WO2025207099A1

WO2025207099A1 - Ppar-delta inhibitors for preventing post-operative atrial fibrillation

Info

Publication number: WO2025207099A1
Application number: PCT/US2024/022032
Authority: WO
Inventors: Olivier VAN TILL
Original assignee: Astellas Pharma Inc; Astellas Engineered Small Molecules Us Inc
Current assignee: Astellas Pharma Inc; Astellas Engineered Small Molecules Us Inc
Priority date: 2024-03-28
Filing date: 2024-03-28
Publication date: 2025-10-02
Anticipated expiration: 2026-09-28

Abstract

The present invention is directed towards a method of reducing likelihood of developing post-operative atrial fibrillation in a surgical patient at risk of developing post-operative atrial fibrillation, comprising administering to the patient an effective amount of a PPARδ modulator. In some embodiments, the PPARδ modulator is Compound (I), represented by the following structural formula (I) or a pharmaceutically acceptable salt thereof.

Description

PPAR-DELTA INHIBITORS FOR PREVENTING POST-OPERATIVE ATRIAL FIBRILLATION

FIELD OF THE INVENTION

The present invention is directed towards methods of reducing likelihood of developing post-operative atrial fibrillation in a human patient.

BACKGROUND OF THE INVENTION

Post-operative atrial fibrillation (POAF) is defined as new-onset atrial fibrillation (AF) in the immediate period after surgery and complicates 20-60% of cardiac surgical procedures and 10-20% of non-cardiac thoracic operations. Typically, POAF onset is 2-4 days postoperatively. Episodes are often self-limiting, but associated adverse consequences of POAF include hemodynamic instability, increased risk of stroke, perioperative mortality, myocardial infarction, acute renal failure, lengthened hospital and intensive care unit stays and greater costs, long-term mortality, and longstanding persistent AF. (See Greenberg JW, et al. Eur J Cardiothorac Surg 2017; 52 : 665-72, Dobrev D, et al. Nat Rev Cardiol. 2019 Jul;16(7):417-436, and Caldonazo T, et al. J Thorac Cardiovasc Surg. 2021 Apr l;S0022- 5223(21)00558-4). Patients who develop POAF incur on average $10,000-$20,000 in additional hospital treatment costs, 12-24 hours of prolonged ICU time, and an additional 2-5 days in the hospital. POAF has been identified as an independent predictor of numerous adverse outcomes, including a 2- to 4-fold increased risk of stroke, reoperation for bleeding, infection, renal or respiratory failure, cardiac arrest, cerebral complications, need for permanent pacemaker placement, and a 2-fold increase in all-cause 30-day and 6-month mortality. While there are methods of managing POAF, the efficacy of these interventions is debated (See Greenberg JW, et al. Eur J Cardiothorac Surg 2017;52:665-72). While betablockers are most commonly used in patients able to take such medicines, there is no standard of preventative care which is used to prevent or reduce likelihood of developing POAF.

Clinical management of POAF includes both prophylactic and therapeutic measures, although the efficacy of many interventions remains in question (See Greenberg JW, et al. Eur J Cardiothorac Surg 2017;52:665-72). In terms of prevention and treatment, there is no univocal approach. Beta-blockers are used in most of the prevention protocols, unless contraindicated (e.g., in poorly controlled asthma or heart failure), but other pharmacological strategies have been considered (z.e., amiodarone, anti-inflammatory drugs and statins). Furthermore, electrolyte correction (mainly potassium and magnesium) seems to have a very important role in POAF. The initial treatment of POAF is aimed to achieve pharmacological ventricular rate control. However, if AF persists for more than 24-48 hours or the patient is hemodynamically compromised despite the attempt of rate control, a rhythm control strategy (e.g., by electric/direct-current cardioversion) should be considered, together with an anti coagulation therapy, e.g. , with warfarin (See Chivasso P, et al. J Cardiol Clin Res 2018;6(5):l 145).

There is a need to find compounds which can reduce a patient’s likelihood of developing POAF.

SUMMARY OF THE INVENTION

It has now been found that modulators of peroxisome proliferator-activated receptor delta (PPAR5), such as Compound (I), the structure of which is shown below, can significantly reduce likelihood of developing POAF:

Compound (I).

Specifically, as demonstrated in Example 1, after administration of Compound (I), the reduction rate of POAF risk within 7 postoperative days is 71%, which is higher than the current standard symptomatic preventative treatment for POAF with beta-blockers (48%).

Thus, the present disclosure relates to methods of reducing likelihood of developing post-operative atrial fibrillation in a human patient.

In one aspect, the present disclosure provides a method of reducing likelihood of developing post-operative atrial fibrillation in a surgical patient at risk of developing postoperative atrial fibrillation, the method comprises administering to the patient an effective amount of a PPAR5 modulator.

In some embodiments, the surgery is an open chest cardiac surgery, and in other embodiments, it is a different type of surgery.

In some embodiments, the PPAR5 modulator (e.g., Compound (I)) is given as a single dose. In some embodiments, the PPAR5 modulator (e.g., Compound (I)) is given as multiple doses. In some embodiments, the effective amount of the PPAR5 modulator (e.g., Compound (I)) is between 0.1 mg and 0.5 g.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the POAF probability versus Exposure (Cmax). The lines are a logistic regression, shaded areas: 95% CI, black squares: the proportion of responders grouped by quartiles of exposure metrics and plotted at the median for the groups with the error bars represent 95%CI. The exposure range in each quartile is denoted by the horizontal black line along with the number of subjects in each quartile.

Figure 2 shows the POAF probability versus Exposure (AUCinf). The lines are a logistic regression, shaded areas: 95% CI, black squares: the proportion of responders grouped by quartiles of exposure metrics and plotted at the median for the groups with the error bars represent 95%CI. The exposure range in each quartile is denoted by the horizontal black line along with the number of subjects in each quartile.

DETAILED DESCRIPTION

Peroxisome proliferator-activated receptor delta (PPAR-5), also known as peroxisome proliferator-activated receptor beta (PPAR-P) or as NR1C2 (nuclear receptor subfamily 1, group C, member 2), refers to a nuclear receptor protein that functions as a transcription factor regulating the expression of genes. Ligands of PPAR6 can promote myoblast proliferation after injury, such as injury to skeletal muscle. PPAR6 (OMIM 600409) sequences are publicly available, for example from GenBank® sequence database e.g., accession numbers NP_001165289.1 (human, protein) NP_035275 (mouse, protein), NM_001171818 (human, nucleic acid) and NM_011145 (mouse, nucleic acid)).

Compound (I) is a potent and selective PPAR5 modulator with a half-maximal effective concentration of 5.9 and 158 nmol/L against human and rat PPAR5. The preparation of Compound (I) is described in Example 2n of WO2017/062468. Compound (I) not only effectively increases PPAR5 activity, but also effectively reduces ischemia-reperfusion induced kidney injury in rats.

Compound (I) is believed to have protective effects on kidney cells that are under cellular stress as a result of ischemia, inflammation and oxidative stress following CABG and/or valve surgery. In addition, Compound (I) will reduce inflammatory responses and increase oxidative stress systemically, which is expected to reduce the immediate consequences of stress responses following CABG and/or valve surgery. Because injury occurs at a discrete point in time (z.e., after cardio-pulmonary bypass pump (CPB) is ended) in these subjects, the timing of interventional treatment can be planned and monitored accurately. This way, treatment with Compound (I) can be timed optimally to provide efficacy in this subject population.

During a clinical trial, a statistically and clinically meaningful improvement of POAF rates was unexpectedly observed in the patient groups administered Compound (I).

Definitions

As used herein, the term “PPAR5 modulator” refers to substances that modify (e.g., increases or decreases) the activity of PPAR5. Substances can be tested for their PPAR5 agonist activity by, for example, contacting the substance with cells expressing PPAR5, detecting their binding with PPAR5 and then detecting signals that serve as the indicator of the activation of PPAR5.

The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “haloalkoxy”, “cycloalkyl”, and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., Ci-C4-alkyl. As used herein, a “Ci-C4-alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “Ci-C4-alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy and butoxy.

The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. For example, “Ci-C4-haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, fluoroethyl, difluoroethyl, di chloroethyl and chloropropyl, and “Ci-C4-haloalkoxy” includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, bromomethoxy, fluoroethoxy, difluoroethoxy, di chloroethoxy and chloropropoxy.

The term “halogen” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

Examples of “aryl” include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl and indenyl. “Cycloalkyl” means a 3-12 membered saturated aliphatic cyclic hydrocarbon radical. It can be monocyclic, bicyclic (e.g., a bridged or fused bicyclic ring), or tricyclic. For example, monocyclic Cs-Ce-cycloalkyl means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring. For example, “Cs-Ce-cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“5- or 6-membered heterocycle” means a radical having from 5 or 6 ring atoms (including 1 to 3 ring heteroatoms) arranged in a monocyclic ring. Examples of “5- or 6- membered heterocycle” include, but are not limited to, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

“5-membered heteroaryl” means a monocyclic aromatic ring system having five ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). Typical examples are 5-membered heteroaryl containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, and the like.

If a group is described as being “substituted”, a non-hydrogen substituent is in the place of hydrogen on a carbon, sulfur or nitrogen of the substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of hydrogen on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each nonhydrogen substituent can be identical or different (unless otherwise stated). A person of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substituent patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are clearly recognized by a person of ordinary skill in the art.

Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms, as well as racemates and mixtures thereof. The term “geometric isomer” refers to compounds having at least one double bond, wherein the double bond(s) may exist in cis, trans, syn, anti, entgegen (E), and zusammen (Z) forms, as well as mixtures thereof. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.

When a geometric isomer is depicted by name or structure, it is to be understood that the geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. The disclosed compounds have basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, e.g., acetic acid, benzenesulfonic, benzoic, methanesulfonic, and /?-toluenesulfonic acids). For example, in one embodiment, the acid addition salt is a hemisulfate salt. Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts) and organic base salts (such as meglumine salt).

As used herein, the term “pharmaceutically acceptable salt” refers to a non-toxic salt form of a compound of this disclosure. Pharmaceutically acceptable salts (e.g., of Compound (I) disclosed herein) include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are, e.g., those disclosed in Berge, S.M., et al. J. Pharma. Sci. 66: 1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in that article include: acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methylnitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate/diphosphate; polygalacturonate; salicylate; stearate; subacetate; succinate; sulfate; tannate; tartrate; teociate; triethiodide; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum; calcium; lithium; magnesium; potassium; sodium; and zinc. In some embodiments, the PPAR5 modulator (c.g, Compound (I) disclosed herein) of the present disclosure is a meglumine salt or a hydrated form of the meglumine salt.

Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Additional non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Nonlimiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Cl-4 alkyl)4 salts. This disclosure also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

As used herein, “an effective amount” of a compound disclosed herein means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., reduces the likelihood of developing post-operative atrial fibrillation in a subject as compared to a control.

As used herein, the term “patient” or “subject” refers to an organism to be treated by the methods of the disclosure. Non-limiting example organisms include mammals, e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like. In some embodiments, the organism is a human. In some embodiments, the patient population comprises surgical patients. In some embodiments, the patient population comprises surgical patients at risk of developing post-operative atrial fibrillation.

A surgical patient is at a risk of developing post-operative atrial fibrillation after a surgery. POAF complicates 20-60% of cardiac surgical procedures and 10-20% of noncardiac thoracic operations. In some embodiments, the surgery is an open chest cardiac surgery or thoracic aortic surgery, and in other embodiments, it is a different type of surgery such as abdominal, colorectal, partial organ removal, organ transplant, neuro, urologic, general, or orthopedic surgery.

As used herein, “reducing the likelihood of developing” refers to a decrease in the prevalence of the specified disease or condition in the patient population treated by the methods of the disclosure in comparison to a control population not being treated by the methods of the disclosure. In some embodiments, the patient population has a reduced risk in developing post-operative atrial fibrillation after being treated by the methods of the disclosure.

PPAR6 modulators

In some embodiments, the PPAR5 modulator is a PPAR5 modulator known in the art, for example Elafibranor, represented by the following structural formula:

Seladelpar, represented by the following structural formula:

GW501516, represented by the following structural formula:

GW0742, represented by the following structural formula:

Bezafibrate, represented by the following structural formula:

Fonadelpar, represented by the following structural formula:

T3D 959, represented by the following structural formula:

KD-3010, represented by the following structural formula: L- 165041, represented by the following structural formula:

Compound A, represented by the following structural formula:

Compound B, represented by the following structural formula:

CER-002, SAR351034, or the compounds disclosed in WO2022/051323, W02020/110126, W02020/163240, W02020/ 172421, WO2021/055725, EP4015623, US9695137, Cheng HS et. al. IntJMol Sci. 2019 Oct l l;20(20):5055, Da'adoosh B et. al. Sci Rep. 2019 Jan

31 ;9(1): 1106, or Cox RL. Proc Natl Acad Sci 2017 Mar 28; 114(13):3284-3285, and the references disclosed therein, as well as their corresponding pharmaceutically acceptable salts thereof. In some embodiments, the PPAR5 modulator is a compound represented by the or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen, halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -CN, -Ci-C4-alkoxy, -Ci-C4-haloalkoxy, or -Cs-Ce-cycloalkyl;

Q¹ is CH or N; R² is hydrogen, halogen, -CN, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Cs-Ce-cycloalkyl, -Ci-C4-alkoxy, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), -SO2(Ci-C4-alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, -^-R^2A, -O(CH2)_mR^2B, -NH(Ci-C4-alkyl), -N(Ci-C4-alkyl)2, or -C(O)(Ci-C4-alkyl), wherein aryl and heteroaryl are optionally substituted with halogen, -OH, -CN, Ci-C4-alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is an integer having value of 1, 2, or 3; x is an integer having a value of 1 or 2;

R^2A and R^2B are each independently -Ci-C4-alkyl, -Ci-C4-haloalkyl, or -Cs-Ce-cycloalkyl; each R²⁰ is independently hydrogen, halogen, -Ci-C4-alkyl, -CN, or -Ci-C4-alkoxy; and

R³ is -CH₃ or -CD₃.

The syntheses of compounds of Formula (I) are disclosed in international application publication No. WO2017/062468, the entire teachings of which are incorporated herein by reference.

In another embodiment, the PPAR5 modulator is a compound represented by Formulas (la) or (lb): or a pharmaceutically acceptable salt thereof, wherein the variables in Formulas (la) or (lb) are as defined for Formula (I) above.

In another embodiment, the PPAR5 modulator is a compound represented by

Formulas (laa) or (Ibb): or a pharmaceutically acceptable salt thereof, wherein the variables in Formulas (laa) or (Ibb) are as defined for Formula (I) above.

In another embodiment, the PPAR5 modulator is a compound represented by

Formulas (laa’) or (Ibb’): or a pharmaceutically acceptable salt thereof, wherein the variables in Formulas (laa’) or (Ibb’) are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with -Ci-C4-alkyl; and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is halogen, -CH3, -Ci-haloalkyl, -Ci -haloalkoxy, -SCH3, or furanyl, wherein the furanyl can be optionally substituted with -CH3; and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is halogen, -CH3, -Ci-haloalkyl, -Ci -haloalkoxy, or -SCH3, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is chloro, unsubstituted furanyl, -CH3, -CF3, -OCF3, -OCHF2, or -SCH3, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is -CF3 or -OCF3, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R² is -CF3, and the remainder of the variables are as defined for Formula (I) above. In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R¹ is hydrogen or halogen, R² is described as any of the embodiments above, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R¹ is hydrogen or fluoro, R² is described as any of the embodiments above, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R²⁰ is independently hydrogen or halogen, R¹ and R² are described as any of the embodiments above, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R²⁰ is hydrogen or fluoro, R¹ and R² are described as any of the embodiments above, and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (I), (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R¹ is hydrogen or halogen; R² is halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with -Ci-C4-alkyl; each R²⁰ is independently hydrogen or halogen; and the remainder of the variables are as defined for Formula (I) above.

In some embodiments, for the compounds represented by Formula (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R¹ is hydrogen or fluoro; R² is Ci-C4-haloalkyl or Ci-C4-haloalkoxy; x is 1, and R²⁰ is hydrogen.

In some embodiments, for the compounds represented by Formula (la), (laa), (laa’), (lb), (Ibb), or (Ibb’), R¹ is hydrogen; R² is trifluoromethyl or trifluoromethoxy; x is 1, and R²⁰ is hydrogen.

In some embodiments, the PPAR5 modulator is Compound (I), represented by the following structural formula: or a pharmaceutically acceptable salt thereof. In one specific embodiment, the PPAR5 modulator is meglumine salt of Compound (I). Pharmaceutical Compositions and Administration Thereof

The PPAR5 modulator can be used in combination with other agents.

The precise amount of compound administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease and/ or condition and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. For example, an effective amount can be from 0.1 mg to about 50 g per day.

The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Oral and intravenous administration are commonly used. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

In some embodiments, the disclosed PPAR5 modulators can be used in combination with other agents known to have beneficial activity with the disclosed PPAR5 modulators. For example, disclosed compounds can be administered alone or in combination with one or more other PPAR5 modulators, such as a thiazolidinedione, including rosiglitazone, pioglitazone, troglitazone, and combinations thereof, or a sulfonylurea agent or a pharmaceutically acceptable salt thereof, such as tolbutamide, tolazamide, glipizide, carbutamide, glisoxepide, glisentide, glibornuride, glibenclamide, gliquidone glimepiride, gliclazide and the pharmaceutically acceptable salts of these compounds, or muraglitazar, farglitazar, naveglitazar, netoglitazone, rivoglitazone, K-l l l, GW-677954, (-)-Halofenate, acid, arachidonic acid, clofbrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate, lovastatin, pravastatin, simvastatin, mevastatin, fluvastatin, indomethacin, fenoprofen, ibuprofen, and the pharmaceutically acceptable salts of these compounds.

In one embodiment, disclosed compounds may be administered in combination with dexamphetamine, amphetamine, mazindole or phentermine; and administered in combination with medicaments having an anti-inflammatory effect.

Further, when used for the treatment of a metabolic condition, the pharmaceutical compositions provided herein can be administered as a combination therapy with one or more pharmacologically active substances having favorable effects on metabolic disturbances or disorders. For example, the disclosed pharmaceutical compositions may be administered in combination with RXR agonists for treating metabolic and cardiovascular diseases medicaments, which lower blood glucose; antidiabetics, such as insulins and insulin derivatives, including Lantus, Apidra, and other fast-acting insulins, and GLP-1 receptor modulators; active ingredients for treating dyslipidemias; anti-atherosclerotic medicaments; anti-obesity agents; anti-inflammatory active ingredients; active ingredients for treating malignant tumors; anti -thrombotic active ingredients; active ingredients for treating high blood pressure; active ingredients for treating heart failure, and combinations thereof.

The pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.

Administration of therapeutic agents by intravenous formulation is well known in the pharmaceutical industry. Intravenous formulations comprise the pharmaceutically active agent dissolved in a pharmaceutically acceptable solvent or solution, such as sterile water, normal saline solutions, lactated Ringer’s, or other salt solutions such as Ringer’s solution. For example, the formulation should promote the overall stability of the active ingredient(s), also, the manufacture of the formulation should be cost-effective. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation.

An oral formulation typically is prepared as a compressed preparation in, for example, the form of a tablet or pill. A tablet may contain, for example, about 5-10% of the active ingredient (e.g., the PPAR5 modulators); about 80% of fillers, disintegrants, lubricants, glidants, and binders; and 10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine. Pills can be coated with sugar, varnish, or wax to disguise the taste.

Dosing Regimen and Amounts

In some embodiments, the effective amount of the PPAR5 modulator (e.g., Compound (I) disclosed herein) is in an amount equivalent to about 0.1 mg to 500 mg per day. For example, the method may comprise administering the PPAR5 modulator (e.g., Compound (I) disclosed herein) in an amount of about 0.1 mg to about 250 mg per day, an amount of about 0.1 mg to about 125 mg per day, an amount of about 0.1 mg to about 100 mg per day, an amount of about 0.1 mg to about 75 mg per day, an amount of about 0.1 mg to about 50 mg per day, an amount of about 125 mg to about 500 mg per day, an amount of about 250 mg to about 500 mg per day, or a pharmaceutically acceptable salt of the PPAR5 modulator (e.g., Compound (I) disclosed herein) in an amount equivalent to any of the foregoing.

In some embodiments, the effective amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 100 or less mg per day, or a pharmaceutically acceptable salt thereof is in an amount equivalent to 100 mg or less per day.

In some embodiments, the effective amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 100 mg per day, or a pharmaceutically acceptable salt thereof is in an amount equivalent to 100 mg per day.

In some embodiments, the effective amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 75 mg per day, or a pharmaceutically acceptable salt thereof is in an amount equivalent to 75 mg per day.

In some embodiments, the effective amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 50 mg per day, or a pharmaceutically acceptable salt thereof is in an amount equivalent to 50 mg per day.

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 0.1 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.1 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g, Compound (I) disclosed herein) is 0.3 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.3 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 0.5 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 1 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 3 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 3 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 5 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 10 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 10 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 20 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 20 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 30 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 30 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 40 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 40 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 50 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 60 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 60 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 70 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 70 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein). In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 80 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 80 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 90 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 90 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 100 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 125 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 125 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the amount of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein) is 150 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 150 mg/day of the PPAR5 modulator as free base (e.g., Compound (I) disclosed herein).

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered orally. In another embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered intravenously.

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered to the patient after surgery. In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered once daily for 3 days after surgery.

In some embodiments the surgery is an open chest cardiac surgery. In some embodiments the open chest cardiac surgery is coronary artery bypass graft or valve surgery. In some embodiments, the surgery is thoracic aortic surgery. In other embodiments, the surgery is abdominal, colorectal, partial organ removal, organ transplant, neuro, urologic, general, or orthopedic surgery.

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered 1, 2, 3, 4, 5, 6, or 7 times every week. In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered once daily for 3 days. In some embodiments, the PPAR5 modulator e.g., Compound (I) disclosed herein) is administered continuously for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks.

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered continuously for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, at least 2 weeks, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks.

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered in a single dose. In other embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered in a multiple doses.

In some embodiments where the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered in multiple doses, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered in three separate doses. In some embodiments, the first dose is administered up to 24 hours after surgery, wherein the second dose is administered approximately 48 hours after surgery, and wherein the third dose is administered approximately 72 hours after surgery.

In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered with food. In some embodiments, the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered without food. In some embodiments, when the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered without food, the patient remains fasting for 4 hours prior to the administration (and at least 1.5 hours after administration). In some embodiments, when the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered without food, the patient remains fasting for 6 hours prior to the administration (and at least 1.5 hours after administration). In some embodiments, when the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered without food, the patient remains fasting for 8 hours prior to the administration (and at least 1.5 hours after administration). In some embodiments, when the PPAR5 modulator (e.g., Compound (I) disclosed herein) is administered without food, the patient remains fasting for 10 hours prior to the administration (and at least 1.5 hours after administration). EXAMPLE

The following example is intended to be illustrative and is not meant in any way to limit the scope of the disclosure.

Example 1 - Effectiveness of Compound (I) at Reducing the Risk of Developing POAF

A Phase 2 proof of concept, double-blind, randomized, placebo-controlled study to evaluate the efficacy of Compound (I) in subjects at risk for acute kidney injury following coronary artery bypass graft (CABG) and/or valve surgery (ClinicalTrials.gov Identifier: NCT03941483) was completed. Subjects were treated with Compound (I) (100 mg once daily intravenously) or placebo within 24 hours after TO (= end of cardio-pulmonary bypass pump [CPB]), and at 48 and 72h. Subjects were followed-up for 7 days in the hospital (or to discharge if that occurred before that) and at day 30 and day 90. The primary endpoint was proportion of subjects developing acute kidney injury (AKI) (any stage) based on serum creatinine (SCr) criteria from the KDIGO (Kidney Disease Improving Global Outcomes) guideline (ie., increase in SCr > 0.3 mg/dL [> 26.5 pmol/L] within any 48 hours, or increase in SCr to > 1.5 times baseline) within 72 hours after TO (AKI SCr72h). Secondary endpoints included additional AKI iterations and major adverse kidney events (MAKE: combination endpoint of as all -cause mortality, dialysis and/or sustained reduction in eGFR), and safety (vital signs, safety laboratory tests, adverse events).

In total, 151 subjects were randomized. The full analysis set (FAS) comprised 150 subjects: 69 in the Compound (I) arm and 81 in the placebo arm (PLC), and the safety analysis set (SAF) comprised 150 subjects (69 Compound (I) and 81 PLC) who received at least 1 dose of study treatment.

When treatment emergent adverse events (AEs) were evaluated, a relevant difference between groups in incidence of post-operative atrial fibrillation (POAF) was observed. As seen in Table 1 below, patients receiving Compound (I) displayed a significant decrease in POAF in comparison to the control group. Specifically, only 8 of 69 (11.6%) of the treatment group experienced POAF as opposed to 24 of 81 (29.6%) of the control group.

Table 1. Summary of POAF prevalence in the Compound (I) treatment versus control groups Of the 8 patients administered Compound (I), 6 (8.7%) had early POAF (within 1 week, of which 5 on Day 2 or Day 3) and 2 had late atrial fibrillation (AF) (Day 11 and Day 18). Placebo all had early POAF (Day 2-Day 5). The rate of POAF within 7 postoperative days was reduced by 71% between placebo and Compound (I) arms. In a meta-analysis, betablockers, a standard symptomatic preventative treatment for POAF, were shown to be effective in reducing isolated POAF risk after cardiac surgery by 48% (See Masuda Y, et al. JTCVS Open. 2020(3):66-85).

Severity (NCI-CTCAE grade) was similar between groups. One POAF SAE (in the PLC group) was regarded possibly related to study drug by the investigator. No POAF events were reported before first dosing; all were reported as treatment emergent AEs (TEAEs). A trend of a shorter duration of POAF was shown for Compound (I): Events that started within 7 days postop: PLC 24.9 (SD 31.4) days vs. Compound (I) 5.2 (SD 2.9) days.

Almost all POAF events required treatment; only 1 of all 36 TEAEs did not need therapy, indicating that POAF is a clinically relevant event. Thirty-three (33) needed medication therapy, 2 needed non-medication therapy, and 6 needed both medication therapy and non-medication therapy. Non-medication therapy in this context was electrical cardioversion. In the placebo group, more patients required cardioversion: 7/81 (8.6%) PLC vs. 1/69 (1.4%) Compound (I); in patients with POAF: 7/24 (29.2%) PLC vs. 1/8 (12.5%) Compound (I).

Prophylactic POAF standard of care (SOC; e.g., beta-blockers, calcium channel blockers, amiodarone) was not regulated or prohibited in the study. The only treatment prohibited following surgery up to 72 hours post-surgery was the use of nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Use of beta-blockers and calcium blockers was comparable between groups: PLC 60.5% vs. Compound (I) 59.4%, PLC 51.9% vs. 53.6%, respectively (Table 2).

Table 2. Post-operative cardiovascular medication (up to 72h postop.)

Use of amiodarone POAF prophylaxis (defined as any use on DI [=1 st postop day]) was also similar between groups (Table 3; PLC 45.7% vs. Compound (I) 55.1%). The rate of POAF was lower in the groups that received amiodarone on day 1. Numerically, rates were lower in the Compound (I) group, but this was not statistically significant (Table 4a). There was a difference PLC vs. Compound (I) between groups in patients without amiodarone on day 1 : PLC 45.5% vs. Compound (I) 16.1% (Table 4b).

Table 3. Amiodarone POAF prophylaxis (defined as any use on DI [=1 st postop day]) Table 4a. POAF in subjects with Amiodarone POAF prophylaxis Table 4b. POAF in subjects without Amiodarone POAF prophylaxis

POAF risk factors were examined to evaluate the effect of their confounding the difference in POAF incidence between group. Factors independently associated with AF after cardiac surgery were included (See Dobrev D, et al. Nat Rev Cardiol. 2019 Jul; 16(7):417- 436). More males were included in the PLC group, and more mitral valve surgery was performed in the Compound (I) group, but overall, the risk-factor profile did not favor a group, so confounding was not an apparent reason for the difference in POAF incidence between study groups. However, there may have been confounders that were not recorded in the current study as it was not designed to evaluate POAF specifically.

Exposure-response modeling was performed evaluating the association between individual plasma exposure parameters (Cmax and area under the curve [AUC]) with study outcomes (e.g., AKI rates, target gene expression, POAF rates). The analysis showed that the probability of POAF event within 7 days after TO was decreased with exposure increase (Figures 1 and 2).

In summary, a statistically and clinically meaningful improvement of POAF rates was observed in the Compound (I) group, including a trend to reduce duration of POAF and the need for cardioversion. The study did not prohibit the SOC for POAF, so the effect was shown on top of SOC. Compound (I) exposure was associated with effect on POAF, while confounding (z.e., imbalance in POAF risk factors, difference in use of prophylactic comedication) was not a clear reason for the difference in POAF rates between study groups. Therefore, it was concluded that a drug effect of Compound (I) on reducing POAF cannot be excluded.

Claims

1. A method of reducing likelihood of developing post-operative atrial fibrillation in a surgical patient at risk of developing post-operative atrial fibrillation, comprising administering to the patient an effective amount of a PPAR5 modulator.

2. The method of claim 1, wherein the surgery is an open chest cardiac surgery.

3. The method of claim 2, wherein the open chest cardiac surgery is coronary artery bypass graft or valve surgery.

4. The method of claim 1, wherein the surgery is thoracic aortic surgery.

5. The method of claim 1, wherein the surgery is abdominal, colorectal, partial organ removal, organ transplant, neuro, urologic, general, or orthopedic surgery.

6. The method of any one of claims 1 to 5, wherein the PPAR5 modulator is administered to the patient after surgery.

7. The method of any one of claims 1 to 6, wherein the PPAR5 modulator is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

Q¹ is CH or N; R² is hydrogen, halogen, -CN, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -C₃-C₆-cycloalkyl, -Ci-C₄-alkoxy, -Ci-C₄-haloalkoxy, -S(Ci-C₄-alkyl), -SO₂(Ci-C₄- alkyl), 5- or 6-membered heterocycle, aryl, 5-membered heteroaryl, -^-R^2A, - O(CH₂)_mR^2B, -NH(Ci-C₄-alkyl), -N(Ci-C₄-alkyl)₂, or -C(O)(Ci-C₄-alkyl), wherein aryl and heteroaryl are optionally substituted with halogen, -OH, -CN, Ci-C4-alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is an integer having value of 1, 2, or 3; x is an integer having a value of 1 or 2;

R³ is -CH₃ or -CD₃.

8. The method of claim 7, wherein the PPAR5 modulator is a compound of Formula

(laa) or (Ibb): or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein:

R¹ is hydrogen or halogen;

R² is halogen, -Ci-C4-alkyl, -Ci-C4-haloalkyl, -Ci-C4-haloalkoxy, -S(Ci-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with -Ci-C4-alkyl; and each R²⁰ is independently hydrogen or halogen. The method of claim 7, wherein the PPAR5 modulator is Compound (I) represented by the following structural formula: or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the PPAR5 modulator is a meglumine salt of Compound (I).

12. The method of any one of claims 1 to 6, wherein the PPAR5 modulator is selected from: p ),

p ,

CER-002, or SAR351034, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1 to 12, wherein the effective amount of the PPAR5 modulator free base, or a pharmaceutically acceptable salt thereof, is from 0.1 mg to 0.5 g per day.

14. The method of claim 13, wherein the effective amount of the PPAR5 modulator free base is 100 mg or less per day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg or less per day of the PPAR5 modulator free base.

15. The method of claim 13, wherein the effective amount of the PPAR5 modulator free base is 100 mg per day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg or less per day of the PPAR5 modulator free base.

16. The method of claim 13, wherein the effective amount of the PPAR5 modulator free base is 75 mg per day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 75 mg or less per day of the PPAR5 modulator free base.

17. The method of claim 13, wherein the effective amount of the PPAR5 modulator free base is 50 mg per day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg or less per day of the PPAR5 modulator free base.

18. The method of any one of claims 1 to 17, wherein the PPAR5 modulator is administered intravenously.

19. The method of any one of claims 1 to 18, wherein the PPAR5 modulator is administered in multiple doses.

20. The method of claim 19, wherein the PPAR5 modulator is administered in three doses.

21. The method of claim 20, wherein the first dose is administered up to 24 hours after surgery, wherein the second dose is administered approximately 48 hours after surgery, and wherein the third dose is administered approximately 72 hours after surgery.