WO2021161218A1 - Sulfinic acid and sulfonic acid compounds for use in modulating peroxisome proliferator-activated receptors - Google Patents

Sulfinic acid and sulfonic acid compounds for use in modulating peroxisome proliferator-activated receptors Download PDF

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WO2021161218A1
WO2021161218A1 PCT/IB2021/051140 IB2021051140W WO2021161218A1 WO 2021161218 A1 WO2021161218 A1 WO 2021161218A1 IB 2021051140 W IB2021051140 W IB 2021051140W WO 2021161218 A1 WO2021161218 A1 WO 2021161218A1
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alkyl
compound
alkoxy
haloalkyl
cycloalkyl
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Robert Judkins
Lambertus BENTHEM
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Inorbit Therapeutics Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton

Definitions

  • the present invention relates to compounds that can act as modulators of the nuclear receptor peroxisome proliferator-activated receptor ⁇ , ⁇ and/or ⁇ ( PPAR ⁇ , PPAR ⁇ and/or PPAR ⁇ ) and that can be useful in the treatment of diseases and/or disorders associated with the PPAR ⁇ , PPAR ⁇ and/or PPAR ⁇ .
  • the present invention relates to compounds and compositions that modulate a PPAR and methods for their preparation and use.
  • Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steato-Hepatitis (NASH) are liver diseases which resemble alcoholic hepatitis on liver biopsy but can occur in patients who have no known history of alcohol abuse.
  • NASH is characterized by hyperinsulinemia, insulin resistance, hyperlipidemia, elevated serum transaminases such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and liver cell injury driven by lipid accumulation, hepatic inflammation and lobular infiltration of inflammatory cells such as macrophages, and activation and transformation of hepatic stellate cells into smooth muscle cell phenotype (Luwig, J, et al. Mayo Clin Proc 1980;55:434-438).
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • Peroxisome proliferator-activated receptors are members of the nuclear hormone super family. There are three PPAR isoforms: alpha (a), beta/delta ( ⁇ / ⁇ ), and gamma ( ⁇ ), which are differently expressed in various tissues (Cave MC, et al.
  • PPAR ⁇ is expressed ubiquitously, but largely present in the liver. PPAR ⁇ / ⁇ is mainly expressed in skeletal muscle and to a lesser extend in adipose tissue and skin. PPAR ⁇ is highly expressed in adipose tissue.
  • Exogenous PPAR ligands include environmental and pharmaceutical molecules that can activate one or all of the PPAR family receptors to varying degrees (Takeuchi S, et al. Toxicol Appl Pharmacol. 2006;217:235-244, Corton JC. Crit Rev Toxicol. 2008;38:857-875, Laughter AR, etal. Toxicology.
  • PPARs form a heterodimer with retinoid X receptor (RXR) to bind response elements that regulate the expression of genes encoding enzymes or proteins involved in beta oxidation, fatty acid uptake, adipogenesis, and adipocyte differentiation (Cave MC, et al. Biochim Biophys Acta. 2016; 1859: 1083-1099, Issemann I, and Green S. Nature. 1990;347:645-650, Evans RM, et al. Nat Med. 2004;10:355-361 Desvergne B, and Wahli W. Endocr Rev. 1999;20:649-688).
  • RXR retinoid X receptor
  • the PPARs have a critical role as master regulators of lipid and glucose metabolism, inflammation, insulin resistance, and fibrinogenesis in multiple cell types and have thus become the target of drug development for the treatment of metabolic diseases including NAFLD and NASH.
  • Different single, dual, or triple PPAR agonists have been investigated for their therapeutic potential in NASH.
  • Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH.
  • Activation of the PPAR has the potential to be a treatment for a range of diseases including diabetes (T1D and/or T2D), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (Y OAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, hypercholesterolemia, obesity, cardiovascular disease, inflammatory disease, neurodegeneration, NAFLD (including related
  • necrosis and apoptosis stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.
  • the present inventors have discovered that replacing a carboxylic acid component with a sulfmic and/or sulfonic group on compounds that are PPAR modulators can alter the metabolism pathway of the compound (compared to the metabolism pathway for the compounds with the carboxylic acid component present), which may result in a decrease in harmful metabolites formed, particularly via acyl-glucuronidation without significant loss of efficacy as PPAR modulators.
  • the present invention relates to the compounds defined by Formula I, II, III, IV and V as detailed below, which are referred to hereinafter as “the compounds of the invention”.
  • R 1a is C 1-3 alkyl, C 3-5 cycloalkyl or -SR 5 , wherein each C 1-3 alkyl and C 3-5 cycloalkyl is optionally substituted with one or more halogen atoms;
  • R 2a and R 3a are independently H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different);
  • a halogen e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different
  • Y a is O, S or CH 2 ;
  • R 4a is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH, CH(CH 3 )S(O) 2 OH or C(CH 3 ) 2 S(O) 2 OH;
  • R 5 is C 1-3 alkyl or C 3-5 cycloalkyl each of which may optionally be substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different); or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
  • a halogen e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different
  • R 1b and R 2b are independently H, halogen, C 1 -C 6 alkyl, CF 3 , CN, COR 4b . OR 4b or phenyl optionally substituted by C 1 -C 4 alkyl or CF 3 ;
  • R 4b is independently selected from the group consisting of C 1 -C 4 alkyl, CF 3 and phenyl optionally substituted by C 1 -C 4 alkyl or CF 3 ;
  • X b is (CH 2 ) n ;
  • Y b is CH 2 or O or S;
  • R 3b is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH,
  • n 0 or 1 or 2;
  • Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5, 6,7,8- tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3- dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- be
  • OR 4b SR 4b , NHCOR 4b .
  • the present invention provides a compound having a structure represented by Formula III: wherein:
  • a c is (CH 2 ) n S(O)OH or (CH 2 ) n S(O) 2 OH n is 0, 1, 2 or 3
  • R 1c is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo or C 1 -C 8 haloalkyl:
  • X c is CH 2 or S or O;
  • R 2c and R 3c are independently H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, or C 1 -C 8 haloalkyl or optionally R 2c and R 3c are joined together to form a 3 to 8 membered ring;
  • Y c is CH 2 or S or O
  • R 4c is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo, C 1 -C 8 haloalkyl.
  • the present invention provides a compound having a structure represented by Formula IV: wherein:
  • a d is (CH 2 ) n S(O)OH or (CH 2 ) n S(O) 2 OH; n is 1 or 2;
  • Z d is O or S
  • R 1d is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo or C 1 -C 8 haloalkyl:
  • X d is CH 2 or S or O
  • R 2d and R 3d arc independently H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, or C 1 -C 8 haloalkyl or optionally R 2c and R 3c are joined together to form a 3 to 8 membered ring;
  • Yd is CH 2 or S or O
  • R 4d is H, C 1 -C 8 alkyl. C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo, C 1 -C 8 haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R 5d : and each R 5d is independently selected from the group consisting of a halogen, C 1 -C 6 alkyl, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 , haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof
  • the present invention provides a compound having a structure represented by Formula V wherein:
  • a e and B e are independently phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 or 2
  • each R 4e is independently selected from the group consisting of a halogen, C 1 -C 3 alkyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and cyclopropyl;
  • W e is C 1 -C 6 alkylene or C 2 -C 6 alkenylene;
  • R 1e is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl;
  • R 2e is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, halo, C 1 - C 3 alkoxy or cyclopropyl;
  • X e is O or S or CH 2 ;
  • Y e is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH,
  • a sixth aspect of the present invention is directed to a pharmaceutical (or veterinary) composition
  • a pharmaceutical (or veterinary) composition comprising a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient, diluent and/or carrier, which are referred to hereinafter as “the compositions of the invention”.
  • Another aspect of the present invention is directed to a method of modulating a Peroxisome Proliferator- Activated Receptor (PPAR).
  • the method comprises administering to a subject in need thereof an effective amount of a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the present invention.
  • a compound of the present invention i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof
  • the present invention is also directed to a compound of the present invention or a composition of the present invention for use in modulating a Peroxisome Proliferator- Activated Receptor (PPAR).
  • the present invention is also directed to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for modulating (e.g. activating) a Peroxisome Proliferator- Activated Receptor (PPAR).
  • the present invention is also directed to a method of treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Still further, the invention is directed to the use of a compound of the invention or a composition of the invention, in the manufacture of a medicament for treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role. It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative thereto.
  • “about X” where X is the measurable value is meant to include X as well as variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of X.
  • a range provided herein for a measureable value may include any other range and/or individual value therein.
  • Peroxisome Proliferator-Activated Receptor or “PPAR” as used herein is a Peroxisome Proliferator-Activated Receptor from any source and/or that is present in a subject and/or expressed in any form.
  • Peroxisome Proliferator- Activated Receptor is from and/or is present and/or expressed in an animal such as, e.g., a mammal.
  • Peroxisome Proliferator-Activated Receptor is from and/or is present and/or expressed in a primate, cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and/or the like.
  • Peroxisome Proliferator- Activated Receptor is from and/or is present and/or expressed in a human.
  • modulate and “modulating”, in reference to a PPAR refer to the ability of a compound (e.g., a compound of the present invention) to activate or inhibit one or more fimction(s), action(s), and/or characteristic(s) of the PPAR, either directly or indirectly. This may occur in-vitro or in-vivo and is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of a function, action, and/or characteristic associated with a PPAR.
  • modulator in reference to a PPAR, refers to a compound (e.g., a compound of the present invention) that modulates a PPAR. In some embodiments, a compound of the present invention modulates a PPAR by activating one or more function(s), action(s), and/or characteristic(s) of the PPAR.
  • activating in reference to a PPAR, refers to the ability of a compound (e.g., a compound of the present invention) to activate, increase or enhance a function, action, and/or characteristic associated with the PPAR, and, thus, the compound is a PPAR agonist.
  • a compound e.g., a compound of the present invention
  • agonist refers to a compound (e.g., a compound of the present invention) that combines with and/or binds to a specific receptor (e.g., a PPAR) and activates, increases or enhances a function, action, and/or characteristic associated with the receptor.
  • agonist includes both a full agonist and a partial agonist, which activates, increases or enhances a function, action, and/or characteristic associated with the receptor (e.g., PPAR) to a lesser extent than a full agonist and/or has partial efficacy at the receptor compared to a full agonist.
  • a compound of the present invention is an PPAR agonist.
  • a compound of the present invention is an agonist and activates a PPAR providing the same or substantially the same reaction and/or pharmacological response typically produced by the binding of an endogenous agonist.
  • substantially the same as used herein in reference to a measurable value and/or response means being within about ⁇ 10% of the compared to value and/or response.
  • C 1 -C x alkyl where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a saturated alkyl chain having 1 to x carbon atoms which may be a straight chain or branched chain.
  • a C 1 -C 8 alkyl is a saturated alkyl chain (straight or branched) having 1 to 8 carbon atoms. Examples thereof include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isopropyl.
  • C 1 -C x alkoxy where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a straight or branched chain saturated hydrocarbon containing 1 to x carbon atoms, containing an oxygen in the chain and the straight or branched chain saturated hydrocarbon is attached to a parent or principal compound through the oxygen. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
  • C 1 -C x haloalkyl where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a saturated alkyl chain having 1 to x carbon atoms which may be a straight chain or branched chain and in which one or more hydrogen atoms have been replaced with a halogen atom (such as F, Cl, Br, I). Examples thereof include, but are not limited to, dichloromethyl, trifluromethyl and trifluroethyl.
  • C 1 -C x haloalkoxy where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a straight or branched chain saturated hydrocarbon containing 1 to x carbon atoms, in which one or more hydrogen atoms have been replaced with a halogen atom (such as F, Cl, Br, I), and the chain contains a terminal oxygen.
  • a halogen atom such as F, Cl, Br, I
  • the straight or branched chain saturated hydrocarbon is attached to a parent or principal compound through the oxygen.
  • Example thereof includes, but is not limited to, trifluromethoxy.
  • C 3 -C 5 cycloalkyl means a saturated monocyclic ring system comprising 3 to 5 carbon atoms. Examples thereof are cyclopropyl, cyclobutyl and cyclopentyl.
  • C 3 -C 6 cycloalkyl means a saturated mono-, bi-, spiro- or multicyclic ring system comprising 3 to 6 carbon atoms. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and spiro[2.3]hexane.
  • C 2 -C 4 alkenyl where x is 2, 3 or 4, means a straight or branched chain hydrocarbon containing 2 to x carbon atoms with at least one point of unsaturation. Examples thereof include, ethylene and propylene.
  • alkylene and alkenylene are used to define the bivalent form of “alkyl” and “alkenyl” respectively.
  • 4- to 7-membered heterocyclic means a saturated mono-, bi-, spiro- or multicyclic ring system that contains 4 to 7 atoms selected from carbon, nitrogen, oxygen, and/or sulfur with 1-2 of those atoms being a heteroatom (i.e., nitrogen, oxygen, and/or sulfur). Examples thereof include, but are not limited to, pyrrolidine, thiolane, tetrahydrofuran, piperidine, tetrahydropyran, thiane, morpholine, piperazine, and dioxane. If not stated otherwise, a 4- to 7 membered mono-, bi-, spiro- or multicyclic ring system as described herein can be connected via a carbon or nitrogen atom.
  • Halogen refers to fluorine, chlorine, bromine and iodine. In some embodiments, the halogen is selected from fluorine and chlorine.
  • sulfinic acid means the functional group -S(O)OH, consisting of a sulfinyl group and a hydroxyl group.
  • sulfinate means the conjugate base of sulfinic acid, where the hydroxyl has been deprotonated to give S(O)O-.
  • sulfonic acid means the functional group -S(O) 2 OH, consisting of a sulfonyl group and a hydroxyl group.
  • sulfonate means the conjugate base of sulfonic acid, where the hydroxyl has been deprotonated to give S(O) 2 O-.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have one or more substituent(s) different from hydrogen. For instance, it can, at any point along the chain, be bound to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • pharmaceutically acceptable salt refers to a salt of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and/or purification for a compound of the invention, or separately by reaction of the free acid function with a suitable inorganic or organic base.
  • suitable salts include, but are not limited to, metals, such as sodium, potassium and calcium, or amines, such as triethylammonium, ethanolammonium and lysine.
  • a compound of the present invention is a sodium salt. In some embodiments, a compound of the present invention is a sulfinate salt (e.g. a sodium sulfinate salt).
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • prodrug refers to a prodrug of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and/or the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of a compound of the present invention.
  • Prodrug as used herein means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford a compound of the present invention (e.g., a compound of Formula I).
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • amino acid conjugate refers to a conjugate of a compound of the present invention (e.g., a compound of Formula I) with an amino acid.
  • amino acid conjugates of the present invention will have the added advantage of enhanced integrity in bile and/or intestinal fluids.
  • Suitable amino acids include, but are not limited to, glycine and taurine.
  • the present invention encompasses the glycine and taurine conjugates of a compound of Formulas I-V.
  • structures depicted herein are meant to include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • R 1a is C 1-3 alkyl, C 3-5 cycloalkyl or -SR 5 , wherein each C 1-3 alkyl and C 3-5 cycloalkyl is optionally substituted with one or more halogen atoms;
  • R 2a and R 3a are independently H or C 1-3 alkyl, optionally wherein the C 1-3 alkyl is substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different);
  • a halogen e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different
  • Y a is O, S or CH 2 ;
  • R 4a is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH,
  • R 5 is C 1-3 alkyl or C 3-5 cycloalkyl, each of which may optionally be substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different); or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
  • a halogen e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different
  • R 4a is CH 2 S(O)OH, CH(CH 3 )S(O)OH or C(CH 3 ) 2 S(O)OH.
  • R 4a is CH 2 S(O) 2 OH, CH(CH 3 )S(O) 2 OH or C(CH 3 ) 2 S(O) 2 OH.
  • the present invention provides a compound having a structure represented by Formula II: wherein:
  • R 1b and R 2b are independently H, halogen, C 1 -C 6 alkyl, CF 3 , CN, COR 4b . OR 4b or phenyl optionally substituted by C 1 -C 4 alkyl or CF 3 ;
  • R 4b is independently selected from the group consisting of C 1 -C 4 alkyl, CF 3 and phenyl optionally substituted by C 1 -C 4 alkyl or CF 3 ;
  • X b is (CH 2 ) n ;
  • Y b is CH 2 or O or S
  • R 3b is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH,
  • n 0 or 1 or 2;
  • Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5, 6,7,8- tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3- dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- be
  • the present invention provides a compound of Formula II, wherein R 1b and R 2b are independently H, halogen, C 1 -C 3 alkyl or CF 3 ;
  • X b is (CH 2 ) n ;
  • Y b is CH 2 ;
  • R 3 is CH 2 S(O)OH or CH(CH 3 )S(O)OH or C(CH 3 ) 2 S(O)OH;
  • n is 1 or 2 or 3;
  • Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl,
  • the present invention provides a compound of Formula II, wherein R 1b and R 2b are independently H, halogen, C 1 -C 3 alkyl, or CF 3 ; X b is (CH 2 ) n ; Y b is CH 2 ; R 3 is CH 2 S(O)OH; n is 1 or 2 or 3; and Ar is benzothiazolyl substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, phenyl, CF 3 , CN, COR 4b , OR 4b , SR 4b , NHCOR 4b , morpholinyl, amino and 4- morpholinosulfonyl or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
  • R 1b and R 2b are independently H, halogen, C 1 -C 3 alkyl
  • R 3b is CH 2 S(O)OH, CH(CH 3 )S(O)OH or C(CH 3 ) 2 S(O)OH.
  • R 3b is CH 2 S(O) 2 OH, CH(CH 3 )S(O) 2 OH or C(CH 3 ) 2 S(O) 2 OH.
  • the present invention provides a compound having a structure represented by Formula III: wherein:
  • a c is (CH 2 ) n S(O)OH or (CH 2 ) n S(O) 2 OH n is 0, 1, 2 or 3
  • R 1c is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo or C 1 -C 8 haloalkyl:
  • X c is CH 2 or S or O
  • R 2c and R 3c are independently H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, or C 1 -C 8 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring;
  • Y c is CH 2 or S or O
  • R 4c is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo, C 1 -C 8 haloalkyl.
  • the present invention provides a compound of Formula III, wherein A c is (CH 2 ) n S(O)OH; n is 2 or 3; R 1c is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo or C 1 -C 3 haloalkyl; X c is CH 2 or S or O; R 2c and R 3c are independently H, C 1 - C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Y c is CH 2 or S or O; and R 4c is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl
  • the present invention provides a compound of Formula III, wherein A c is CH 2n S(O)OH; n is 2 or 3; R 1c is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, halo or C 1 -C 3 haloalkyl; X c is O; R2c and R 3c are independently H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Y c is S and R 4c is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl or an enantiomer, stereoisomer, tautomer,
  • a c is (CH 2 ) n S(O)OH.
  • a c is (CH 2 ) n S(O) 2 OH.
  • the present invention provides a compound having a structure represented by Formula IV: wherein:
  • a d is (CH 2 ) n S(O)OH or (CH 2 ) n S(O) 2 OH; n is 1 or 2;
  • Z d is O or S
  • R 1d is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo or C 1 -C 8 haloalkyl:
  • X d is CH 2 or S or O;
  • R 2d and R 3d are independently H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, or C 1 -C 8 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring;
  • Y d is CH 2 or S or O
  • R 4d is H, C 1 -C 8 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 8 alkoxy, halo, C 1 -C 8 haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R 5d : and each R 5d is independently selected from the group consisting of a halogen, C 1 -C 6 alkyl, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 , haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof
  • the present invention provides a compound of Formula IV, wherein A d is (CH 2 ) n S(O)OH; n is 1 or 2; Z d is O or S; R 1d is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo or C 1 -C 3 haloalkyl; X d is CH 2 or S or O; R 2d and R 3d are independently H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Y d is CH 2 or S or O; and R 4d is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo,
  • a d is (CH 2 ) n S(O)OH; n is 1 or 2; Z d is O or S; R 1d is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, halo or C 1 -C 3 haloalkyl; X d is O; R 2d and R 3d are independently H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, C 1 -C 3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Yd is S; and R4d is H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 3 alkoxy, halo, or C 1 -C 3 haloalkyl; or an enantiomer, stereoisomer, tautomer, solv
  • a d is (CH 2 ) n S(O)OH.
  • a d is (CH 2 ) n S(O) 2 OH.
  • the present invention provides a compound having a structure represented by Formula V wherein:
  • a e and B e are independently phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 or 2
  • each R 4e is independently selected from the group consisting of a halogen, C 1 -C 3 alkyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and cyclopropyl;
  • W e is C 1 -C 6 alkylene or C2-C 6 alkenylene
  • R 1e is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl;
  • R 2e is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, halo, C 1 - C 3 alkoxy or cyclopropyl;
  • X e is O or S or CH 2 ;
  • Y e is CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH, CH 2 S(O) 2 OH,
  • the present invention provides a compound of Formula V, wherein A e is phenyl, optionally substituted with R 4e ; B e is 5 to 10 membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5 to 10 bicyclic heteroaryl is optionally substituted with R 4e ; R 4e is independently selected from the group consisting of a halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and cyclopropyl; W e is C 1 -C 3 alkylene or C2-C 4 alkenylene; R 1e is C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl; R 2e is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alk
  • Y e is CH 2 S(O)OH, CH(CH 3 )S(O)OH or C(CH 3 ) 2 S(O)OH.
  • Y e is CH 2 S(O) 2 OH, CH(CH 3 )S(O) 2 OH or C(CH 3 ) 2 S(O) 2 OH.
  • the compound of the present invention as defined above are a metabolite (i.e. having undergone metabolism or biotransformation in the subject).
  • Exemplary compounds of the present invention include, but are not limited to, the following:
  • Compounds of Formula I to V as defined herein may be useful as PPAR modulators and/or may have an improved toxicity profile.
  • the improved toxicity profile may be due to a reduced propensity for forming toxic metabolites as compared to corresponding compounds in which the sulfinic acid or sulfonic acid component is replaced with a carboxylic acid component.
  • the compounds or composition of the invention may therefore be used in medicine.
  • a compound of the present invention has a different metabolic profile compared to a corresponding carboxylic acid compound (i.e., a compound having a -COOH or -COO- group replacing the mandatory -S(O)OH, -S(O)O- , -S(O) 2 OH or -S(O) 2 O- group in the compound of Formula I to V).
  • a corresponding carboxylic acid compound i.e., a compound having a -COOH or -COO- group replacing the mandatory -S(O)OH, -S(O)O- , -S(O) 2 OH or -S(O) 2 O- group in the compound of Formula I to V.
  • corresponding carboxylic acid compounds are typically metabolised to an acyl-glucuronide and such metabolism can give rise to reactive metabolites that cause liver toxicity and drug induced liver injury (Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl
  • the compounds of the present invention may only be metabolised by oxidative pathways, such as Cyp oxidation, and/or may minimise the formation of acyl glucuronide-like metabolites compared to a corresponding carboxylic acid compound.
  • a compound of the present invention may have a different distribution profile when orally dosed in-vivo, such as increased exposure in the liver versus plasma, compared to a corresponding carboxylic acid compound.
  • a compound of the present invention may break down in- vivo via a different metabolic pathway than a corresponding carboxylic acid compound and/or the compound of the invention may have beneficial liver safety effects and/or improved liver safety and/or improved efficacy compared to a corresponding carboxylic acid compound.
  • the compounds of the present invention may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical or chemical properties than a compound known in the prior art.
  • Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.
  • the compounds of the present invention as defined above are metabolites (i.e. having undergone metabolism or biotransformation in the subject).
  • a compound of the present invention may be a sulfinic acid metabolite, which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(O) 2 OH or -S(O) 2 O- group replacing a -S(O)OH or -S(O)O- group in the compound) or a corresponding sulfinate ester of the compound (e.g., a compound having a -S(O)O(C 1-6 alkyl) group replacing a -S(O)OH or -S(O)O- group in the compound).
  • a sulfinic acid metabolite which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(O) 2 OH or -S(O) 2 O- group replacing a -S(O)OH or -S(O)O- group in the compound) or a corresponding s
  • the compounds of the present invention as defined above may be a sulfinic acid (or its corresponding sulfinate salt) compounds or sulfonic acid (or its corresponding sulfonate salt) compounds.
  • the compounds of the invention are sulfinic acid (or its corresponding sulfinate salt) compounds, i.e. compounds containing CH 2 S(O)OH, CH(CH 3 )S(O)OH, C(CH 3 ) 2 S(O)OH or (CH 2 ) n S(O)OH.
  • the compounds of the present invention are provided in the form of a sodium salt, for example a sodium sulfinate salt.
  • reaction schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention.
  • the examples provided herein are offered to illustrate but not limit the compounds of the present invention, as well as the preparation of such compounds and intermediates.
  • a reaction may be carried out in the presence of a suitable solvent or diluent or of mixture thereof in a manner known to those skilled in the art of organic synthesis.
  • a reaction may also be carried out, if needed, in the presence of an acid or a base, with cooling or heating, for example in a temperature range from about -30 °C to about 150 °C.
  • a reaction is carried out in a temperature range from about 0 °C to about 100 °C, and more particularly, in a temperature range from room temperature to about 80 °C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen.
  • a composition i.e.
  • compositions comprising a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof).
  • a compound of the present invention i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
  • the compositions comprise an excipient, diluent and/or carrier as required.
  • the invention relates to a pharmaceutical composition comprising a compound of the present invention (e.g.
  • the term "pharmaceutically acceptable excipient, diluent and/or carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, that are suitable for use in a pharmaceutical product.
  • Such excipients, diluents and/or carriers include those which would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
  • a compound of the invention i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof
  • a pharmaceutical (or veterinary) composition of the invention for use as a pharmaceutical (e.g. for use in medicine).
  • the compounds of the invention or compositions of the invention may be administered to patients or subjects in need thereof.
  • the term “patient” and “subject” refer to an animal. Typically, the animal is a mammal. A “patient” or “subject” also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the present invention provides a method of modulating a Peroxisome Proliferator- Activated Receptor (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention.
  • PPAR Peroxisome Proliferator- Activated Receptor
  • the present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in modulating a Peroxisome Proliferator- Activated Receptor (PPAR).
  • the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for modulating a Peroxisome Proliferator-Activated Receptor (PPAR).
  • the present invention also provides a method of activating a Peroxisome Proliferator-Activated Receptor (PPAR), the method comprising administering to a subject a compound of the invention or a pharmaceutical composition of the invention.
  • the present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in activating a Peroxisome Proliferator-Activated Receptor (PPAR).
  • the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for activating a Peroxisome Proliferator-Activated Receptor (PPAR).
  • a PPAR plays a role in a disease or disorder, i.e. the PPAR is involved in a pathway, mechanism, or action associated with the disease and/or disorder such as, e.g. transcriptional regulation of glucose and lipid metabolism.
  • the present invention also provides a method of treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition of the invention.
  • PPAR Peroxisome Proliferator-Activated Receptor
  • the present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role.
  • the present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role.
  • PPAR Peroxisome Proliferator-Activated Receptor
  • the disease or disorder is diabetes (T1D and/or T2D), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis,
  • necrosis and apoptosis stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.
  • the disease or disorder may preferably be fatty liver disease, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFFD).
  • NASH nonalcoholic steatohepatitis
  • NAFFD nonalcoholic fatty liver disease
  • a therapeutically effective amount refers to an amount of a compound of the present invention (i.e., a compound of Formula I - V) and/or composition of the present invention that is sufficient to achieve or elicit a therapeutically useful response or a stated effect in a subject.
  • a therapeutically effective amount of a compound of Formula I used for the treatment of a condition mediated by PPAR can be an amount sufficient for to achieve a clinically relevant improvement in at least one symptom arising from a disease or disorder mediated by PPAR.
  • treat refers to any type of treatment that imparts a benefit to a subject and may mean that the severity of the subject’s condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom associated with a disease, disorder, or condition is achieved and/or there is a delay in the progression of the symptom.
  • the severity of a symptom associated with a disease, disorder, or condition mediated by PPAR may be reduced in a subject compared to the severity of the symptom in the absence of a method of the present invention.
  • "treat”, “treating”, “treatment of' and grammatical variations thereof in reference to a disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or disorder or at least one clinical symptom thereof). In some embodiments, “treat”, “treating” or “treatment of' and grammatical variations thereof in reference to a disease or disorder refer to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the subject.
  • treat refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.
  • a compound of the present invention and/or composition of the present invention may be administered to a subject in a treatment effective amount.
  • a "treatment effective" amount as used herein is an amount that is sufficient to treat (as defined herein) a subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • a treatment effective amount may be achieved by administering a composition of the present invention.
  • prevent refers to avoidance, reduction and/or delay of the onset of a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) and/or a reduction in the severity of the onset of symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) relative to what would occur in the absence of a method of the present invention.
  • the prevention can be complete, e.g., the total absence of the symptom.
  • the prevention can also be partial, such that the occurrence of the symptom in the subject and/or the severity of onset is less than what would occur in the absence of a method of the present invention.
  • a compound of the present invention and/or composition of the present invention may be administered in a prevention effective amount.
  • a "prevention effective" amount as used herein is an amount that is sufficient to prevent (as defined herein) a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) in a subject.
  • a prevention effective amount may be achieved by administering a composition of the present invention.
  • administer refers to directly administering to a subject a compound of the present invention (or a pharmaceutically acceptable salt, etc., thereof) and/or a composition of the present invention.
  • a compound and/or composition of the present invention is administered to the subject in an amount that can form an equivalent amount of the active compound within the subject's body.
  • a compound of the present invention and/or composition of the present invention can be administered in a therapeutically effective amount to treat and/or prevent a disease or disorder and/or to prevent the development thereof in a subject.
  • Administration of a compound of the present invention can be accomplished via any mode of administration for therapeutic agents such as, for example oral, rectal, topical, and/or parenteral administration may be employed.
  • a compound of the present invention is administered orally.
  • a compound of the present invention and/or composition of the present invention can be in a dosage form known to those skilled in the pharmaceutical practices, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, emulsions, syrups, powders, liquids, suspensions, and/or the like.
  • Typical pharmaceutical compositions include, but are not limited to, tablets, pills, powders or gelatin capsules comprising the active ingredient (e.g., a compound of the present invention) and a pharmaceutically acceptable excipient, diluent and/or carrier, such as for example: a) a diluent, e.g., purified water, com oil, olive oil, sunflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid its magnesium or calcium salt and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, natural and synthetic gums such
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • a compound of the present invention is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and/or the like, to thereby form an injectable isotonic solution or suspension.
  • Said composition may be sterilized and/or contain adjuvants, such as preserving, stabilizing wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers.
  • a compound of the present invention and/or composition of the present invention may also be formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • a compound of the present invention and/or composition of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound is coupled.
  • a compound of the present invention and/or composition of the present invention may be coupled with a soluble polymer as a targetable drug carrier.
  • soluble polymer can include, but are not limited to, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • a compound of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphillic block copolymers of hydrogels.
  • a polymer e.g., a poly carboxylic acid polymer, or a polyacrylate.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions may be prepared according to conventional mixing, granulating and/or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • Ointments, pastes, creams and gels may contain, in addition to an active compound and/or composition of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound or composition of the invention to the body.
  • dosage forms can be made by dissolving or dispensing a compound of the present invention in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions of the present invention can be prepared according to conventional mixing, granulating and/or coating methods, respectively, and the present pharmaceutical (or veterinary) compositions can contain from about 0.1% to about 99% of compound by weight or volume.
  • the present invention further provides pharmaceutical (or veterinary) compositions and dosage forms that comprise one or more agents that reduce the rate by which a compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, and/or salt buffers, etc.
  • the dosage regimen utilizing a compound or composition of the present invention may be selected in accordance with a variety of factors including type, species, age, weight, sex and/or medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular disclosed compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • Effective dosage amounts of a compound of the present invention when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the compound as needed to treat the condition.
  • a method of the present invention comprises administering to a subject a compound of the present invention in an amount of about 0.05 to about 5 mg of the compound per kg of the subject, such as, for example, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 1 mg/kg, or about 1 mg/kg to about 3 mg/kg.
  • a compound of the present invention may be administered to a subject in an amount of about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 mg of the compound per kg of the subject.
  • a compound of the present invention may be administered to a subject one or more times per day and/or week (e.g., 1, 2, 3, 4, 5, or more times per day and/or week) for a period of time (e.g., about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved).
  • a compound of the present invention is administered to a subject one, two or three times per day.
  • a compound of the present invention is administered to a subject two or three times a week or every two or three days.
  • a compound of the present invention is administered to a subject once a day for about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved.
  • compositions of the invention can contain from about 0.1% to about 99% of a compound of the invention by weight or volume.
  • a compound or composition of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s).
  • a compound or composition of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other therapeutic agent(s).
  • the invention provides a product comprising a compound of the invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • a compound of the invention e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof
  • the one or more additional therapeutic agent(s) are an ACE inhibitor, acetyl CoA carboxylase inhibitor, adenosine A3 receptor agonist, adiponectin receptor agonist, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK), amylin receptor agonist, angiotensin II AT-1 receptor antagonist, autotaxin inhibitors, bioactive lipid, calcitonin agonist, caspase inhibitor, caspase-3 stimulator, cathepsin inhibitor, caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, chloride channel stimulator, CNR1 inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1/2 inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, famesoid X receptor agonist, fatty acid
  • the therapy is the treatment or prevention of a disease or condition mediated by PPAR.
  • Products provided as a combined preparation include, but are not limited to, a composition comprising a compound of the invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the invention and one or more therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the invention (e.g.
  • composition of the invention and one or more therapeutic agent(s) in a separate form, e.g. in the form of a kit.
  • a compound of the present invention is an isotopically labelled compound.
  • An “isotopically labelled compound” as used herein refers to a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
  • one or more hydrogen atom positions in a compound can be enriched with deuterium to a level that is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%.
  • Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analogue, and therefore exhibit a longer half-life when administered to a subject (Annual Reports In Medicinal Chemistry, Vol. 26, 2011, Chapter 24 - Deuterium in Drug Discovery and Development, pages 403-417).
  • Such compounds can be synthesized using methods known in the art, for example, by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable. The present invention is explained in greater detail in the following non-limiting examples.
  • liver hepatocytes for example primary human hepatocytes
  • the reaction is stopped at 15, 30, 60, 90, 120 min by precipitating a sample of incubation mixture with acetonitrile.
  • the precipitated sample is subjected to subsequent analysis by HPLC and mass spectrometry to ascertain which metabolites are formed.
  • the analysis may show that the compound is oxidized to provide hydroxy derivatives, but that there is no presence of acyl-glucuronide like metabolites in which a glucuronide group has been added to the sulfmic acid functionality.

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Abstract

The present invention relates to compounds that can act as modulators of the nuclear receptor peroxisome proliferator-activated receptor α, y and/or δ (PPARα, PPARy and/or PPARδ) and that can be useful in the treatment of diseases and/or disorders associated with the PPARα, PPARy and/or PPARδ. In some embodiments, the present invention relates to compounds and compositions that modulate a PPAR and methods for their preparation and use.

Description

SULFINIC ACID AND SULFONIC ACID COMPOUNDS FOR USE IN MODULATING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/972,787, filed February 11, 2020, the disclosure of which is incorporated herein by reference in its entirety.
FIELD
The present invention relates to compounds that can act as modulators of the nuclear receptor peroxisome proliferator-activated receptor α, γ and/or δ ( PPARα, PPARγ and/or PPARδ) and that can be useful in the treatment of diseases and/or disorders associated with the PPARα, PPARγ and/or PPARδ. In some embodiments, the present invention relates to compounds and compositions that modulate a PPAR and methods for their preparation and use.
BACKGROUND
Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH) are liver diseases which resemble alcoholic hepatitis on liver biopsy but can occur in patients who have no known history of alcohol abuse.
NASH is characterized by hyperinsulinemia, insulin resistance, hyperlipidemia, elevated serum transaminases such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and liver cell injury driven by lipid accumulation, hepatic inflammation and lobular infiltration of inflammatory cells such as macrophages, and activation and transformation of hepatic stellate cells into smooth muscle cell phenotype (Luwig, J, et al. Mayo Clin Proc 1980;55:434-438). In humans, NAFLD progresses from the relatively benign stage of hepatic steatosis through an intermediary stage of NASH in which fibrosis appears and begins to accumulate to frank cirrhosis culminating in liver failure.
Due to current high energy intake and sedentary lifestyle characteristics of modem day living, the global prevalence of NAFLD has reached 25% of the adult population and continues to rise. Some 20 % ofthese NAFLD patients are expected to develop overt NASH with significant chance to develop cirrhosis and ultimately liver failure. Although NAFLD and NASH represent a major burden to the patient and the supporting health system, there is currently no approved pharmacotherapy targeting the disease, emphasizing the current need for novel intervention strategies. Peroxisome proliferator-activated receptors are members of the nuclear hormone super family. There are three PPAR isoforms: alpha (a), beta/delta (β/δ), and gamma (γ), which are differently expressed in various tissues (Cave MC, et al. Biochim Biophys Acta. 2016;1859: 1083-1099, Tailleux A, et al. Biochim Biophys Acta. 2012; 1821 : 809— 818.). PPARα is expressed ubiquitously, but largely present in the liver. PPAR β/δ is mainly expressed in skeletal muscle and to a lesser extend in adipose tissue and skin. PPARγ is highly expressed in adipose tissue.
Several endogenous PPAR ligands have been suggested including free fatty acids, eicosanoids, and various complex lipids (Yu K, et al. J Biol Chem. 1995;270:23975- 23983, Wahli W, and Michalik L. Trends Endocrinol Metab. 2012;23:351-363). Exogenous ligands include environmental and pharmaceutical molecules that can activate one or all of the PPAR family receptors to varying degrees (Takeuchi S, et al. Toxicol Appl Pharmacol. 2006;217:235-244, Corton JC. Crit Rev Toxicol. 2008;38:857-875, Laughter AR, etal. Toxicology. 2004;203:83-98, Fisher CD, et al. Arch Toxicol. 2008;82:959-964, and Sznaidman et al. Bioorg Med Chem Lett. 2003;13: 1517-1521). Once ligand-bound, PPARs form a heterodimer with retinoid X receptor (RXR) to bind response elements that regulate the expression of genes encoding enzymes or proteins involved in beta oxidation, fatty acid uptake, adipogenesis, and adipocyte differentiation (Cave MC, et al. Biochim Biophys Acta. 2016; 1859: 1083-1099, Issemann I, and Green S. Nature. 1990;347:645-650, Evans RM, et al. Nat Med. 2004;10:355-361 Desvergne B, and Wahli W. Endocr Rev. 1999;20:649-688).
Although PPAR was originally named for the ability of ligands to induce hepatic peroxisome proliferation and resulting hepatocellular carcinoma (Issemann I, and Green S. Nature. 1990; 347:645-650), this phenomenon is specific to rodents (Holden PR, and Tugwood JD. J Mol Endocrinol. 1999;22: 1-8, Gonzalez FJ, and Shah YM. Toxicology. 2008;246:2-8.).
The PPARs have a critical role as master regulators of lipid and glucose metabolism, inflammation, insulin resistance, and fibrinogenesis in multiple cell types and have thus become the target of drug development for the treatment of metabolic diseases including NAFLD and NASH. Different single, dual, or triple PPAR agonists have been investigated for their therapeutic potential in NASH. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH.
Activation of the PPAR has the potential to be a treatment for a range of diseases including diabetes (T1D and/or T2D), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (Y OAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, hypercholesterolemia, obesity, cardiovascular disease, inflammatory disease, neurodegeneration, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.
Although several PPAR modulators are known and have been disclosed (for recent examples see, Kim H.H. Liss and Brian N. Finck, PPARs and Nonalcoholic Fatty Liver Disease, Biochimie, 2017, 136, 65-73; Narendra S., Choudhary· Naveen Kumar, Ajay Duseja, Peroxisome Proliferator- Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease, J Clin Exp Hepatol. 2019 Nov-Dec;9(6):731-739, B. Boubia et al, Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate, J. Med Chem., 2018, Mar 22, 61, 6, 2246), there is still a need for the development of novel and potent compounds for the treatment and prevention of disease.
This is particularly because the administration of those PPAR modulators can give rise to reactive metabolites that cause liver toxicity and drug -induced liver injury (Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16; Regan S, Maggs J, Hammond T, Lambert C, Williams D and Park BK (2010) Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos 31: 367-395; Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16). The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
SUMMARY
The present inventors have discovered that replacing a carboxylic acid component with a sulfmic and/or sulfonic group on compounds that are PPAR modulators can alter the metabolism pathway of the compound (compared to the metabolism pathway for the compounds with the carboxylic acid component present), which may result in a decrease in harmful metabolites formed, particularly via acyl-glucuronidation without significant loss of efficacy as PPAR modulators.
The present invention relates to the compounds defined by Formula I, II, III, IV and V as detailed below, which are referred to hereinafter as “the compounds of the invention”.
One aspect of the present invention is directed to compounds represented by Formula I:
Figure imgf000005_0001
wherein:
R1a is C1-3 alkyl, C3-5 cycloalkyl or -SR5, wherein each C1-3 alkyl and C3-5 cycloalkyl is optionally substituted with one or more halogen atoms;
Xa is CH2CH2 or CH=CH; R2a and R3a are independently H or C1-3 alkyl, wherein the C1-3alkyl is optionally substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different);
Ya is O, S or CH2;
R4a is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; and
R5 is C1-3 alkyl or C3-5 cycloalkyl each of which may optionally be substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different); or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof. In a second aspect, the present invention provides a compound having a structure represented by Formula II:
Figure imgf000006_0001
wherein:
R1b and R2b are independently H, halogen, C1-C6 alkyl, CF3, CN, COR4b. OR4b or phenyl optionally substituted by C1-C4 alkyl or CF3;
R4b is independently selected from the group consisting of C1-C4 alkyl, CF3 and phenyl optionally substituted by C1-C4 alkyl or CF3;
Xb is (CH2)n;
Yb is CH2 or O or S; R3b is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; n is 0 or 1 or 2; and
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5, 6,7,8- tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3- dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b. OR4b. SR4b, NHCOR4b. morpholinyl, N(C1-C4 alkyl)2 and 4-morpholinosulfonyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In a third aspect, the present invention provides a compound having a structure represented by Formula III:
Figure imgf000007_0001
wherein:
Ac is (CH2)nS(O)OH or (CH2)nS(O)2OH n is 0, 1, 2 or 3
R1c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo or C1-C8haloalkyl: Xc is CH2 or S or O;
R2c and R3c are independently H, C1-C8 alkyl, C1-C8 alkoxy, halo, or C1-C8haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring;
Yc is CH2 or S or O;
R4c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo, C1-C8haloalkyl. phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5c; and each R5c is independently selected from the group consisting of a halogen, C1-C6 alkyl, C1-C6, haloalkyl. C1-C6 alkoxy, C1-C6, haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In a fourth aspect, the present invention provides a compound having a structure represented by Formula IV:
Figure imgf000008_0001
wherein:
Ad is (CH2)nS(O)OH or (CH2)nS(O)2OH; n is 1 or 2;
Zd is O or S;
R1d is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8alkoxy, halo or C1-C8 haloalkyl:
Xd is CH2 or S or O;
R2d and R3d arc independently H, C1-C8 alkyl, C1-C8alkoxy, halo, or C1-C8 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring;
Yd is CH2 or S or O;
R4d is H, C1-C8 alkyl. C3-C5 cycloalkyl, C1-C8alkoxy, halo, C1-C8 haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5d: and each R5d is independently selected from the group consisting of a halogen, C1-C6 alkyl, halo, C1-C6 alkyl, C1-C6alkoxy, C1-C6, haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In a fifth aspect, the present invention provides a compound having a structure represented by Formula V
Figure imgf000008_0002
wherein:
Ae and Be are independently phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 or 2
R4e; each R4e is independently selected from the group consisting of a halogen, C1-C3 alkyl, halo, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and cyclopropyl;
We is C1-C6alkylene or C2-C6alkenylene; R1e is C1-C6 alkyl, C3-C6 cycloalkyl, aryl or aralkyl;
R2e is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, C1- C3alkoxy or cyclopropyl;
Xe is O or S or CH2; and
Ye is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
A sixth aspect of the present invention is directed to a pharmaceutical (or veterinary) composition comprising a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient, diluent and/or carrier, which are referred to hereinafter as “the compositions of the invention”.
Another aspect of the present invention is directed to a method of modulating a Peroxisome Proliferator- Activated Receptor (PPAR). The method comprises administering to a subject in need thereof an effective amount of a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the present invention.
The present invention is also directed to a compound of the present invention or a composition of the present invention for use in modulating a Peroxisome Proliferator- Activated Receptor (PPAR). The present invention is also directed to the use of a compound of the present invention or a composition of the present invention in the manufacture of a medicament for modulating (e.g. activating) a Peroxisome Proliferator- Activated Receptor (PPAR).
The present invention is also directed to a method of treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a composition of the invention. Still further, the invention is directed to the use of a compound of the invention or a composition of the invention, in the manufacture of a medicament for treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role. It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim and/or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim or claims although not originally claimed in that manner. These and other objects and/or aspects of the present invention are explained in detail in the specification set forth below. Further features, advantages and details of the present invention will be appreciated by those of ordinary skill in the art from a reading of the figures and the detailed description of the preferred embodiments that follow, such description being merely illustrative of the present invention.
DETAILED DESCRIPTION Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.
As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed.
The term “about,” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified value as well as the specified value. For example, “about X” where X is the measurable value, is meant to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of X. A range provided herein for a measureable value may include any other range and/or individual value therein.
A “Peroxisome Proliferator-Activated Receptor” or “PPAR” as used herein is a Peroxisome Proliferator-Activated Receptor from any source and/or that is present in a subject and/or expressed in any form. In some embodiments, Peroxisome Proliferator- Activated Receptor is from and/or is present and/or expressed in an animal such as, e.g., a mammal. In some embodiments, Peroxisome Proliferator-Activated Receptor is from and/or is present and/or expressed in a primate, cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and/or the like. In some embodiments, Peroxisome Proliferator- Activated Receptor is from and/or is present and/or expressed in a human.
The terms “modulate” and “modulating”, in reference to a PPAR, refer to the ability of a compound (e.g., a compound of the present invention) to activate or inhibit one or more fimction(s), action(s), and/or characteristic(s) of the PPAR, either directly or indirectly. This may occur in-vitro or in-vivo and is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of a function, action, and/or characteristic associated with a PPAR. The term “modulator”, in reference to a PPAR, refers to a compound (e.g., a compound of the present invention) that modulates a PPAR. In some embodiments, a compound of the present invention modulates a PPAR by activating one or more function(s), action(s), and/or characteristic(s) of the PPAR.
The term “activating”, in reference to a PPAR, refers to the ability of a compound (e.g., a compound of the present invention) to activate, increase or enhance a function, action, and/or characteristic associated with the PPAR, and, thus, the compound is a PPAR agonist.
The term “agonist” refers to a compound (e.g., a compound of the present invention) that combines with and/or binds to a specific receptor (e.g., a PPAR) and activates, increases or enhances a function, action, and/or characteristic associated with the receptor. The term “agonist” includes both a full agonist and a partial agonist, which activates, increases or enhances a function, action, and/or characteristic associated with the receptor (e.g., PPAR) to a lesser extent than a full agonist and/or has partial efficacy at the receptor compared to a full agonist. In some embodiments, a compound of the present invention is an PPAR agonist. In some embodiments, a compound of the present invention is an agonist and activates a PPAR providing the same or substantially the same reaction and/or pharmacological response typically produced by the binding of an endogenous agonist.
“Substantially the same” as used herein in reference to a measurable value and/or response means being within about ± 10% of the compared to value and/or response.
The term "C1-Cx alkyl", where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a saturated alkyl chain having 1 to x carbon atoms which may be a straight chain or branched chain. For example, a C1-C8 alkyl is a saturated alkyl chain (straight or branched) having 1 to 8 carbon atoms. Examples thereof include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isopropyl.
The term “C1-Cx alkoxy”, where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a straight or branched chain saturated hydrocarbon containing 1 to x carbon atoms, containing an oxygen in the chain and the straight or branched chain saturated hydrocarbon is attached to a parent or principal compound through the oxygen. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
The term "C1-Cx haloalkyl", where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a saturated alkyl chain having 1 to x carbon atoms which may be a straight chain or branched chain and in which one or more hydrogen atoms have been replaced with a halogen atom (such as F, Cl, Br, I). Examples thereof include, but are not limited to, dichloromethyl, trifluromethyl and trifluroethyl.
The term “C1-Cx haloalkoxy”, where x is 1, 2, 3, 4, 5, 6, 7 or 8, means a straight or branched chain saturated hydrocarbon containing 1 to x carbon atoms, in which one or more hydrogen atoms have been replaced with a halogen atom (such as F, Cl, Br, I), and the chain contains a terminal oxygen. The straight or branched chain saturated hydrocarbon is attached to a parent or principal compound through the oxygen. Example thereof includes, but is not limited to, trifluromethoxy.
The term “C3-C5 cycloalkyl” means a saturated monocyclic ring system comprising 3 to 5 carbon atoms. Examples thereof are cyclopropyl, cyclobutyl and cyclopentyl. The term “C3-C6 cycloalkyl” means a saturated mono-, bi-, spiro- or multicyclic ring system comprising 3 to 6 carbon atoms. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and spiro[2.3]hexane.
The term “C2-C4 alkenyl”, where x is 2, 3 or 4, means a straight or branched chain hydrocarbon containing 2 to x carbon atoms with at least one point of unsaturation. Examples thereof include, ethylene and propylene.
The terms “alkylene” and “alkenylene” are used to define the bivalent form of “alkyl” and “alkenyl” respectively.
The term “4- to 7-membered heterocyclic” means a saturated mono-, bi-, spiro- or multicyclic ring system that contains 4 to 7 atoms selected from carbon, nitrogen, oxygen, and/or sulfur with 1-2 of those atoms being a heteroatom (i.e., nitrogen, oxygen, and/or sulfur). Examples thereof include, but are not limited to, pyrrolidine, thiolane, tetrahydrofuran, piperidine, tetrahydropyran, thiane, morpholine, piperazine, and dioxane. If not stated otherwise, a 4- to 7 membered mono-, bi-, spiro- or multicyclic ring system as described herein can be connected via a carbon or nitrogen atom.
“Halogen” refers to fluorine, chlorine, bromine and iodine. In some embodiments, the halogen is selected from fluorine and chlorine.
The term “sulfinic acid” means the functional group -S(O)OH, consisting of a sulfinyl group and a hydroxyl group.
The term “sulfinate” means the conjugate base of sulfinic acid, where the hydroxyl has been deprotonated to give S(O)O-.
The term “sulfonic acid” means the functional group -S(O)2OH, consisting of a sulfonyl group and a hydroxyl group.
The term “sulfonate” means the conjugate base of sulfonic acid, where the hydroxyl has been deprotonated to give S(O)2O-.
The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituent(s) different from hydrogen. For instance, it can, at any point along the chain, be bound to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
The term "pharmaceutically acceptable salt" refers to a salt of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
For a detailed review of pharmaceutically acceptable salts see J. Pharmaceutical Sciences, 66: 1-19 (1977), by Berge et al. In some embodiments, the salts can be prepared in situ during the final isolation and/or purification for a compound of the invention, or separately by reaction of the free acid function with a suitable inorganic or organic base. Suitable salts include, but are not limited to, metals, such as sodium, potassium and calcium, or amines, such as triethylammonium, ethanolammonium and lysine.
In some embodiments, a compound of the present invention is a sodium salt. In some embodiments, a compound of the present invention is a sulfinate salt (e.g. a sodium sulfinate salt).
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
The term "prodrug" refers to a prodrug of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and/or the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of a compound of the present invention. "Prodrug", as used herein means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford a compound of the present invention (e.g., a compound of Formula I). Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).
The term "amino acid conjugate" refers to a conjugate of a compound of the present invention (e.g., a compound of Formula I) with an amino acid. Preferably, such amino acid conjugates of the present invention will have the added advantage of enhanced integrity in bile and/or intestinal fluids. Suitable amino acids include, but are not limited to, glycine and taurine. Thus, the present invention encompasses the glycine and taurine conjugates of a compound of Formulas I-V.
Unless indicated otherwise, nomenclature used to describe chemical groups or moieties as used herein follow the convention where, reading the name from left to right, the point of attachment to the rest of the molecule is at the right-hand side of the name. For example, the group "(C1-C3alkoxy)C1-C3alkyl" is attached to the rest of the molecule at the alkyl end. Further examples include methoxyethyl, where the point of attachment is at the ethyl end, and methylamino, where the point of attachment is at the amine end.
Unless indicated otherwise, where a mono or bivalent group is described by its chemical formula, including one or two terminal bond moieties indicated by
Figure imgf000015_0001
it will be understood that the attachment is read from left to right.
Unless otherwise stated, structures depicted herein are meant to include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Provided according to embodiments of the present invention are compounds represented by Formula I:
Figure imgf000016_0001
wherein:
R1a is C1-3 alkyl, C3-5 cycloalkyl or -SR5, wherein each C1-3 alkyl and C3-5 cycloalkyl is optionally substituted with one or more halogen atoms;
Xa is CH2CH2 or CH=CH;
R2a and R3a are independently H or C1-3 alkyl, optionally wherein the C1-3alkyl is substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different);
Ya is O, S or CH2;
R4a is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; and
R5 is C1-3 alkyl or C3-5 cycloalkyl, each of which may optionally be substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different); or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the invention provides a compound of Formula I, wherein R1a is CH3 or CH2CH3 or SCH3; Xa is CH2CH2 or CH=CH; R2a and R3a are independently H or C1-3 alkyl; Ya is O, S or CH2; and R4a is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(O)OH or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, for example, the invention provides a compound of Formula I, wherein R1a is SCH3; Xa is CH=CH; R2a and R3a are each CH3; Ya is O or CH2; and R4a is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(C))OH or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In an aspect of the invention, in the compound of Formula I or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, R4a is CH2S(O)OH, CH(CH3)S(O)OH or C(CH3)2S(O)OH. In an aspect of the invention, in the compound of Formula I or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, R4a is CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH.
In a second aspect, the present invention provides a compound having a structure represented by Formula II:
Figure imgf000017_0001
wherein:
R1b and R2b are independently H, halogen, C1-C6 alkyl, CF3, CN, COR4b. OR4b or phenyl optionally substituted by C1-C4 alkyl or CF3;
R4b is independently selected from the group consisting of C1-C4 alkyl, CF3 and phenyl optionally substituted by C1-C4 alkyl or CF3;
Xb is (CH2)n;
Yb is CH2 or O or S;
R3b is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; n is 0 or 1 or 2; and
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5, 6,7,8- tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3- dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b, OR4b, SR4b, NHCOR4b, morpholinyl, N(C1-C4 alkyl)2 and 4-morpholinosulfonyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a compound of Formula II, wherein R1b and R2b are independently H, halogen, C1-C3 alkyl or CF3; Xb is (CH2)n; Yb is CH2; R3 is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(O)OH; n is 1 or 2 or 3; and Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl,
2.1.3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2- oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl,
2.3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b, OR4b. SR4b. NHCOR4b. morpholinyl, N(C1- C4 alkyl)2 and 4- morpholinosulfonyl or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, for example, the present invention provides a compound of Formula II, wherein R1b and R2b are independently H, halogen, C1-C3 alkyl, or CF3; Xb is (CH2)n; Yb is CH2; R3 is CH2S(O)OH; n is 1 or 2 or 3; and Ar is benzothiazolyl substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b, OR4b, SR4b, NHCOR4b, morpholinyl, amino and 4- morpholinosulfonyl or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In an aspect of the invention, in the compound of Formula II or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, R3b is CH2S(O)OH, CH(CH3)S(O)OH or C(CH3)2S(O)OH.
In an aspect of the invention, in the compound of Formula II or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, R3b is CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH.
In a further aspect, the present invention provides a compound having a structure represented by Formula III:
Figure imgf000018_0001
wherein:
Ac is (CH2)nS(O)OH or (CH2)nS(O)2OH n is 0, 1, 2 or 3 R1c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo or C1-C8 haloalkyl:
Xc is CH2 or S or O;
R2c and R3care independently H, C1-C8 alkyl, C1-C8 alkoxy, halo, or C1-C8 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring;
Yc is CH2 or S or O;
R4c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl. phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5c: and each R5c is independently selected from the group consisting of a halogen, C1-C6 alkyl, C1-C6, haloalkyl. C1-C6 alkoxy, C1-C6, haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a compound of Formula III, wherein Ac is (CH2)nS(O)OH; n is 2 or 3; R1c is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo or C1-C3 haloalkyl; Xc is CH2 or S or O; R2c and R3c are independently H, C1- C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Yc is CH2 or S or O; and R4c is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, for example, the present invention provides a compound of Formula III, wherein Ac is CH2nS(O)OH; n is 2 or 3; R1c is H, C1-C3 alkyl, C3-C5 cycloalkyl, halo or C1-C3 haloalkyl; Xc is O; R2c and R3c are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Yc is S and R4c is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In an aspect of the invention, in the compound of Formula III or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ac is (CH2)nS(O)OH.
In an aspect of the invention, in the compound of Formula III or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ac is (CH2)nS(O)2OH. In a further aspect, the present invention provides a compound having a structure represented by Formula IV:
Figure imgf000020_0001
wherein:
Ad is (CH2)nS(O)OH or (CH2)nS(O)2OH; n is 1 or 2;
Zd is O or S;
R1d is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo or C1-C8 haloalkyl: Xd is CH2 or S or O;
R2d and R3d are independently H, C1-C8 alkyl, C1-C8 alkoxy, halo, or C1-C8 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring;
Yd is CH2 or S or O;
R4d is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8alkoxy, halo, C1-C8 haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5d: and each R5d is independently selected from the group consisting of a halogen, C1-C6 alkyl, halo, C1-C6 alkyl, C1-C6alkoxy, C1-C6, haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the present invention provides a compound of Formula IV, wherein Ad is (CH2)nS(O)OH; n is 1 or 2; Zd is O or S; R1d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo or C1-C3 haloalkyl; Xd is CH 2 or S or O; R2d and R3d are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Yd is CH 2 or S or O; and R4d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof. In some embodiments, for example, the present invention provides a compound of
Formula IV, wherein Ad is (CH2)nS(O)OH; n is 1 or 2; Zd is O or S; R1d is H, C1-C3 alkyl, C3-C5 cycloalkyl, halo or C1-C3 haloalkyl; Xd is O; R2d and R3d are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl or optionally both may be joined together to form a 3 to 8 membered ring; Yd is S; and R4d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In an aspect of the invention, in the compound of Formula IV or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ad is (CH2)nS(O)OH.
In an aspect of the invention, in the compound of Formula IV or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ad is (CH2)nS(O)2OH.
In another aspect, the present invention provides a compound having a structure represented by Formula V
Figure imgf000021_0001
wherein:
Ae and Be are independently phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 or 2
R4e; each R4e is independently selected from the group consisting of a halogen, C1-C3 alkyl, halo, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and cyclopropyl;
We is C1-C6alkylene or C2-C6alkenylene;
R1e is C1-C6 alkyl, C3-C6 cycloalkyl, aryl or aralkyl;
R2e is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, C1- C3alkoxy or cyclopropyl;
Xe is O or S or CH2; and
Ye is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound of Formula V, wherein Ae is phenyl, optionally substituted with R4e; Be is 5 to 10 membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5 to 10 bicyclic heteroaryl is optionally substituted with R4e; R4e is independently selected from the group consisting of a halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and cyclopropyl; We is C1-C3 alkylene or C2-C4alkenylene; R1e is C1-C3 alkyl, C3-C6 cycloalkyl; R2e is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1- C3 haloalkoxy or cyclopropyl; Xe is O or S or CH2; Ye is CH2S(O)OH, CH(CH3)S(O)OH or C(CH3)2S(O)OH or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
In an aspect of the invention, in the compound of Formula V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ye is CH2S(O)OH, CH(CH3)S(O)OH or C(CH3)2S(O)OH.
In an aspect of the invention, in the compound of Formula V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof, Ye is CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH.
In an aspect of the invention, the compound of the present invention as defined above are a metabolite (i.e. having undergone metabolism or biotransformation in the subject).
Exemplary compounds of the present invention include, but are not limited to, the following:
4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5 -chloroindol-2-yl]butan-1-sulfinic acid; 4-[1-(1,3- benzothiazol-6-ylsulfonyl)-5-chloromdol-2-yl]ethan-1-sulfinicacid;2-[2,6-dimethyl-4- [(E}~3-(4-methylsulfanylphenyl)-3-oxoprop-1-enyl]phenoxy]-2-methylpropan-1sufinic acid;2-[2,6-dimethyl-4-[(E)-3-(4-methylsulfanylphenyl)-3-oxoprop-1- enyl]phenoxy]ethan-1-sufinicacid;2-[2,6-dimethyl-4-[(E)-3-(4-methylsulfanylphenyl)-3- oxoprop-1-enyl]phenyl]-2-methylpropan-1-sufinicacid;2-[2,6-dimethyl-4-[(E)-3-(4- methylsulfanylphenyl)-3-oxoprop-1-enyl]phenyl]ethan-1-sufinicacid;2-[4-[(2R)-2- ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2~methylphenoxy]ethan-1-sulfinic acid;and/or2-[4-[(2R)~2-ethoxy-3~[4-(trifluoromethyl)phenoxy]propyi]sulfanyl-2~ methylphenyl]propan-1-sulfinicacid. Compounds of Formula I to V as defined herein may be useful as PPAR modulators and/or may have an improved toxicity profile. The improved toxicity profile may be due to a reduced propensity for forming toxic metabolites as compared to corresponding compounds in which the sulfinic acid or sulfonic acid component is replaced with a carboxylic acid component. The compounds or composition of the invention may therefore be used in medicine.
In some embodiments, a compound of the present invention has a different metabolic profile compared to a corresponding carboxylic acid compound (i.e., a compound having a -COOH or -COO- group replacing the mandatory -S(O)OH, -S(O)O- , -S(O)2OH or -S(O)2O- group in the compound of Formula I to V). These corresponding carboxylic acid compounds are typically metabolised to an acyl-glucuronide and such metabolism can give rise to reactive metabolites that cause liver toxicity and drug induced liver injury (Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16; Regan S, Maggs J, Hammond T, Lambert C, Williams D and Park BK (2010) Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos 31 : 367- 395; Shipkova M, Armstrong VW, Oellerich M, and Wieland E (2003) Acyl glucuronide drug metabolites: Toxicological and analytical implications. Ther Drug Monit 25: 1-16).
For example, the compounds of the present invention may only be metabolised by oxidative pathways, such as Cyp oxidation, and/or may minimise the formation of acyl glucuronide-like metabolites compared to a corresponding carboxylic acid compound.
In some embodiments, a compound of the present invention may have a different distribution profile when orally dosed in-vivo, such as increased exposure in the liver versus plasma, compared to a corresponding carboxylic acid compound.
In some embodiments, a compound of the present invention may break down in- vivo via a different metabolic pathway than a corresponding carboxylic acid compound and/or the compound of the invention may have beneficial liver safety effects and/or improved liver safety and/or improved efficacy compared to a corresponding carboxylic acid compound.
For example, the compounds of the present invention may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical or chemical properties than a compound known in the prior art. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.
In some embodiments, the compounds of the present invention as defined above are metabolites (i.e. having undergone metabolism or biotransformation in the subject).
For example, a compound of the present invention may be a sulfinic acid metabolite, which may be a corresponding sulfonic acid of the compound (e.g., a compound having a -S(O)2OH or -S(O)2O- group replacing a -S(O)OH or -S(O)O- group in the compound) or a corresponding sulfinate ester of the compound (e.g., a compound having a -S(O)O(C1-6 alkyl) group replacing a -S(O)OH or -S(O)O- group in the compound).
In other embodiments, the compounds of the present invention as defined above may be a sulfinic acid (or its corresponding sulfinate salt) compounds or sulfonic acid (or its corresponding sulfonate salt) compounds. In a preferred aspect, the compounds of the invention are sulfinic acid (or its corresponding sulfinate salt) compounds, i.e. compounds containing CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH or (CH2)nS(O)OH.
In a further embodiment of the invention, the compounds of the present invention are provided in the form of a sodium salt, for example a sodium sulfinate salt.
The reaction schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. The examples provided herein are offered to illustrate but not limit the compounds of the present invention, as well as the preparation of such compounds and intermediates.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be routinely prepared by procedures described in the literature, for example, Houben-Weyl “Science of Synthesis” volumes 1-48, Georg Thieme Verlag, and subsequent versions thereof.
A reaction may be carried out in the presence of a suitable solvent or diluent or of mixture thereof in a manner known to those skilled in the art of organic synthesis. A reaction may also be carried out, if needed, in the presence of an acid or a base, with cooling or heating, for example in a temperature range from about -30 °C to about 150 °C. In some embodiments, a reaction is carried out in a temperature range from about 0 °C to about 100 °C, and more particularly, in a temperature range from room temperature to about 80 °C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Provided according to embodiments of the present invention is a composition (i.e. a pharmaceutical or veterinary composition) comprising a compound of the present invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof). The compositions comprise an excipient, diluent and/or carrier as required. For example, in one embodiment, the invention relates to a pharmaceutical composition comprising a compound of the present invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient, diluent and/or carrier.
As used herein, the term "pharmaceutically acceptable excipient, diluent and/or carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, that are suitable for use in a pharmaceutical product. Such excipients, diluents and/or carriers include those which would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional excipient, diluent and/or carrier is incompatible with the active ingredient (e.g., a compound of the present invention), its use in the therapeutic and/or pharmaceutical compositions is contemplated.
Compounds of the invention are indicated as pharmaceuticals. Therefore, according to a seventh aspect of the invention, there is provided a compound of the invention (i.e. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof), or a pharmaceutical (or veterinary) composition of the invention for use as a pharmaceutical (e.g. for use in medicine).
According to aspects and embodiments of the present invention, the compounds of the invention or compositions of the invention may be administered to patients or subjects in need thereof.
As used herein, the term “patient” and "subject" refer to an animal. Typically, the animal is a mammal. A “patient” or “subject” also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
Therefore, the present invention provides a method of modulating a Peroxisome Proliferator- Activated Receptor (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention. Said methods are hereinafter referred to as “methods of the invention”.
The present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in modulating a Peroxisome Proliferator- Activated Receptor (PPAR). The present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for modulating a Peroxisome Proliferator-Activated Receptor (PPAR).
The present invention also provides a method of activating a Peroxisome Proliferator-Activated Receptor (PPAR), the method comprising administering to a subject a compound of the invention or a pharmaceutical composition of the invention. The present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in activating a Peroxisome Proliferator-Activated Receptor (PPAR). The present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for activating a Peroxisome Proliferator-Activated Receptor (PPAR).
In some embodiments, a PPAR plays a role in a disease or disorder, i.e. the PPAR is involved in a pathway, mechanism, or action associated with the disease and/or disorder such as, e.g. transcriptional regulation of glucose and lipid metabolism. The present invention also provides a method of treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition of the invention.
The present invention also provides a compound of the invention or a pharmaceutical composition of the invention for use treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role. The present invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role.
In some embodiments, the disease or disorder is diabetes (T1D and/or T2D), idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2D (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma), HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.
For example, the disease or disorder may preferably be fatty liver disease, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFFD).
The term "therapeutically effective amount" refers to an amount of a compound of the present invention (i.e., a compound of Formula I - V) and/or composition of the present invention that is sufficient to achieve or elicit a therapeutically useful response or a stated effect in a subject. For example, a therapeutically effective amount of a compound of Formula I used for the treatment of a condition mediated by PPAR can be an amount sufficient for to achieve a clinically relevant improvement in at least one symptom arising from a disease or disorder mediated by PPAR.
The terms "treat", "treating", "treatment of' and grammatical variations thereof in reference to a disease, or condition refer to any type of treatment that imparts a benefit to a subject and may mean that the severity of the subject’s condition is reduced, at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom associated with a disease, disorder, or condition is achieved and/or there is a delay in the progression of the symptom. In some embodiments, the severity of a symptom associated with a disease, disorder, or condition mediated by PPAR may be reduced in a subject compared to the severity of the symptom in the absence of a method of the present invention. In some embodiments, "treat", "treating", "treatment of' and grammatical variations thereof in reference to a disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or disorder or at least one clinical symptom thereof). In some embodiments, "treat", "treating" or "treatment of' and grammatical variations thereof in reference to a disease or disorder refer to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the subject. In some embodiments, "treat", "treating" or "treatment of' and grammatical variations thereof in reference to a disease or disorder refer to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.
In some embodiments, a compound of the present invention and/or composition of the present invention may be administered to a subject in a treatment effective amount. A "treatment effective" amount as used herein is an amount that is sufficient to treat (as defined herein) a subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. In some embodiments, a treatment effective amount may be achieved by administering a composition of the present invention.
The terms "prevent," "preventing" and "prevention" (and grammatical variations thereof) refer to avoidance, reduction and/or delay of the onset of a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) and/or a reduction in the severity of the onset of symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) relative to what would occur in the absence of a method of the present invention. The prevention can be complete, e.g., the total absence of the symptom. The prevention can also be partial, such that the occurrence of the symptom in the subject and/or the severity of onset is less than what would occur in the absence of a method of the present invention.
In some embodiments, a compound of the present invention and/or composition of the present invention may be administered in a prevention effective amount. A "prevention effective" amount as used herein is an amount that is sufficient to prevent (as defined herein) a symptom associated with a disease or disorder (e.g., a disease, disorder, or condition mediated by PPAR) in a subject. Those skilled in the art will appreciate that the level of prevention need not be complete, as long as some benefit is provided to the subject. In some embodiments, a prevention effective amount may be achieved by administering a composition of the present invention.
The terms "administer", "administering", "administration" and grammatical variations thereof as used herein refer to directly administering to a subject a compound of the present invention (or a pharmaceutically acceptable salt, etc., thereof) and/or a composition of the present invention. In some embodiments, a compound and/or composition of the present invention is administered to the subject in an amount that can form an equivalent amount of the active compound within the subject's body.
A compound of the present invention and/or composition of the present invention can be administered in a therapeutically effective amount to treat and/or prevent a disease or disorder and/or to prevent the development thereof in a subject. Administration of a compound of the present invention can be accomplished via any mode of administration for therapeutic agents such as, for example oral, rectal, topical, and/or parenteral administration may be employed. In some embodiments, a compound of the present invention is administered orally.
Depending on the intended mode of administration, a compound of the present invention and/or composition of the present invention can be in a dosage form known to those skilled in the pharmaceutical practices, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, emulsions, syrups, powders, liquids, suspensions, and/or the like.
Typical pharmaceutical compositions include, but are not limited to, tablets, pills, powders or gelatin capsules comprising the active ingredient (e.g., a compound of the present invention) and a pharmaceutically acceptable excipient, diluent and/or carrier, such as for example: a) a diluent, e.g., purified water, com oil, olive oil, sunflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid its magnesium or calcium salt and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, natural and synthetic gums such as acacia tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, algic acid or its sodium salt, and/or effervescent mixtures; e) absorbent, colorant, flavorant and/or sweetener; f) an emulsifier or dispersing agent, e.g. Labrasol, HPMC, labrafil, peceol, capmul, vitamin E TGPS and/or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and/or PEG200.
Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, a compound of the present invention is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and/or the like, to thereby form an injectable isotonic solution or suspension. Said composition may be sterilized and/or contain adjuvants, such as preserving, stabilizing wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers.
A compound of the present invention and/or composition of the present invention may also be formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
A compound of the present invention and/or composition of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound is coupled.
A compound of the present invention and/or composition of the present invention may be coupled with a soluble polymer as a targetable drug carrier. Such polymers can include, but are not limited to, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, a compound of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphillic block copolymers of hydrogels. In one embodiment disclosed compounds are not covalently bound to a polymer, e.g., a poly carboxylic acid polymer, or a polyacrylate.
Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. In addition, they may also contain other therapeutically valuable substances. Said compositions may be prepared according to conventional mixing, granulating and/or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Ointments, pastes, creams and gels may contain, in addition to an active compound and/or composition of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound or composition of the invention to the body. Such dosage forms can be made by dissolving or dispensing a compound of the present invention in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Compositions of the present invention can be prepared according to conventional mixing, granulating and/or coating methods, respectively, and the present pharmaceutical (or veterinary) compositions can contain from about 0.1% to about 99% of compound by weight or volume.
The present invention further provides pharmaceutical (or veterinary) compositions and dosage forms that comprise one or more agents that reduce the rate by which a compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, and/or salt buffers, etc.
The dosage regimen utilizing a compound or composition of the present invention may be selected in accordance with a variety of factors including type, species, age, weight, sex and/or medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; and the particular disclosed compound employed. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
Effective dosage amounts of a compound of the present invention, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the compound as needed to treat the condition.
In some embodiments, a method of the present invention comprises administering to a subject a compound of the present invention in an amount of about 0.05 to about 5 mg of the compound per kg of the subject, such as, for example, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 1 mg/kg, or about 1 mg/kg to about 3 mg/kg. In some embodiments, a compound of the present invention may be administered to a subject in an amount of about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 mg of the compound per kg of the subject. A compound of the present invention may be administered to a subject one or more times per day and/or week (e.g., 1, 2, 3, 4, 5, or more times per day and/or week) for a period of time (e.g., about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved). In some embodiments, a compound of the present invention is administered to a subject one, two or three times per day. In some embodiments, a compound of the present invention is administered to a subject two or three times a week or every two or three days. In some embodiments, a compound of the present invention is administered to a subject once a day for about 1 to about 52 weeks or until a desired therapeutic effect and/or treatment and/or prevention is achieved.
The compositions of the invention (e.g. pharmaceutical compositions) can contain from about 0.1% to about 99% of a compound of the invention by weight or volume.
A compound or composition of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s). A compound or composition of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other therapeutic agent(s).
In some embodiments, the invention provides a product comprising a compound of the invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
In some embodiments, the one or more additional therapeutic agent(s) are an ACE inhibitor, acetyl CoA carboxylase inhibitor, adenosine A3 receptor agonist, adiponectin receptor agonist, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK), amylin receptor agonist, angiotensin II AT-1 receptor antagonist, autotaxin inhibitors, bioactive lipid, calcitonin agonist, caspase inhibitor, caspase-3 stimulator, cathepsin inhibitor, caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, chloride channel stimulator, CNR1 inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1/2 inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, famesoid X receptor agonist, fatty acid synthase inhibitors, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G-protein coupled bile acid receptor 1 agonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, HMG CoA reductase inhibitor, IL-10 agonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, integrin modulator, intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, ketohexokinase inhibitor, klotho beta stimulator, 5 -lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor modulator, LPL gene stimulator, lysophosphatidate- 1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, matrix metalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG binding protein 2 modulator, microRNA-21(miR-21) inhibitor, mitochondrial uncoupler, myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, phospholipase C inhibitor, , protease-activated receptor-2 antagonist, protein kinase modulator, Rho associated protein kinase inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl CoA desaturase-1 inhibitor, suppressor of cytokine signalling- 1 stimulator, suppressor of cytokine signalling-3 stimulator, transforming growth factor 3 (TGF-β3), transforming growth factor β activated Kinase 1 (TAKi), thyroid hormone receptor beta agonist, TLR-4 antagonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulators, and/or YAP/TAZ modulator.
In some embodiments, the therapy is the treatment or prevention of a disease or condition mediated by PPAR. Products provided as a combined preparation include, but are not limited to, a composition comprising a compound of the invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or a composition of the invention and one or more therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the invention (e.g. a compound of Formula I, II, III, IV or V or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof) or composition of the invention and one or more therapeutic agent(s) in a separate form, e.g. in the form of a kit.
In some embodiments, a compound of the present invention is an isotopically labelled compound. An "isotopically labelled compound" as used herein refers to a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level that is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analogue, and therefore exhibit a longer half-life when administered to a subject (Annual Reports In Medicinal Chemistry, Vol. 26, 2011, Chapter 24 - Deuterium in Drug Discovery and Development, pages 403-417). Such compounds can be synthesized using methods known in the art, for example, by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable. The present invention is explained in greater detail in the following non-limiting examples.
EXAMPLES
Example 1 - Assessing Metabolite Formation
The compound is incubated with liver hepatocytes (for example primary human hepatocytes) in an incubator at 37 °C. The reaction is stopped at 15, 30, 60, 90, 120 min by precipitating a sample of incubation mixture with acetonitrile. The precipitated sample is subjected to subsequent analysis by HPLC and mass spectrometry to ascertain which metabolites are formed. The analysis may show that the compound is oxidized to provide hydroxy derivatives, but that there is no presence of acyl-glucuronide like metabolites in which a glucuronide group has been added to the sulfmic acid functionality.

Claims

THAT WHICH IS CLAIMED IS:
1. A compound having a structure represented by Formula I:
Figure imgf000036_0001
wherein:
R1a is C1-3 alkyl, C3-5 cycloalkyl or -SR5, wherein each C1-3 alkyl and C3-5 cycloalkyl is optionally substituted with one or more halogen atoms;
Xa is CH2CH2 or CH=CH; R2a and R3a are independently H or C1-3 alkyl, optionally wherein the C1-3alkyl is substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different);
Ya is O, S or CH2;
R4a is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; and
R5 is C1-3 alkyl or C3-5 cycloalkyl each of which may be optionally substituted with a halogen (e.g., 1, 2, 3, 4, or more halogen atoms that may be the same or different); or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R1a is CH3 or CH2CH3 or SCH3; Xa is CH2CH2 or CH=CH; R2a and R3a are independently H or C1-3 alkyl; Ya is O, S or CH2; and R4a is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(O)OH.
3. The compound of claim 1 or 2, wherein R1a is SCH3; Xa is CH=CH; R2a and R3a are each CH3; Ya is O or CH2; and R4a is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(O)OH.
4. A compound having a structure represented by Formula II:
Figure imgf000037_0001
wherein:
R1b and R2b are independently H, halogen, C1-C6 alkyl, CF3, CN, COR4b. OR4b or phenyl optionally substituted by C1-C4 alkyl or CF3;
R4b is independently selected from the group consisting of C1-C4 alkyl, CF3 and phenyl optionally substituted by C1-C4 alkyl or CF3;
Xb is (CH2)n;
Yb is CH2 or O or S;
R3b is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH, CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; n is 0 or 1 or 2; and
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5, 6,7,8- tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3- dihydroindolyl, benzofiiranyl, 2,3-dihydrobenzofiiranyl, 1,3-benzodioxolyl, 1,4- benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b, OR4b, SR4b, NHCOR4b, morpholinyl, N(C1-C4 alkyl)2 and 4-morpholinosulfonyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
5. The compound of claim 4, wherein R1b and R2b are independently H, halogen, C1- C3 alkyl or CF3; Xb is (CH2)n; Yb is CH2; R3 is CH2S(O)OH or CH(CH3)S(O)OH or C(CH3)2S(O)OH; n is 1 or 2 or 3; and Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3, 4-dihydro- 1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H- benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofiiranyl, 2,3-dihydrobenzofiiranyl, 1,3- benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b. OR4b, SRft, NHCOR4b, morpholinyl, N(C1-C4alkyl)2 and 4-morpholinosulfonyl.
6. The compound of claim 4 or 5, wherein R1b and R2b are independently H, halogen, C1-C3 alkyl, or CF3; Xb is (CH2)n; Yb is CH2; R3 is CH2S(O)OH; n is 1 or 2 or 3; and Ar is benzothiazolyl substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, COR4b, OR4b, SR4b, NHCOR4b, morpholinyl, N(C1-C4 alkyl)2 and 4-morpholinosulfonyl.
7. A compound having a structure represented by Formula III:
Figure imgf000038_0001
wherein:
Ac is (CH2)nS(O)OH or (CH2)nS(O)2OH n is 0, 1, 2 or 3
R1c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo or C1-C8 haloalkyl;
Xc is CH2 or S or O;
R2c and R3care independently H, C1-C8 alkyl, C1-C8 alkoxy, halo, or C1-C8 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring; Yc is CH2 or S or O;
R4c is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo, C1-C8haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5c: and each R5c is independently selected from the group consisting of a halogen, C1-C6 alkyl, C1-C6, haloalkyl. C1-C6 alkoxy, C1-C6, haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
8. The compound of claim 7, wherein Ac is (CH2)nS(O)OH; n is 2 or 3; R1c is H, C1- C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo or C1-C3 haloalkyl; Xc is CH2 or S or O; R2c and R3c are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring; Yc is CH2 or S or O; and R4c is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, C1-C3 haloalkyl.
9. The compound of claim 7 or 8, wherein Ac is CH2nS(O)OH; n is 2 or 3; R1c is H, C1-C3 alkyl, C3-C5 cycloalkyl, halo or C1-C3 haloalkyl; Xc is O; R2c and R3c are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring; Yc is S and R4c is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl.
10. A compound having a structure represented by Formula IV :
Figure imgf000039_0001
wherein: Ad is (CH2)nS(O)OH or (CH2)nS(O)2OH; n is 1 or 2;
Zd is O or S;
R1d is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo or C1-C8 haloalkyl;
Xd is CH2 or S or O; R2dandR3dare independently H, C1-C8 alkyl, C1-C8 alkoxy, halo, or C1-C8 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring;
Yd is CH2 or S or O;
R4d is H, C1-C8 alkyl, C3-C5 cycloalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R5d: and each R5d is independently selected from the group consisting of a halogen, C1-C6 alkyl, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6haloalkoxy and cyclopropyl; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
11. The compound of claim 10, wherein Ad is (CH2)nS(O)OH; n is 1 or 2; Zd is O or S;
R1d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo or C1-C3 haloalkyl; Xd is CH2 or S or O; R2d and R3d are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring; Yd is CH2 or S or O; and R4d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl.
12. The compound of claim 10 or 11, wherein Ad is (CH2)nS(O)OH; n is 1 or 2; Zd is O or S; R1d is H, C1-C3 alkyl, C3-C5 cycloalkyl, halo or C1-C3 haloalkyl; Xd is O; R2d and R3d are independently H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl or optionally R2c and R3c are joined together to form a 3 to 8 membered ring; Yd is S; and R4d is H, C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, halo, or C1-C3 haloalkyl.
13. A compound having a structure represented by Formula V
Figure imgf000040_0001
wherein:
Ae and Be are independently phenyl or a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the phenyl or 5 to 10 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1 to 2 R4e; each R4e is independently selected from the group consisting of a halogen, C1-C3 alkyl, halo, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and cyclopropyl;
We is C1-C6alkylene or C2-C6alkenylene;
R1e is C1-C6 alkyl, C3-C6 cycloalkyl, aryl or aralkyl; R2e is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halo, C1- C3alkoxy or cyclopropyl;
Xe is O or S or CH2; and
Ye is CH2S(O)OH, CH(CH3)S(O)OH, C(CH3)2S(O)OH, CH2S(O)2OH,
CH(CH3)S(O)2OH or C(CH3)2S(O)2OH; or an enantiomer, stereoisomer, tautomer, solvate, hydrate, prodrug, amino acid conjugate, metabolite, or pharmaceutically acceptable salt thereof.
14. The compound of claim 13, wherein Ae is phenyl, optionally substituted with 1 or 2 R4e; Be is a 5 to 10 membered monocyclic heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5 to 10 bicyclic heteroaryl is optionally substituted with 1 or 2 R4e: R4e is independently selected from the group consisting of a halogen, C1- C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and cyclopropyl; We is C1-C3 alkylene or C2-C4 alkenylene; R1e is C1-C3 alkyl, C3-C6 cycloalkyl; R2e is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or cyclopropyl; Xe is O or S or CH2; and Ye is CH2S(O)OH, CH(CH3)S(O)OH or C(CH3)2S(O)OH.
15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14 and a pharmaceutically acceptable excipient, diluent and/or carrier.
16. A compound of any one of claims 1 to 14, or a pharmaceutical composition of claim 15, for use in medicine.
17. A method of modulating a Peroxisome Proliferator- Activated Receptor (PPAR), the method comprising administering to a subject in need thereof a compound of any one of claims 1 to 14 or the pharmaceutical composition of claim 15.
18. Use of a compound of any one of claims 1 to 14, or the pharmaceutical composition of claim 15 in the manufacture of a medicament for modulating a Peroxisome Proliferator- Activated Receptor (PPAR).
19. A method of activating a Peroxisome Proliferator- Activated Receptor (PPAR), the method comprising administering to a subject in need thereof a compound of any one of claims 1 to 14 or the pharmaceutical composition of claim 15.
20. Use of a compound of any one of claims 1 to 14, or the pharmaceutical composition of claim 15 in the manufacture of a medicament for activating a Peroxisome Proliferator- Activated Receptor (PPAR).
21. A method of treating and/or preventing a disease or disorder in which a Peroxisome Proliferator- Activated Receptor (PPAR) plays a role, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 14 or the pharmaceutical composition of claim 15.
22. Use of a compound of any one of claims 1 to 14, or the pharmaceutical composition of claim 15 in the manufacture of a medicament for treating and/or preventing a disease or disorder in which a Peroxisome Proliferator-Activated Receptor (PPAR) plays a role.
23. The method of claim 21 or the use of claim 22, wherein the disease or disorder is T1D, T2D, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, low HDL cholesterol, hyperinsulinemia, NAFLD, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, ulcerative colitis, Crohn's disease or irritable bowel syndrome.
24. The method or use of claim 23, wherein the disease or disorder is fatty liver disease, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFFD).
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