pathways of interest were also analyzed in IPA based upon observed differentially expressed genes. PPARα/RXR activation was predicted with predicted increased fatty acid oxidation, fatty acid uptake, glucose homeostasis, lipoprotein metabolism, β-oxidation, and anti- inflammation. Consistent with this activation, investigation of the inhibited LPS/IL-1 Mediated Inhibition of RXR Function pathway demonstrates predicted activation of retinoid X receptor-mediated pathways including master regulators liver X receptor, farsenoid X receptor, retinoic acid receptor, pregnane X receptor, and PPARs. Notably, this includes genes involved in bile acid and organic ion transport, in addition to fatty acid metabolism. Nuclear factor kappa B (NF-κB) signaling (which is downregulated by both PPARγ and PPARα) was predicted to be inhibited. Finally, hepatic fibrosis signaling was investigated. Fibrosis pathways mediated by transforming growth factor β (TGF-β), SMAD 2/3/4, c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) were predicted to be inhibited, resulting in predicted decreased hepatic stellate cell activation and liver fibrosis. Upstream regulator analysis by IPA identified candidate upstream regulators consistent with observed downstream pathway enrichment. The activation z-score provides the degree of downstream activation or inhibition, with upstream regulators with a z-score > |2| considered significant. Identification of PPARγ co-activator 1α (PPARGC1A) as one of the greatest activated upstream regulators (z-score 3.234) is consistent with PPARγ agonism (as it is a transcriptional coactivator for PPARγ). Similarly, hepatocyte nuclear factor 4 alpha (HNF4A) interacts with PPARα to drive fatty acid metabolism, consistent with activation of pathways downstream of PPARα. Inhibited upstream regulators included key pro- inflammatory signaling molecules such as MYD88, NR4A1, and TNF (consistent with anti-inflammatory effects). Multiple transcription regulators were identified as possible activated upstream regulators including HAND2, GATA4, TBX5, MEF2C, and MYOCD which all inhibit transcription of collagen genes COL1A2 and COL3A1, consistent with downstream anti-fibrotic activity. Eukaryotic initiation factor 6 (EIF6) inhibition is also associated with reduction in nonalcoholic fatty liver disease through downregulation of de novo lipogenesis genes and collagen-encoding genes, resulting in decreased steatosis and fibrosis (Scagliola et al., Nat. Commun.; 12: 4878 (2021)). Predicted upstream regulators are consistent with PPARγ and PPARα agonism as the key mechanisms mediating the metabolic, anti-inflammatory, and anti-fibrotic effects of Compound A in this model. Mode of Action Study GPR84 activation Attorney Reference: 14622.0007-00304 The activity of Compound A towards GPR84 was determined in vitro using a Hit Hunter® cAMP assay (Eurofins DiscoverX, CA, US) with Embelin acting as a positive control. cAMP Hunter cell lines were expanded from freezer stocks according to standard procedures and cells were seeded in a total volume of 20 µL into white walled, 384-well microplates and incubated at 37°C/5% CO2 overnight prior to incubation with either Compound A or Embelin at 37°C/5% CO2 or room temperature for 60 minutes at 10-point concentration curve from 0.001 to 100 mM. Compound activity was determined via chemiluminescence using β-galactosidase (β-Gal) as the functional reporter. Percentage activity was calculated using the following formula: % Activity=100% x (mean relative luminescence units (RLU) of test sample - mean RLU of vehicle control) / (mean MAX control ligand-mean RLU of vehicle control). PPARα and PPARγ activation The activity of Compound A towards human PPARα and PPARγ was determined in vitro using PathHunter NHR cell lines (Eurofins DiscoverX, CA, US) with GW7647 (2-[[4-[2- [[(Cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid) or troglitazone (5-[[4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methoxy]phenyl]methyl]- 1,3-thiazolidine-2,4-dione) acting as respective positive controls. NHR cell lines were expanded from freezer stocks according to standard procedure and seeded in a total volume of 20 µL into white walled, 384-well microplates and incubated at /5% CO2 overnight prior to incubation with either Compound A or GW7647 or Troglitazone at 37°C/5% CO2 or room temperature for 3-16 hours at 10-point concentration curve from 0.001 to 100 mM. Compound activity was determined via chemiluminescence after the addition of PathHunter Detection reagent cocktail. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection. Percentage activity was calculated using the following formula: % Activity=100% x (mean RLU of test sample - mean RLU of vehicle control) / (mean MAX control ligand-mean RLU of vehicle control). Results The results showed that Compound A is a partial GPR84 agonist (69%) with an EC50 value of 12 µM. Furthermore Compound A is a partial PPARα agonist (59% efficacy) and full PPARγ agonist (100% efficacy) with corresponding EC50 values of 4.4 and 40 µM respectively. Conclusion The results show that with Compound A treatment, piglets gained similar weight in both groups with increasing albumin and protein levels throughout the study, consistent with improving nutritional status. After 15 days of treatment, both 24 mg/kg/day or 48 mg/kg/day Compound A reduced direct and total bilirubin levels to day 1 levels. Furthermore, GGT levels, which indicate cholestatic liver injury, were also reduced to day 1 levels following Compound A treatment at either dose. Measures of hepatic steatosis and liver fibrosis were also significantly decreased following 48 mg/kg/day Compound A. These results Attorney Reference: 14622.0007-00304 suggest Compound A as a potential treatment for treatment in patients with IFALD or for prevention in patients at risk of developing IFALD.

Claims

Attorney Reference: 14622.0007-00304 We claim: 1. A method of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a human wherein
Figure imgf000050_0001
• 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group; • 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, a OR10 group, a S(O)mR10 group, or a NR9R10 group; • R3, R4 are the same or different and may be chosen from a hydrogen atom or a halogen atom, • 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 bond 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group;, • with the proviso that if R1 is a OR11 group and R5 is a hydrogen atom, a haloalkyl group, a C1- C4 alkyl group, a OR11 group, a SR11 group, or a NR12R13 group, then R2 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, C4-C6 alkynyl group, or a C4-C6 alkyl-Y- group; Attorney Reference: 14622.0007-00304 • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and an C1-C6 alkyl group, wherein R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; • 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; • R9 is a hydrogen atom or a C1-C11 alkyl group; • R10 is 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; • R11 is a C1-C4 alkyl group; • R12 and R13 are independently chosen from a hydrogen atom and a C1-C4 alkyl group; • X is a hydroxymethyl or a carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic ester, a glyceride, an anhydride, a carboxamide, or a phospholipid, or a prodrug thereof; • Y is an oxygen atom, a sulphur atom, or a NR12R13 group; • m is 0, 1, or 2; and • n is 0, 1, or 2. 2. The method of claim 1, wherein the method reduces cholestasis in the subject. 3. The method of claim 1, wherein the method reduces hepatic steatosis in the subject. 4. The method of claim 1, wherein the method reduces hepatic fibrosis in the subject. 5. The method of claim 1, wherein the method reduces cirrhosis in the subject. 6. The method of claim 1, wherein the method reduces gallbladder disease in the subject. 7. The method of claim 1, wherein the method reduces plasma bilirubin levels in the subject. 8. The method of claim 1, wherein the method reduces direct plasma bilirubin levels in the subject. 9. The method of claim 1, wherein the method reduces total plasma bilirubin levels in the subject. 10. The method of claim 1, wherein gamma glutamyl transferase (GGT) levels are reduced in the subject. 11. The method of claim 1, wherein the method reduces alanine aminotransferase levels in the subject. 12. The method of claim 1, wherein the method reduces aspartate aminotransferase levels in the subject. 13. The method of claim 1, wherein the method raises serum albumin levels in the subject. 14. The method of claim 1, wherein nutrition markers are improved in the subject. 15. The method of claim 1, wherein weight gain is observed in the subject. 16. The method of claim 1, wherein serum albumin levels are raised in the subject. 17. The method of claim 1, wherein plasma total protein levels are raised in the subject. Attorney Reference: 14622.0007-00304 18. The method of claim 1, wherein the method is prophylactic. 19. The method of claim 1, wherein the subject is a human child that is receiving parenteral nutrition. 20. The method of claim 1, wherein the subject is a human child that has previously received parenteral nutrition. 21. The method of claim 1, wherein the subject is a human child is 12 to 18 years old. 22. The method of claim 1, wherein the subject is a human child less than 12 years old. 23. The method of claim 1, wherein the subject is a human child that is 2 to 12 years old. The method of claim 1, wherein the subject is a human child that is 2 years old or less. 24. The method of claim 1, wherein the compound of formula I is administered in a dosage ranging from about 250 mg to about 2 g per kg of body weight per day. 25. The method of claim 1, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.5 g per kg of body weight per day. 26. The method of claim 1, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.2 g per kg of body weight. 27. The method of claim 1, wherein the administration is intravenous administration. 28. The method according to claim 1, wherein • 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 atom is a heteroatom; • R2 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, a OR14 group, a S(O)mR14 group, or a NR9R14 group; and • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1- C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms of which 1 atom is a heteroatom; wherein • R14 is 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 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. 29. The method according to claim 1, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group. 30. The method according to claim 1, wherein 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 is a heteroatom, or a phenyl group. Attorney Reference: 14622.0007-00304 31. The method according to claim 1, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group 32. The method according to claim 1, wherein R1 is a methyl group or an ethyl group. 33. The method according to claim 1, wherein R1 is a methyl group. 34. The method according to claim 1, wherein R2 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, an -O- (C3-C8) alkyl group, an -O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3- C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 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, a -S-(C3-C8) alkyl group, a -S-(C3-C8) hydroxyalkyl group, a -S-(C3-C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, a -C(O)-(C3-C8) alkyl group, a -S(O)-(C3-C8) alkyl group, a -S(O)2- (C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group, or an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. 35. The method according to claim 1, wherein R2 is a C4-C9 alkyl 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, an - O-(C3-C8) alkyl group, O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O- heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C4-C8) haloalkenyl group having 1-2 double bonds, a -S-(C3-C8) alkyl group, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C4-C8) alkenyl group having 1-2 double bonds, or a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond. 36. The method according to claim 1, wherein R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position. 37. The method according to claim 1, wherein R5 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 atom is a heteroatom. 38. The method according to claim 1, wherein R3, R4, and R5 are each a hydrogen atom. 39. The method according to claim 1, wherein • R1 is a methyl group or an ethyl group; Attorney Reference: 14622.0007-00304 • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in 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 independently chosen from a hydrogen atom and a methyl group; and • X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group. 40. The method according to claim 1, wherein • R1 is a methyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R3, R4, and R5 are each a hydrogen atom; • n is 0; and • X is a carboxylic acid. 41. The method according to claim 1, wherein X is a carboxylic acid derivative chosen from a carboxylate, a glyceride, an anhydride, a carboxamide, and a phospholipid. 42. The method according to claim 1, wherein X is a carboxylic ester. 43. The method according to claim 1, wherein X is a carboxamide chosen from N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide and N,N-diethyl carboxamide. 44. The method according to claim 1, wherein X is a glyceride chosen from a triglyceride, a 1,2- diglyceride, a 1,3 diglyceride, a 1-monoglyceride, or a 2-monoglyceride. 45. The method according to claim 1, wherein X is a carboxylic acid, a carboxamide, or a hydroxymethyl. 46. The method according to claim 1, wherein X is a carboxylic acid. 47. The method according to claim 1, wherein n is 1 or 2 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C6 alkyl group. 48. The method according to claim 1, wherein n is 1 or 2 and R6 and R7 together form a cycloalkyl group chosen from cyclopropane, cyclobutane, cyclopentane, or cyclohexane. 49. The method according to claim 1, wherein n is 0. 50. The method according to claim 1, wherein the compound is
Figure imgf000054_0001
yloxy)benzoic acid. 51. The method according to claim 1, wherein the compound is Attorney Reference: 14622.0007-00304 acid. 52.
Figure imgf000055_0001
1, wherein the compound is a salt comprising a monovalent cation chosen from Li+, Na+, K+, Mg2+, or Ca2+. 53. The method according to claim 1, wherein the compound is in a mixture of diastereomers or in racemic form. 54. The method according to claim 1, wherein the compound is in the form of a diastereomer or an enantiomer. 55. The method according to claim 1, wherein the compound is in the form of its R stereoisomer. 56. The method according to claim 1, wherein the compound is in the form of its S stereoisomer. 57. The method according to claim 1, wherein the compound is a salt chosen from: benzoate; benzoate;
Figure imgf000055_0002
Figure imgf000055_0003
benzoate; and
Figure imgf000055_0004
benzoate. 58. A method of treating intestinal failure-associated liver disease (IFALD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof Attorney Reference: 14622.0007-00304 (I) wherein the subject is a human wherein
Figure imgf000056_0001
• 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group; • 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, a OR10 group, a S(O)mR10 group, or a NR9R10 group; • R3, R4 are the same or different and may be chosen from a hydrogen atom or a halogen atom, • 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 bond 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group;, • with the proviso that if R1 is a OR11 group and R5 is a hydrogen atom, a haloalkyl group, a C1- C4 alkyl group, a OR11 group, a SR11 group, or a NR12R13 group, then R2 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, C4-C6 alkynyl group, or a C4-C6 alkyl-Y- group; • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and an C1-C6 alkyl group, wherein R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; • 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 Attorney Reference: 14622.0007-00304 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; • R9 is a hydrogen atom or a C1-C11 alkyl group; • R10 is 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; • R11 is a C1-C4 alkyl group; • R12 and R13 are independently chosen from a hydrogen atom and a C1-C4 alkyl group; • X is a hydroxymethyl or a carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic ester, a glyceride, an anhydride, a carboxamide, or a phospholipid, or a prodrug thereof; • Y is an oxygen atom, a sulphur atom, or a NR12R13 group; • m is 0, 1, or 2; and • n is 0, 1, or 2. 59. The method of claim 58, wherein the method reduces cholestasis in the subject. 60. The method of claim 58, wherein the method reduces hepatic steatosis in the subject. 61. The method of claim 58, wherein the method reduces hepatic fibrosis in the subject. 62. The method of claim 58, wherein the method reduces cirrhosis in the subject. 63. The method of claim 58, wherein the method reduces gallbladder disease in the subject. 64. The method of claim 58, wherein the method reduces plasma bilirubin levels in the subject. 65. The method of claim 58, wherein the method reduces direct plasma bilirubin levels in the subject. 66. The method of claim 58, wherein the method reduces total plasma bilirubin levels in the subject. 67. The method of claim 58, wherein gamma glutamyl transferase (GGT) levels are reduced in the subject. 68. The method of claim 58, wherein the method reduces alanine aminotransferase levels in the subject. 69. The method of claim 58, wherein the method reduces aspartate aminotransferase levels in the subject. 70. The method of claim 58, wherein the method raises serum albumin levels in the subject. 71. The method of claim 58, wherein nutrition markers are improved in the subject. 72. The method of claim 58, wherein weight gain is observed in the subject. 73. The method of claim 58, wherein serum albumin levels are raised in the subject. 74. The method of claim 58, wherein plasma total protein levels are raised in the subject. 75. The method of claim 58, wherein the method is prophylactic. 76. The method of claim 58, wherein the subject is a human infant that is receiving parenteral nutrition. 77. The method of claim 58, wherein the subject is a human infant that has previously received parenteral nutrition. 78. The method of claim 58, wherein the subject is a human infant that is 6 months old or less. Attorney Reference: 14622.0007-00304 79. The method of claim 58, wherein the subject is a human infant born less than about 140 days prior to initial administration of a compound of formula (I). 80. The method of claim 58, wherein the subject is a human infant born less than about 140 days prior to initial administration of a compound of formula (I) and receiving parenteral nutrition. 81. The method of claim 58, wherein the subject is a human infant born less than about 2 weeks prior to initial administration of a compound of formula (I). 82. The method of claim 58, wherein the subject is a human infant born less than about 1 week prior to initial administration of a compound of formula (I). 83. The method of claim 58, wherein the subject is a pre-term human infant. 84. The method of clam 58, wherien the subject is a pre-term human infant born ranging from: 22 to 36 weeks gestation. 85. The method of claim 58, wherein the subject is a human infant born ranging from 30 to 32 weeks gestation. 86. The method of claim 58, wherein the compound of formula I is administered in a dosage ranging from about 250 mg to about 2 g per kg of body weight per day. 87. The method of claim 58, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.5 g per kg of body weight per day. 88. The method of claim 58, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.2 g per kg of body weight. 89. The method according to claim 58, wherein • 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 atom is a heteroatom; • R2 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, a OR14 group, a S(O)mR14 group, or a NR9R14 group; and • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1- C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms of which 1 atom is a heteroatom; wherein • R14 is 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 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. 90. The method according to claim 58, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group. Attorney Reference: 14622.0007-00304 91. The method according to claim 58, wherein 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 is a heteroatom, or a phenyl group. 92. The method according to claim 58, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group 93. The method according to claim 58, wherein R1 is a methyl group or an ethyl group. 94. The method according to claim 58, wherein R1 is a methyl group. 95. The method according to claim 58, wherein R2 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, an - O-(C3-C8) alkyl group, an -O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O- (C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 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, a -S-(C3-C8) alkyl group, a -S-(C3-C8) hydroxyalkyl group, a -S-(C3- C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, a -C(O)-(C3-C8) alkyl group, a -S(O)-(C3-C8) alkyl group, a -S(O)2- (C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group, or an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. 96. The method according to claim 58, wherein R2 is a C4-C9 alkyl 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, an - O-(C3-C8) alkyl group, O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O- heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C4-C8) haloalkenyl group having 1-2 double bonds, a -S-(C3-C8) alkyl group, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C4-C8) alkenyl group having 1-2 double bonds, or a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond. 97. The method according to claim 58, wherein R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position. 98. The method according to claim 58, wherein R5 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 atom is a heteroatom. Attorney Reference: 14622.0007-00304 99. The method according to claim 58, wherein R3, R4, and R5 are each a hydrogen atom. 100. The method according to claim 58, wherein • R1 is a methyl group or an ethyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in 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 independently chosen from a hydrogen atom and a methyl group; and • X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group. 101. The method according to claim 58, wherein • R1 is a methyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R3, R4, and R5 are each a hydrogen atom; • n is 0; and • X is a carboxylic acid. 102. The method according to claim 58, wherein X is a carboxylic acid derivative chosen from a carboxylate, a glyceride, an anhydride, a carboxamide, and a phospholipid. 103. The method according to claim 58, wherein X is a carboxylic ester. 104. The method according to claim 58, wherein X is a carboxamide chosen from N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide and N,N-diethyl carboxamide. 105. The method according to claim 58, wherein X is a glyceride chosen from a triglyceride, a 1,2- diglyceride, a 1,3 diglyceride, a 1-monoglyceride, or a 2-monoglyceride. 106. The method according to claim 58, wherein X is a carboxylic acid, a carboxamide, or a hydroxymethyl. 107. The method according to claim 58, wherein X is a carboxylic acid. 108. The method according to claim 58, wherein n is 1 or 2 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C6 alkyl group. 109. The method according to claim 58, wherein n is 1 or 2 and R6 and R7 together form a cycloalkyl group chosen from cyclopropane, cyclobutane, cyclopentane, or cyclohexane. 110. The method according to claim 58, wherein n is 0. 111. The method according to claim 58, wherein the compound is Attorney Reference: 14622.0007-00304 yloxy)benzoic acid. 112.
Figure imgf000061_0001
58, wherein the compound is acid. 113.
Figure imgf000061_0002
58, wherein the compound is a salt comprising a monovalent cation chosen from Li+, Na+, K+, Mg2+, or Ca2+. 114. The method according to claim 58, wherein the compound is in a mixture of diastereomers or in racemic form. 115. The method according to claim 58, wherein the compound is in the form of a diastereomer or an enantiomer. 116. The method according to claim 58, wherein the compound is in the form of its R stereoisomer. 117. The method according to claim 58, wherein the compound is in the form of its S stereoisomer. 118. The method according to claim 58, wherein the compound is a salt chosen from: benzoate;
Figure imgf000061_0003
benzoate;
Figure imgf000061_0004
benzoate; and
Figure imgf000061_0005
benzoate. Attorney Reference: 14622.0007-00304 119. A method of treating cholestasis in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof (I) wherein the subject is a human wherein
Figure imgf000062_0001
• 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group; • 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, a OR10 group, a S(O)mR10 group, or a NR9R10 group; • R3, R4 are the same or different and may be chosen from a hydrogen atom or a halogen atom, • 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 bond 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, a OR8 group, a S(O)mR8 group or a NR8R9 group, a phenyl group, or a benzyl group;, • with the proviso that if R1 is a OR11 group and R5 is a hydrogen atom, a haloalkyl group, a C1- C4 alkyl group, a OR11 group, a SR11 group, or a NR12R13 group, then R2 is not a C4-C6 alkyl group, a C4-C6 alkenyl group, C4-C6 alkynyl group, or a C4-C6 alkyl-Y- group; • R6 and R7 are the same or different and are independently chosen from a hydrogen atom and an C1-C6 alkyl group, wherein R6 and R7 together can form a cycloalkyl group, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; Attorney Reference: 14622.0007-00304 • 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; • R9 is a hydrogen atom or a C1-C11 alkyl group; • R10 is 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; • R11 is a C1-C4 alkyl group; • R12 and R13 are independently chosen from a hydrogen atom and a C1-C4 alkyl group; • X is a hydroxymethyl or a carboxylic acid or a derivative thereof, wherein the derivative is a carboxylate, such as a carboxylic ester, a glyceride, an anhydride, a carboxamide, or a phospholipid, or a prodrug thereof; • Y is an oxygen atom, a sulphur atom, or a NR12R13 group; • m is 0, 1, or 2; and • n is 0, 1, or 2. 120. The method of claim 119, wherein the method reduces hepatic steatosis in the subject. 121. The method of claim 119, wherein the method reduces hepatic fibrosis in the subject. 122. The method of claim 119, wherein the method reduces cirrhosis in the subject. 123. The method of claim 119, wherein the method reduces gallbladder disease in the subject. 124. The method of claim 119, wherein the method reduces plasma bilirubin levels in the subject. 125. The method of claim 119, wherein the method reduces direct plasma bilirubin levels in the subject. 126. The method of claim 119, wherein the method reduces total plasma bilirubin levels in the subject. 127. The method of claim 119, wherein gamma glutamyl transferase (GGT) levels are reduced in the subject. 128. The method of claim 119, wherein the method reduces alanine aminotransferase levels in the subject. 129. The method of claim 119, wherein the method reduces aspartate aminotransferase levels in the subject. 130. The method of claim 119, wherein the method raises serum albumin levels in the subject. 131. The method of claim 119, wherein nutrition markers are improved in the subject. 132. The method of claim 119, wherein weight gain is observed in the subject. 133. The method of claim 119, wherein serum albumin levels are raised in the subject. 134. The method of claim 119, wherein plasma total protein levels are raised in the subject. Attorney Reference: 14622.0007-00304 135. The method of claim 119, wherein the method is prophylactic. 136. The method of claim 119, wherein the subject is a human child that is receiving parenteral nutrition. 137. The method of claim 119, wherein the subject is a human child that has previously received parenteral nutrition. 138. The method of claim 119, wherein the subject is a human child that is 12 to 18 years old. 139. The method of claim 119, wherein the subject is a human child less than 12 years old. 140. The method of claim 119, wherein the subject is a human child that is 2 to 12 years old. 141. The method of claim 119, wherein the subject is a human child that is 2 years old or less. 142. The method of claim 119, wherein the subject is a human infant that is receiving parenteral nutrition. 143. The method of claim 119, wherein the subject is a human infant that has previously received parenteral nutrition. 144. The method of claim 119, wherein the subject is a human infant that is 6 months old or less. 145. The method of claim 130, wherein the subject is a human infant born less than about 140 days prior to initial administration of a compound of formula (I). 146. The method of claim 119, wherein the subject is a human infant born less than about 2 weeks prior to initial administration of a compound of formula (I). 147. The method of claim 119, wherein the subject is a human infant born less than about 1 week prior to initial administration of a compound of formula (I). 148. The method of claim 119, wherein the subject is a pre-term human infant. 149. The method of clam 119, wherien the subject is a pre-term human infant born ranging from 22 to 36 weeks gestation. 150. The method of claim 119, wherein the subject is a human infant born ranging from 30 to 32 weeks gestation. 151. The method of claim 119, wherein the compound of formula I is administered in a dosage ranging from about 250 mg to about 2 g per kg of body weight per day. 152. The method of claim 119, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.5 g per kg of body weight per day. 153. The method of claim 119, wherein the compound of formula I is administered in a dosage ranging from about 500 mg to about 1.2 g per kg of body weight. 154. The method according to claim 119, wherein • 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 atom is a heteroatom; • R2 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 Attorney Reference: 14622.0007-00304 having 1-2 triple bonds, a C(O)R14 group, a OR14 group, a S(O)mR14 group, or a NR9R14 group; and • R5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1- C4 haloalkyl group, or a heteroalkyl group having 3-4 atoms of which 1 atom is a heteroatom; wherein • R14 is 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 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. 155. The method according to claim 119, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group. 156. The method according to claim 119, wherein 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 is a heteroatom, or a phenyl group. 157. The method according to claim 119, wherein R1 is a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C2 haloalkyl group, or a phenyl group 158. The method according to claim 119, wherein R1 is a methyl group or an ethyl group. 159. The method according to claim 119, wherein R1 is a methyl group. 160. The method according to claim 119, wherein R2 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, an -O-(C3-C8) alkyl group, an -O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl group, an -O-(C3-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 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, a -S-(C3-C8) alkyl group, a -S-(C3-C8) hydroxyalkyl group, a -S-(C3-C8) haloalkyl, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C3-C8) alkenyl group having 1-2 double bonds, a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, a -C(O)-(C3-C8) alkyl group, a -S(O)- (C3-C8) alkyl group, a -S(O)2-(C3-C8) alkyl group, an amine group having a hydrogen atom and a C3-C8 alkyl group, an amine group having a hydrogen atom and a (C1-C6) ketone group, or an amine group having a C1-C9 alkyl group and a C3-C8 alkyl group. 161. The method according to claim 119, wherein R2 is a C4-C9 alkyl 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, an -O-(C3-C8) alkyl group, O-(C3-C8) hydroxyalkyl group, an -O-(C3-C8) haloalkyl Attorney Reference: 14622.0007-00304 group, an -O-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, an -O-(C4-C8) alkenyl group having 1-2 double bonds, an -O-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond, an -O-(C4-C8) haloalkenyl group having 1-2 double bonds, a -S-(C3- C8) alkyl group, a -S-heteroalkyl group having 4-8 atoms of which 1 -2 are heteroatoms, a -S-(C4- C8) alkenyl group having 1-2 double bonds, or a -S-heteroalkenyl group having 5-8 atoms of which 1 is heteroatom and 1 double bond. 162. The method according to claim 119, wherein R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position. 163. The method according to claim 119, wherein R5 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 atom is a heteroatom. 164. The method according to claim 119, wherein R3, R4, and R5 are each a hydrogen atom. 165. The method according to claim 119, wherein • R1 is a methyl group or an ethyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in 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 independently chosen from a hydrogen atom and a methyl group; and • X is chosen from a hydroxymethyl group, a carboxylic acid, a carboxamide, and a carboxylic ester such as an acetate group. 166. The method according to claim 130, wherein • R1 is a methyl group; • R2 is a C5-C8 straight chain alkyl group, a C6-C8 alkenyl group having 1 double bond and the double bond is in the ω-3 position, an -O-(C4-C6) straight chain alkyl group, or an -O-(C5-C8) alkenyl group having 1 double bond and the double bond is in the ω-3 position; • R3, R4, and R5 are each a hydrogen atom; • n is 0; and • X is a carboxylic acid. 167. The method according to claim 119, wherein X is a carboxylic acid derivative chosen from a carboxylate, a glyceride, an anhydride, a carboxamide, and a phospholipid. 168. The method according to claim 119, wherein X is a carboxylic ester. Attorney Reference: 14622.0007-00304 169. The method according to claim 119, wherein X is a carboxamide chosen from N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide and N,N-diethyl carboxamide. 170. The method according to claim 119, wherein X is a glyceride chosen from a triglyceride, a 1,2- diglyceride, a 1,3 diglyceride, a 1-monoglyceride, or a 2-monoglyceride. 171. The method according to claim 119, wherein X is a carboxylic acid, a carboxamide, or a hydroxymethyl. 172. The method according to claim 119, wherein X is a carboxylic acid. 173. The method according to claim 119, wherein n is 1 or 2 and R6 and R7 are the same or different and are independently chosen from a hydrogen atom and a C1-C6 alkyl group. 174. The method according to claim 119, wherein n is 1 or 2 and R6 and R7 together form a cycloalkyl group chosen from cyclopropane, cyclobutane, cyclopentane, or cyclohexane. 175. The method according to claim 119, wherein n is 0. 176. The method according to claim 119, wherein the compound is yloxy)benzoic acid.
Figure imgf000067_0001
177. The method according to claim 119, wherein the compound is
Figure imgf000067_0002
acid. 178. The method according to claim 119, wherein the compound is a salt comprising a monovalent cation chosen from Li+, Na+, K+, Mg2+, or Ca2+. 179. The method according to claim 119, wherein the compound is in a mixture of diastereomers or in racemic form. 180. The method according to claim 119, wherein the compound is in the form of a diastereomer or an enantiomer. 181. The method according to claim 119, wherein the compound is in the form of its R stereoisomer. 182. The method according to claim 119, wherein the compound is in the form of its S stereoisomer. 183. The method according to claim 119, wherein the compound is a salt chosen from: benzoate; Attorney Reference: 14622.0007-00304 potassium 2-methyl-3-(pentyloxy)benzoate; benzoate; and
Figure imgf000068_0001
benzoate.
Figure imgf000068_0002
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