WO2023177667A1 - Agonistes du récepteur des hormones thyroïdiennes - Google Patents

Agonistes du récepteur des hormones thyroïdiennes Download PDF

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WO2023177667A1
WO2023177667A1 PCT/US2023/015193 US2023015193W WO2023177667A1 WO 2023177667 A1 WO2023177667 A1 WO 2023177667A1 US 2023015193 W US2023015193 W US 2023015193W WO 2023177667 A1 WO2023177667 A1 WO 2023177667A1
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phenyl
methyl
dichloro
phenoxy
hydroxy
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PCT/US2023/015193
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English (en)
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Lianhong Xu
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Brii Biosciences, Inc.
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings

Definitions

  • THYROID HORMONE RECEPTOR AGONISTS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/320,570 filed March 16, 2022, the contents of which is incorporated herein by reference in its entirety.
  • FIELD [0002] The present disclosure is directed to compounds that are thyroid hormone receptor (THR) agonists, the pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof for preventing and/or treating metabolic diseases, CNS diseases, including but not limited to NASH (nonalcoholic steatohepatitis), hyperlipidemia, hypercholesterolemia, obesity and diabetes, multiple sclerosis, as well as associated conditions, in mammals and especially in humans.
  • NASH nonalcoholic steatohepatitis
  • hyperlipidemia hyperlipidemia
  • hypercholesterolemia hypercholesterolemia
  • obesity and diabetes multiple sclerosis
  • Thyroid hormones e.g., T4 and T3 are synthesized in the thyroid in response to thyroid stimulating hormone, and play a critical role in growth, development, metabolism, and homeostasis.
  • THRs thyroid hormone receptors
  • THRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain, and are encoded by two distinct genes (THR- ⁇ and THR- ⁇ ).
  • THR- ⁇ isoform is ubiquitous expressed (highest expression in heart, brain, and lungs) and regulates most cardiac functions, while the THR- ⁇ isoform predominates in the liver, kidney, pituitary gland, brain and regulates cholesterol metabolism and thyroid stimulating hormone (TSH) production.
  • THR- ⁇ isoform predominates in the liver, kidney, pituitary gland, brain and regulates cholesterol metabolism and thyroid stimulating hormone (TSH) production.
  • THR- ⁇ thyroid stimulating hormone
  • THR agonists which exhibit increased THR- ⁇ selectivity and/or tissue selective action is expected to lead to desirable therapeutic effects (such as lowered LDL-cholesterol, lowered triglycerides, lowered liver fat and thus reduced lipotoxicity, no thyrotoxicosis), while avoiding the cardiovascular and other toxicity of native THRs.
  • Many CNS disorders, including multple sclerosis (MS) are associated with the degeneration of myelin (demyelination). Thyroid hormone plays an important role in the production of myelin, the protective sheath that forms around nerves.
  • MS Multiple sclerosis
  • MS is characterized by both damage to the myelin sheath (Demyelination) and a failure to repair the damaged myelin (remyelination). Without the protective myelin coating, messages traveling along nerve fibers maybe be slowed or stopped, and, over time, the axons and cell bodies of neurons can also become damaged.
  • Current treatments for MS exclusively targer the immune system to prevent or slow down further demyelination. Although immunomodulatory drugs can ease inflammation in patients with MS, none of them prevents the progression of this chronic disease, largely due to their inability to stop or reverse the failure of remyelination.
  • More research has focused on attempting to find treatments that work by promoting repair of damaged myelin.
  • oligodendrocytes which mature from oligodendrocyte progenitor cells (OPCs) in the central nervous system. While MS patients possess aboundant OPCs, they fail to differentiate into oligodendrocytes and cannot help repairing damaged myelin. Promoting OPC differentiation is a promising target for drug treatment.
  • THR beta (THR- ⁇ ) agonist promotes the differentiation of OPCs into mature oligodendrocytes. These cells regenerate myelin to protect demyelinated neurons and restore neural conduction velocity to halt and potentially reverse the progressive course of MS.
  • THR agonists in particular selective THR- ⁇ agonists, that are able to drive beneficial effects on lipids and lipoproteins, and OPCs and demonstrate a utility for preventing or treating diseases associated with adverse TH acitivity in mammals and especially in humans.
  • SUMMARY [0012] The present disclosure is related to compounds and compositions thereof that can be used to treat metabolic diseases and CNS diseases.
  • the present disclosure provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein R 1 and R 2 are each independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano; R 3 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, and cyano; R 4 is ary or heteroaryl, wherein said ary or heteroaryl is optionally substituted with one or more groups independently selected from halogen, alkyl, hydroxyl, alkoxy, and cyano; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, alkoxy, and cyano, wherein said alkyl is optionally substituted with one or more groups independently
  • R 5 is -H, -F, or -Cl;
  • R 6 is -H or -CH 3 ;
  • R 7 is -H or -CH 3 ;
  • R 8 is OH or -NHSO 2 CH 3 ;
  • R 11 is -H or -CH 3 ; with the proviso that when R 4 is 3 5 6 7 , then at least one of R, R, R, R and R 11 is not -H and/or R 8 is -NHSO 2 CH 3 .
  • R 4 is [0016] In some embodiments R 4 is , or . [0017] In some embodiments R 4 is , or . [0018] In some embodiments R 4 is , or . [0019] In some embodiments R 4 is
  • R 4 is , or .
  • the present disclosure provides a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof: (Ia) wherein R 4 is aryl or heteroaryl.
  • the present disclosure provides a compound of formula (Ia) or pharmaceutically acceptable salt thereof wherein R 4 is
  • R 4 is , or . [0023] In some embodiments R 4 is , or . [0024] In some embodiments R 4 is , or . [0025] In some embodiments R 4 is , or . [0026] In some embodiments R 4 is , or . [0027] In some embodiments wherein R 4 is , or . [0028] In some embodiments, the present disclosure provides a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof: ( Ib). [0029] In some embodiments, the present disclosure provides a compound having structure of formula (Ic), or a pharmaceutically acceptable salt thereof: (Ic). [0030] In some embodiments, the compound is selected from the group consisting of: Table 1.
  • the present disclosure is further directed to a pharmaceutical composition comprising one or more compounds having formula (I), formula (Ia), formula (Ib), formula (Ic), or as disclosed in Table 1, or pharmaceutically acceptable salt thereof, or a combination thereof, and one or more pharmaceutically acceptable carriers.
  • the present disclosure is also directed to a process for making a compound having a structure of formula (I). In one embodiment, the process for making compound having a structure of formula (I) is as described in the Examples provided herein.
  • the present disclosure is also directed to a method for the treatment of a disease or condition modulated by thyroid hormones (including its functional analogs and derivatives), the method comprising administering to a subject in need thereof a dosage of a pharmaceutical composition comprising one or more of the compounds disclosed herein, [0034]
  • the present disclosure is also directed to a method for the prevention of a disease or condition modulated by thyroid hormones, the method comprising administering to a subject in need thereof an effective dosage of a pharmaceutical composition comprising one or more of the compounds disclosed herein.
  • the present disclosure is also directed to a use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases or conditions modulated by THs.
  • the present disclosure is also directed to a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, administered simultaneously, separately, or sequentially with one or more additional agents.
  • the present disclosure is also directed to a kit for the treatment or prevention of diseases or conditions modulated by thyroid hormone analogs, said kit comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, a container, and optionally a package insert or label indicating a treatment.
  • the kit may further comprise a second compound or formulation comprising a second pharmaceutical agent useful for treating said disease or disorder.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • Ci-j indicates a range of the carbon atoms numbers, wherein i and j are integers, and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 12 carbon atoms.
  • alkyl groups contain 1 to 11 carbon atoms.
  • alkyl groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2- propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (i-butyl), 2-butyl (s-butyl), 2-methyl- 2-propyl (t-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2- butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the
  • C 1-12 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl.
  • C 1-6 alkyl are methyl, ethyl, propyl, isopropyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2- butyl, 3,3-dimethyl-2-butyl, and the like.
  • the alkyl groups can be further substituted by substituents which independently replace one or more hydrogen atoms on one or more carbons of the alkyl groups.
  • substituents can include, but are not limited to, acyl, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbon
  • alkenyl, alkynyl, saturated or partically unsaturated cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl and heteroaryl groups as described below may also be similarly substituted.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group examples include, but are not limited to, ethylenyl (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2 buten-1- yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon- carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, alkoxy groups contain 1 to 11 carbon atoms.
  • alkoxy groups contain 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • Examples of “C 1-12 alkoxyl” include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.
  • aryl or “aromatic”, whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more additional rings.
  • polycyclic ring system only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline).
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Aryl groups may be optionally substituted at one or more ring positions with one or more substituents as described herein.
  • arylalkyl means an alkyl moiety substituted with one or more aryl moieties.
  • arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, and the like.
  • aryloxy or “aryloxyl”, whether as part of another term or used independently, refers to an aryl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • cycloalkyl As used herein, the terms “cycloalkyl”, “carbocyclyl” and “carbocycle” are interchangeable and whether as part of another term or used independently, refer to a monovalent, saturated, partially unsaturated, or fully unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon, and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be optionally substituted independently with one or more substituents described herein. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be an unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system.
  • the cycloalkyl group may be saturated or unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-l-enyl, 1-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • the cycloalkyl group may be saturated or unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring system, which can be arranged as a fused, spiro or bridged ring system.
  • fused ring refers to a ring system having two rings sharing two adjacent atoms
  • spiro ring refers to a ring systems having two rings connected through one single common atom
  • bridged ring refers to a ring system with two rings sharing three or more atoms.
  • fused carbocyclyl examples include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl and the like.
  • spiro carbocyclyl examples include, but are not limited to, spiro[5.5]undecanyl, spiro-pentadienyl, spiro[3.6]-decanyl, and the like.
  • bridged carbocyclyl examples include, but are not limited to bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.3]undecanyl, and the like.
  • cyano refers to –CN.
  • halo or “halogen” refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo) and iodine (or iodo).
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, S or P.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkenyl refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, S or P.
  • the heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, S or P.
  • the heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) and may be optionally substituted independently with one or more substituents described herein.
  • heteroatom refers to nitrogen, oxygen, sulfur or phosphor, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms, and may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl examples include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l ,4-ox
  • the term "5- to 10-membered heteroaryl” refers to a 5-to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphor, or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphor.
  • the term “5- to 12-membered heteroaryl” refers to a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphor, or an 8- to 12-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphor.
  • heterocycle refers to a saturated or unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substitutents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen, sulfur or phosphor, and any quaternized form of a basic nitrogen.
  • “Heterocyclyl” also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked).
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked).
  • the term “3- to 12-membered heterocyclyl” refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridiny
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza- bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4- diazabicyclo[2.2.2]octane (DABCO), and the like.
  • hydroxyl or “hydroxy” refers to –OH group.
  • nitro refers to —NO 2 group.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • COMPOUNDS [0070] The present disclosure provides compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.
  • the present disclosure provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein R 1 and R 2 are each independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano; R 3 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, and cyano; R 4 is ary or heteroaryl, wherein said ary or heteroaryl is optionally substituted with one or more groups independently selected from halogen, alkyl, hydroxyl, alkoxy, and cyano; R 5 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, alkoxy, and cyano, wherein said alkyl is optionally substituted with one or more groups independently
  • R 1 and R 2 are each independently halogen or alkyl. In some embodiments, R 1 and R 2 are the same and are chloro. [0073] In some embodiments, R 4 is aryl or heteroaryl. In some embodiments, R 4 is phenyl. [0074] In some embodiments, R 5 is H or halogen. In some embodiments, R 5 is H [0075] In some embodiments, both R 6 and R 7 are H. [0076] In some embodiments, R 8 is OH or NHSO 2 R 10 . [0077] In some embodiments, R 10 is alkyl or cycloalkyl.
  • the present disclosure provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is -Cl; R 2 is -Cl; R 3 is -H or -F; R 4 is , or ; R 5 is -H, -F, or -Cl; R 6 is -H or -CH 3 ; R 7 is -H or -CH 3 ; R 8 is OH or -NHSO 2 CH 3 ; and R 11 is -H or -CH 3 ; with the proviso that when R 4 is , then at least one of R 3 5 6 7 , R , R , R and R 11 is not -H and/or R 8 is -NHSO 2 CH 3 .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is or .
  • R 4 is or .
  • the present disclosure provides a compound having the structure of formula (Ia), or a pharmaceutically acceptable saltthereof: (Ia) wherein R 4 is aryl or heteroaryl.
  • R 4 is aryl or heteroaryl.
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is , or .
  • the present disclosure provides a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof: ( Ib).
  • the present disclosure provides a compound having structure of formula (Ic), or a pharmaceutically acceptable salt thereof: (Ic).
  • the compound is a compound disclosed in Table 1 or a pharmaceuticall acceptable salt thereof.
  • the present disclosure provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of: 2-[3,5-dichloro-4-[[4-hydroxy-3-(3-pyridyl)phenyl]methyl]phenoxy]acetic acid; 2-[3,5-dichloro-4-[[4-hydroxy-3-(2-pyridyl)phenyl]methyl]phenoxy]acetic acid; 2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid; 2-[3,5-dichloro-4-[[3-(3-fluorophenyl)-4-hydroxy-phenyl] methyl]phenoxy]acetic acid; 2-[3,5-dichloro-4-[(4-hydroxy-3-pyrazin-2-yl-phenyl) methyl]phenoxy]acetic acid; 2-[3,5-dichloro-4-[(4-hydroxy-3-
  • compounds of the present disclosure may exist in a number of different forms or derivatives, all within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs, solvated forms, different crystal forms or polymorphs, and active metabolites.
  • the compounds of present disclosure can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • inventive compounds and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the present disclosure are enantiopure compounds.
  • mixtures of enantiomers or diastereomers are provided.
  • enantiomer refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • diastereomer refers to a pair of optical isomers which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
  • certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.
  • this disclosure also encompasses compositions comprising one or more compounds.
  • isomers includes any and all geometric isomers and stereoisomers.
  • “isomers” include cis- and trans-isomers, E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • a stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as “stereochemically enriched”.
  • a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the opposite enantiomer and may also be referred to as “optically enriched”.
  • Optically enriched means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole).
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the compounds of the present disclosure also include prodrugs, active metabolic derivatives (active metabolites), active intermediates, and their pharmaceutically acceptable salts.
  • prodrugs refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.
  • prodrugs Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro- drugs as Novel Delivery Systems”, Vol.14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • metabolite e.g., active metabolite overlaps with prodrug as described above.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • active intermediate refers to intermediate compound in the synthetic process, which exhibits the same or essentially the same biological activity as the final synthesized compound.
  • Compounds of the present disclosure can be formulated as or be in the form of pharmaceutically acceptable salts. Unless specified to the contrary, a compound provided herein includes pharmaceutically acceptable salts of such compound.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt”, unless otherwise indicated, includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered.
  • the preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect.
  • Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t- butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t- butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared using the appropriate corresponding bases.
  • Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L- arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • organic salts derived from amino acids such as L-glycine, L-lysine, and L- arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • solvents that form solvates include, but are not limited to, water, isopfopanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form”, “crystalline form”, “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility.
  • Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • the present disclosure is further directed to a pharmaceutical composition comprising one or more compounds, pharmaceutically acceptable salt, or a combination thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present disclosure comprises a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein R 1 and R 2 are each independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, alkyl, hydroxyl, alkoxy, and cyano; R 3 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, and cyano; R 4 is ary or heteroaryl, wherein said ary or heteroaryl is optionally substituted with one or more groups independently selected from halogen, alkyl, hydroxyl, alkoxy;
  • the pharmaceutical composition of the present disclosure comprises a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is -Cl; R 2 is -Cl; R 3 is -H or -F; R 4 is
  • R 5 is -H, -F, or -Cl
  • R 6 is -H or -CH 3
  • R 7 is -H or -CH 3
  • R 8 is OH or -NHSO 2 CH 3
  • R 11 is -H or -CH 3 ; with the proviso that when R 4 is , then at least one of R 3 , R 5 , R 6 , R 7 and R 11 is not -H and/or R 8 is -NHSO 2 CH 3 .
  • R 4 is
  • R 4 is , or . [0124] In some embodiments, R 4 is , , or . [0125] In some embodiments, R 4 is
  • R 4 is , or .
  • R 4 is , or .
  • the pharmaceutical composition of the present disclosure comprises a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof: (Ia) wherein R 4 is aryl or heteroaryl.
  • R 4 is , or .
  • R 4 is F , or .
  • R 4 is , or .
  • R 4 is , or .
  • R 4 is or .
  • R 4 is , or .
  • the pharmaceutical composition of the present disclosure comprises a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof: (Ib).
  • the pharmaceutical composition of the present disclosure comprises a compound having structure of formula (Ic), or a pharmaceutically acceptable salt thereof: (Ic).
  • the pharmaceutical composition of the present disclosure comprises a compound selected from the group consisting of compound disclosed in Table 1 and a pharmaceutically acceptable salt thereof.
  • the present disclosure provides pharmaceutical compositions comprising one or more compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a compound selected from formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a first compound selected from formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • the pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable carrier or excipient.
  • a “pharmaceutical composition”, as used herein, is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), spray, ointment, paste, cream, lotion, gel, patch, inhalant, or suppository.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the compound of the present disclosure is mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers or propellants that are required.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like suitable for administration to a subject. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be includes. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent”. [0142] The particular excipient, carrier, or diluent will depend upon the means and purpose for which the compounds of the present disclosure is being applied.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
  • Acceptable excipients, diluents, and carriers, and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparag
  • the composition may also comprise one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal.
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • the pharmaceutical compositions of compounds of the present disclosure can be formulated depending on the particular route of administration and dosage form.
  • the pharmaceutical compositions are generally formulated to achieve a physiologically compatible pH, for example, a pH of about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, or about 5 to about 7.
  • a physiologically compatible pH for example, a pH of about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, or about 5 to about 7.
  • the pharmaceutical compositions of the present disclosure may be formulated for parenteral or oral administration.
  • the pharmaceutical compositions of the present disclosure may be formulated as solids, liquid solutions, emulsions or suspensions.
  • the pharmaceutical compositions of the present disclosure may
  • the pharmaceutical compositions of the present disclosure may be formulated as liquids or powders.
  • the pharmaceutical compositions of the present disclosure may be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration.
  • the pharmaceutical compositions of the present disclosure may be formulated in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder).
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used for administering the drug.
  • an article for distribution can include a container having deposited therein the pharmaceutical composition in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • veterinary compositions comprising a compound of formula (I) or pharmaceutically acceptable salts thereof together with a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.
  • compositions may be administered parenterally, orally or by any other desired route.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.2-200 mg/kg body weight/day, for example, 0.25-150 mg/kg body weight/day, 0.25-100 mg/kg body weight/day, 0.25-50 mg/kg body weight/day, 0.25-25 mg/kg body weight/day, 0.25-10 mg/kg body weight/day, 0.25-7.5 mg/kg body weight/day, 0.25-5 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 1-100 mg/kg body weight/day, 1.5-100 mg/kg body weight/day of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, can be administered.
  • a dosage of between 0.2-200 mg/kg body weight/day for example, 0.25-150 mg/kg body weight/day, 0.25-100 mg/kg body weight/day, 0.25-50 mg/kg body weight/day, 0.25-25 mg/kg body weight/day, 0.25-10 mg/kg body weight/day, 0.25-7.5 mg/kg body weight
  • the pharmaceutical compositions of the present disclosure can be formulated in unit dosage form.
  • a “unit dosage form” is a composition containing an amount of a compound that is suitable for administration to a subject in a single dose, according to good medical practice. Such single or unit dosage form are contemplated to be administered once, twice, three times or more per day.
  • the pharmaceutical compositions of the present disclosure can be formulated to contain 2.5 mg to 1,500 mg, 2.5 mg to 25 mg, 20 mg to 75 mg, 70 mg to 150 mg, 100 mg to 250 mg, 200 mg to 600 mg, 500 mg to 800 mg, or 750 mg to 1,500 mg of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, for example, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1,000 mg, or 1,500 mg of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the unit dose is administered once a day. In other embodiments, the unit dose is administered twice a day. In further embodiments, the unit dose is administered three times a day. In further embodiments, the unit dose is administered four times a day.
  • a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more additional active ingredients.
  • additional active ingredient of the pharmaceutical combination formulation or dosing regimen has complementary activities to the compounds of disclosure such that they do not adversely affect each other. Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the pharmaceutical composition may comprise the compounds of the present disclosure combined with other active ingredients that lower serum cholesterol.
  • acitve ingredents include but are not limited to a cholesterol biosynthesis inhibitor (e.g., a HMG-CoA reductase inhibitor) or a cholesterol absorption inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a bile acid sequesterant, a bile acid reabsorption inhibitor, a cholesterol absorption inhibitor, a PPARalpha agonist, a mixed PPAR alpha/gamma agonist, a MTP inhibitor, a fibrate, an ACAT inhibitor, an angiotensin II receptor antagonist, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, combined squalene epoxidase/squalene cyclase inhibitor, a lipoprotein lipa
  • a cholesterol biosynthesis inhibitor
  • HMG-CoA reductase inhibitor refers to a compound that inhibits the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by the enzyme HMG-CoA reductase.
  • HMG-CoA reductase inhibitors examples include but are not limited to lovastatin, simvastatin, pravastatin, lactones of pravastatin, fluvastatin, lactones of fluvastatin, atorvastatin, lactones of atorvastatin, cerivastatin, lactones of cerivastatin, rosuvastatin, lactones of rosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin, bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin, pitivastatin, mevastatin, and velostatin.
  • bile acid sequestrants include but are not limited to cholestyramine, colestipol, colesevelam hydrochloride, and the like.
  • the term “fibrate” refers to a medicament for inhibiting synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase, thereby lowering the triglyceride level in the blood.
  • fibrates include but are not limited to bezafibrate, beclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate and theofibrate.
  • Examples of ACAT inhibitors include but are not limited to those compounds disclosed in WO 92/09561, WO 94/26702, EP 421441, WO 97/19918, EP 790240, WO 96/26948, WO 98/54153, WO 92/09572,EP 718281,WO 96/10559, WO 96/09287, and WO 97/12860.
  • Examples of angiotensin II receptor antagonist include but are not limited to a biphenyl tetrazole compound or biphenylcarboxylic acid derivative such as losartan, irbesartan, valsartan, candesartan, olmesartan, or telmisartan.
  • the term “squalene synthetase inhibitor” refers to compounds that inhibit the condensation of two molecules of farnesylpyrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase.
  • examples of squalene synthetase inhibitors include but are not limited to those compiled in Curr. Op. Ther Patents, 861-4, (1993).
  • the pharmaceutical composition may comprise the compounds of the present disclosure combined with other naturally occurring active ingredients that acts to lower plasma cholesterol levels. Such naturally occurring active ingredients are commonly called nutraceuticals and include, for example, garlic extract and niacin.
  • lipid lowering agent such as statins
  • a lipase inhibitor such as gastric or pancreatic lipase inhibitors
  • a glucosidase inhibitor such as amylase inhibitors
  • a anti-obesity agent such as ⁇ 3 -adrenergic receptor agonist, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, a melanocyte- stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone receptor analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin
  • statins such as statins
  • a lipase inhibitor such as gastric or pancreatic lipase
  • the compound(s) of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof and the additional active ingredient(s) may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of formula (I), formula (Ia), formula (Ib), and the additional active ingredient(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.
  • the term “combination” refers to simultaneous, separate or sequential administration. In some embodiments, “combination” refers to simultaneous administration. In some embodiments, “combination” refers to separate administration. In some embodiments, “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof in combination with one or more additional active ingredients such as those listed above, in association with a pharmaceutically acceptable excipient.
  • kits comprising a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof in combination with one or more additional active ingredients.
  • a kit comprising: (a) a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof in a first unit dosage form; (b) an additional active ingredients selected from those listed above in a second unit dosage form; and (c) container for containing the first and second unit dosage forms.
  • the present disclosure is also directed to a method for the treatment of a disease or condition modulated by a thyroid hormone (including its functional analogs and derivatives), the method comprising administering to a subject in need thereof a pharmaceutical composition comprising one or more of the compounds, or pharmaceutically acceptable salt thereof, disclosed herein, [0169]
  • the present disclosure is also directed to a method for the prevention of a disease or condition modulated by a thyroid hormone, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective dosage of one or more of the compounds, or pharmaceutically acceptable salt thereof, disclosed herein.
  • the compound is a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof as described herein.
  • the compound is a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof as described herein.
  • the compound is a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof as described herein.
  • the compound is a compound having structure of formula (Ic), or a pharmaceutically acceptable salt thereof as described herein.
  • the compound is a compound selected from the group consisting of compound disclosed in Table 1 and a pharmaceutically acceptable salt thereof.
  • a method of preventing or treating a TH-associated disease or condition in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, owning to the THR activating activity, in particular THR- ⁇ activating activity of the compounds of the present disclosure.
  • the term “subject in need thereof” is a subject having a TH- associated disease or condition.
  • a “subject” includes a warm-blooded animal.
  • the warm-blooded animal is a human.
  • the term “therapeutically effective amount” or “an effective dosage” refers to an amount of a compound of formula (I), formula (Ib), formula (Ic), or pharmaceutically acceptable salts thereof which is effective to provide “therapy” in a subject, or to “treat” a TH-associated disease or disorder in a subject.
  • effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents.
  • the amount of the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or pharmaceutcially acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder in the subject.
  • the combined amounts are in a “therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of a disease associated with TH as described above.
  • the TH-associated disease or disorder is a metabolic disease, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, multiple sclerosis and related disorders and diseases.
  • the TH-associated disease or disorder is a hypercholesterolemia or NASH.
  • the TH-associated disease or disorder is multiple sclerosis.
  • the method of preventing or treating a TH-associated disease or condition described in this specification may be used as a monotherapy.
  • the term “monotherapy” refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of one or more of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
  • the method of preventing or treating a TH-associated disease or condition described in this specification may involve, in addition to administration of the compounds of the present disclosure, one or more additional therapies, for example, conventional surgery, radiotherapy, chemotherapy, or a combination of such additional therapies.
  • the additional therapy may be administered separately from the compounds of the present disclosure, as part of a multiple dosage regimen.
  • the additional therapy may be part of a single dosage form, mixed with a compound of the present disclosure in a single composition.
  • the compounds of the present disclosure may be administered simultaneously, sequentially or separately to treatment with the conventional surgery, radiotherapy or chemotherapy.
  • the present disclosure provides compounds of formula (I), formula (Ia), formula (Ib), formula (Ic) or pharmaceutically acceptable salts thereof, which are capable of binding to THR and producing a change in some hepatic gene expression, thereby demonstrating a utility for preventing or treating diseases associated with TH activity in mammals and especially in humans.
  • the compounds of the present disclosure bind to at least one THR with an Ki of less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 2 nM, less than 1 nM or even lower.
  • THR binding is readily determined using assays described in the literature. For example, nuclear extracts from animal livers can be prepared according to the methods described by Yokoyama et al. (J. Med.
  • Binding assays can also be performed using purified THRs. For example, using the methods used by Chiellini et al. (Bioorg Med. Chem., 10: 333-346 (2002)) competition ligand binding affinities are determined using 125 IT3 and the human thyroid receptors THR- ⁇ 1 and THR- ⁇ 1. The latter methods advantageously enable determination of THR selectivity.
  • the compounds of the present disclosure are effective in activating the THR. Evidence for activating activity is obtained using standard assay described in literatures.
  • a compound of the present disclosure is capable of selectively activating THR- ⁇ over THR- ⁇ .
  • the term “selective agonist of THR- ⁇ ” or “selectively activate THR- ⁇ ” means that a provided compound activates THR- ⁇ in at least one assay described herein over THR- ⁇ .
  • the compounds of the present disclosure are at least 2 to 500-fold more selective for THR- ⁇ over THR- ⁇ .
  • the compounds of the present disclosure are at least 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40- fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, or at least 500-fold more selective for THR- ⁇ over THR- ⁇ .
  • the compounds of the present disclosure can lower cholesterol levels, triglyceride levels or the fat content, which is associated with prevention or treatment of hypercholesterolemia; lower levels of lipoprotein such as lipoprotein (a) (Lp(a)) or low density lipoprotein (LDL) or raise levels of lipoproteins such as Apolipoprotein AI (apoAI) or high density lipoprotein (HDL), which is associated with prevention or treatment of atherosclerosis and heart disease; reduce weight or prevent weight gain; lower blood glucose levels, which is associated with prevention or treatment of diabetes; promote repair of damaged myelin, which is associated with treatment of multiple sclerosis.
  • lipoprotein such as lipoprotein (a) (Lp(a)) or low density lipoprotein (LDL) or raise levels of lipoproteins such as Apolipoprotein AI (apoAI) or high density lipoprotein (HDL)
  • apoAI Apolipoprotein AI
  • HDL high density lipoprotein
  • the compounds of formula (I), formula (Ia), formula (Ib), and formula (Ic) and pharmaceutically acceptable salts thereof are useful in therapy, for example in the prevention or treatment of TH-associated diseases or conditions.
  • the TH-associated diseases or conditions are, for example but are not limited to, metabolic diseases, such as obesity, dyslipidemia, hypercholesterolemia and diabetes, and NASH (nonalcoholic steatohepatitis), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, and multiple sclerosis and related disorders and diseases.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • the term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of diseases or conditions associated alone or in part with THs.
  • a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of TH-associated diseases or conditions.
  • a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of multiple sclerosis, hypercholesterolemia or NASH.
  • SYNTHESIS OF THE COMPOUNDS [0199] Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein.
  • the reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • MS measurement is carried out using Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD or 1969A TOF mass spectrometer using electrospray, chemical and electron impact ionization methods from a range of instruments.
  • TLC measurement is carried out using Yantai Huanghai HSGF254 silica gel or Anhui Liang Chen Gui Yuan plates.
  • the silica gel plates used for TLC are 0.15mm ⁇ 0.2mm.
  • the silica gel plates used for separating and purifying products by TLC are 0.4mm ⁇ 0.5mm.
  • Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), dichloroethane (DCE), dioxane and 1,1,2,2-tetrachloroethane were purchased from Aldrich in Sure seal bottles and used as received. [0208] Unless otherwise specified, the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.
  • Example 1 2-[3,5-dichloro-4-[[4-hydroxy-3-(3- pyridyl)phenyl]methyl]phenoxy]acetic acid (Compound 1) [0213] Preparation of (2,6-dichloro-4-triisopropylsilyloxy-phenyl)- (4- methoxyphenyl)methanol [0214] To a solution of 1-bromo-4-methoxy-benzene (1.20 g, 6.42 mmol, 0.80 mL, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 3.08 mL, 1.2 eq) at -78 °C.
  • reaction mixture was stirred at -78 °C for 0.5 h, and then 2,6-dichloro-4-triisopropylsilyloxy- benzaldehyde (2.01 g, 5.77 mmol, 0.9 eq) was added.
  • the reaction mixture was stirred at 25 °C for 2 h, and then diluted with H 2 O (20 mL) and extracted with with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Example 2 2-[3,5-dichloro-4-[[4-hydroxy-3-(2- pyridyl)phenyl]methyl]phenoxy]acetic acid (Compound 2) [0228] Preparation of ethyl 2-[3,5-dichloro-4-[[4-hydroxy-3-(2- pyridyl)phenyl]methyl]phenoxy]acetate [0229] To a solution of ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]-3,5-dichloro- phenoxy]acetate (60 mg, 0.14 mmol, 1 eq) in dioxane (2 mL) was added Pd(PPh 3 ) 4 (31.9 mg, 0.028 mmol, 0.2 eq) and tributyl(2-pyridyl)stannane (56.7 mg, 0.15 mmol, 1.1 eq).
  • the resulting mixture was stirred at 150 °C for 0.5 h under microwave irradiation.
  • the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (25 mL), dried overNa 2 SO 4 , filtered and concentrated.
  • Example 3 2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 3) [0233] Preparation of 2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-methoxy- phenyl]methyl]phenoxy]acetic acid [0234] To a solution of ethyl 2-[4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5- dichloro- phenoxy]acetate (100 mg, 0.22 mmol, 1 eq) and (4-fluorophenyl)boronic acid (40.6 mg, 0.29 mmol, 1.3 eq) in THF (6 mL) and H 2 O (2 mL) were added Pd(PPh 3 ) 4 (38.1 mg, 0.033 mmol, 0.15 eq) and Na 2 CO 3 (47.3 mg,
  • the mixture was degassed and purged with N 2 for 3 times, and then stirred at 80 °C for 16 h under N 2 atmosphere.
  • the mixture was diluted with H 2 O (5 mL), adjusted to pH ⁇ 6 with aqueous 1.0 M HCl, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Example 4 2-[3,5-dichloro-4-[[3-(3-fluorophenyl)-4-hydroxy-phenyl] methyl]phenoxy]acetic acid (Compound 4)
  • the title compound was prepared (2.2 mg, 11.3% yield, white solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with (3-fluorophenyl)boronic acid.
  • the crude residue was purified by pre-HPLC (column: Venusil ASB Phenyl 250*5010u; mobile phase: [water (0.05%HCl)-ACN]; B%: 51%-81%, 9min).
  • Example 5 2-[3,5-dichloro-4-[(4-hydroxy-3-pyrazin-2-yl-phenyl) methyl]phenoxy]acetic acid (Compound 5) [0240] The title compound was prepared (5.1 mg, 11.0% yield, yellow-green solid) using the same procedure as in the preparation of Example 2, substituting tributyl(2- pyridyl)stannane with tributyl(pyrazin-2-yl)stannane.
  • Example 6 2-[3,5-dichloro-4-[(4-hydroxy-3-pyridazin-4-yl- phenyl)methyl]phenoxy]acetic acid (Compound 6)
  • the title compound was prepared (13.5 mg, 40% yield, yellow solid) using the same procedure as in the preparation of Example 2, substituting tributyl(2-pyridyl)stannane with tributyl(pyridazin-4-yl)stannane.
  • the crude residue was purified by pre-HPLC (column: Venusil ASB Phenyl 250*5010u; mobile phase: [water(0.05%HCl)-ACN]; B%: 38%-68%, 9min).
  • Example 7 2-[3,5-dichloro-4-[[4-hydroxy-3-(o- tolyl)phenyl]methyl]phenoxy]acetic acid (Compound 7)
  • the title compound was prepared (11.8 mg, 23.5% yield, white solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with o-tolylboronic acid.
  • the crude residue was purified by prep-HPLC (HCl condition; column: Agela ASB 150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%- 80%, Gradient Time: 8 min; Flow Rate: 25 mL/min).
  • Example 8 2-[3,5-dichloro-4-[[3-(3,5-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 8) [0246]
  • the title compound was prepared (5.5 mg, 10.6% yield, white solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with (3,5-difluorophenyl)boronic acid.
  • the crude residue was purified by prep-HPLC (HCl: column: Agela DuraShell 150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 8min).
  • Example 9 2-[3,5-dichloro-4-[[3-(2-chlorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 9)
  • the title compound was prepared (10.2 mg, 19.8% yield, yellow solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with (2-chlorophenyl)boronic acid.
  • the crude residue was purified by prep-HPLC (HCl: column: Agela DuraShell 150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 8min).
  • Example 10 2-[3,5-dichloro-4-[(4-hydroxy-3-pyrimidin-5-yl-phenyl) methyl] phenoxy]acetic acid (Compound 10) [0250] The title compound was prepared (2.0 mg, 3.29% yield, 95.56% purity, white solid) using the same procedure as in the preparation of Example 3 at 120 °C for 0.5 h under microwave irradiation instead, substituting (4-fluorophenyl)boronic acid with pyrimidin-5- ylboronic acid.
  • Example 11 2-[3,5-dichloro-4-[[4-hydroxy-3-(4- pyridyl)phenyl]methyl]phenoxy]acetic acid (Compound 11) [0252]
  • the title compound was prepared (1.2 mg, 1.9% yield, light yellow solid) using the same procedure as in the preparation of Example 3, substituting (4- fluorophenyl)boronic acid with 4-pyridylboronic acid.
  • the crude residue was purified by prep-HPLC (HCl: column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 20%-50%, 8min).
  • Example 12 2-[3,5-dichloro-4-[[3-(2-chloro-5-fluoro-phenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 12) [0254] The title compound was prepared (26.8 mg, 24.5% yield, white solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with 2-(2-chloro-5-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
  • Example 13 2-[3,5-dichloro-4-[(4-hydroxy-3-pyrimidin-4-yl- phenyl)methyl]phenoxy]acetic acid (Compound 13) [0256]
  • the title compound was prepared (10.3 mg, 16% yield, light yellow solid) using the same procedure as in the preparation of Example 2, substituting tributyl(2- pyridyl)stannane with dibutyl-pentyl-pyrimidin-4-yl-stannane.
  • the crude residue was purified by prep-HPLC (HCl condition; column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 45%-71%, 6min).
  • Example 14 2-[3,5-dichloro-4-[[3-(2-fluoro-4-pyridyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 14) [0258] The title compound was prepared (4.5 mg, 22.4% yield, light yellow solid) using the same procedure as in the preparation of Example 3, substituting (4- fluorophenyl)boronic acid with 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)pyridine.
  • Example 15 2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 15) [0260] To a mixture of ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]-3,5-dichloro- phenoxy] acetate (30 mg, 0.069 mmol, 1 eq) in dioxane (2 mL) and water (1 mL) were added (3,4-difluorophenyl)boronic acid (16.4 mg, 0.10 mmol, 1.5 eq), Pd(dppf)Cl 2 (5.1 mg, 0.0069 mmol, 0.1 eq), Na 2 CO 3 (22.0 mg, 0.21 mmol, 3 eq).
  • the mixture was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N 2 atmosphere.
  • the mixture was diluted with water (15 mL), adjusted to pH ⁇ 1 with aqueous 1.0 M HCl, and then extracted with EtOAc (15 mL x 4). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Example 16 2-[3,5-dichloro-4-[[3-(4-chloro-3-fluoro-phenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 16) [0262]
  • the title compound was prepared (23.8 mg, 43.5% yield, off-white solid) using the same procedure as in the preparation of Example 15, substituting (3,4- difluorophenyl)boronic acid with (4-chloro-3-fluoro-phenyl)boronic acid.
  • the crude residue was purified by prep-HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%:65%-95%, 9min).
  • Example 17 2-[3,5-dichloro-4-[[3-(4-chlorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 17) [0264] The title compound was prepared (14 mg, 27.7 % yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with (4-chlorophenyl)boronic acid.
  • Example 18 2-[3,5-dichloro-4-[[3-(3-chloro-4-fluoro-phenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 18) [0266]
  • the title compound was prepared (26.4 mg, 48.9% yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4- difluorophenyl)boronic acid with (3-chloro-4-fluoro-phenyl)boronic acid.
  • the crude residue was purified by pre-HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 65%-95%, 9min).
  • Example 19 2-[3,5-dichloro-4-[[3-(3-chloro-4,5-difluoro-phenyl)-4- hydroxy-phenyl]methyl]phenoxy]acetic acid (Compound 19) [0268] The title compound was prepared (23.4 mg, 21.3% yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4- difluorophenyl)boronic acid with 2-(3-chloro-4,5-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane.
  • Example 20 2-[3,5-dichloro-4-[[3-(4-chloro-3,5-difluoro-phenyl)-4- hydroxy-phenyl]methyl]phenoxy]acetic acid (Compound 20) [0270] The title compound was prepared (38.7 mg, 35% yield, off-white solid) using the same procedure as in the preparation of Example 15, substituting (3,4- difluorophenyl)boronic acid with 2-(4-chloro-3,5-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane.
  • Example 21 2-[3,5-dichloro-4-[[4-hydroxy-3-(2,4,5- trifluorophenyl)phenyl]methyl]phenoxy]acetic acid (Compound 21) [0272] The title compound was prepared (5.8 mg, 13.5% yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with 4,4,5,5-tetramethyl-2-(2,4,5-trifluorophenyl)-1,3,2-dioxaborolane.
  • Example 22 2-[3,5-dichloro-4-[[3-(2,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 22) [0274] The title compound was prepared (8.4 mg, 16.4% yield, off-white solid) using the same procedure as in the preparation of Example 15, substituting (3,4- difluorophenyl)boronic acid with (2,4-difluorophenyl)boronic acid.
  • Example 23 2-[3,5-dichloro-4-[[3-(5-fluoro-3-pyridyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 23) [0276] The title compound was prepared (3.4 mg, 5.3% yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with (5-fluoropyridin-3-yl)boronic acid.
  • Example 24 2-[3,5-dichloro-4-[[3-(2-chloro-3-fluoro-phenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 24) [0278] The title compound was prepared (35.8 mg, 40.2% yield, white solid) using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl) boronic acid with 2-(2-chloro-3-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
  • Example 25 2-[3,5-dichloro-4-[[4-hydroxy-3-(3,4,5- trifluorophenyl)phenyl]methyl]phenoxy]acetic acid (Compound 25) [0280] The title compound was prepared (40 mg, 35.6% yield, white solid) using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with (3,4,5-trifluorophenyl)boronic acid.
  • the mixture was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 85 °C for 8 h under N 2 atmosphere.
  • the mixture was diluted with water (15 mL), and then extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • the mixture was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 85 °C for 4 h under N 2 atmosphere.
  • the mixture was diluted with water (20 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Example 27 2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]-N-methylsulfonyl-acetamide (Compound 27) [0293] Preparation of 2-[3,5-dichloro-4-[(4-methoxy-3-phenyl- phenyl)methyl]phenoxy]-N-methylsulfonyl-acetamide [0294] To a solution of 2-[3,5-dichloro-4-[(4-methoxy-3-phenyl- phenyl)methyl]phenoxy]acetic acid (200 mg, 0.48 mmol, 1 eq) and HATU (273 mg, 0.72 mmol, 1.5 eq) in DCM (5 mL) were added methanesulfonamide (137 mg, 1.44 mmol, 3 eq) and DIEA (186 mg, 0.25 mL, 1.44 mmol, 3 eq).
  • Example 28 (2S)-2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]-N-methylsulfonyl-propanamide (Compound 28) [0298]
  • the title compound was prepared (45.2 mg, 43.4% yield, white solid) using the same procedure as in the preparation of Example 27, substituting 2-[3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenoxy]acetic acid with (2S)-2-[3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenoxy]propanoic acid.
  • Example 29 2-[3,5-dichloro-4-[[4-hydroxy-3-(4- pyridyl)phenyl]methyl]phenoxy]-N-methylsulfonyl-acetamide (Compound 29) [0300] To a solution of 2-[3,5-dichloro-4-[[4-hydroxy-3-(4- pyridyl)phenyl]methyl]phenoxy]acetic acid (120 mg, 0.29 mmol, 1 eq, HCl salt) and methanesulfonamide (112 mg, 1.18 mmol, 4 eq) in DCM (20 mL) were added DIEA (152 mg, 1.18 mmol, 4 eq) and HATU (123 mg, 0.32 mmol, 1.1 eq).
  • DIEA 152 mg, 1.18 mmol, 4 eq
  • HATU 123 mg, 0.32 mmol, 1.1 eq.
  • Example 30 2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]-N-methylsulfonyl-acetamide (Compound 30) [0302] The title compound was prepared (25.1 mg, 28.4% yield, white solid) using the same procedure as in the preparation of Example 27, substituting 2-[3,5-dichloro-4-[[3- (4-fluorophenyl)-4-methoxy-phenyl]methyl] phenoxy]acetic acid with 2-[3,5-dichloro-4-[[3- (4-fluorophenyl)-4-methoxy-phenyl]methyl] phenoxy]acetic acid.
  • Example 31 2-[3,5-dichloro-4-[[3-(3-chloro-4-fluoro-phenyl)-4-hydroxy- phenyl] methyl]phenoxy]-N-methylsulfonyl-acetamide (Compound 31) [0304]
  • the title compound was prepared (3.2 mg, 19.2 % yield, light yellow solid) using the same procedure as in the preparation of Example 29, substituting 2-[3,5-dichloro-4- [[4-hydroxy-3-(4-pyridyl)phenyl]methyl]phenoxy]acetic acid with 2-[3,5-dichloro-4-[[3-(3- chloro-4-fluoro-phenyl)-4-hydroxy-phenyl]methyl]phenoxy]acetic acid.
  • Example 32 (2S)-2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]propanoic acid (Compound 32) [0306] Preparation of ethyl (2S)-2-[3,5-dichloro-4-[(4-methoxy-3-phenyl- phenyl)methyl]phenoxy]propanoate [0307] To a solution of 3,5-dichloro-4-[(4-methoxy-3-phenyl-phenyl)methyl]phenol (100 mg, 0.28 mmol, 1 eq) in THF (5 mL) were added ethyl (2R)-2-hydroxypropanoate (49.3 mg, 0.42 mmol, 0.048 mL, 1.5 eq), PPh 3 (110 mg,0.42 mmol, 1.5 eq) and tert-butyl (NE)-N- tert-butoxycarbonyliminocarbamate
  • Example 33 (2R)-2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]propanoic acid (Compound 33) [0311]
  • the title compound was prepared (25.1 mg, 55.0% yield, white solid) using the same procedure as in the preparation of Example 32, substituting ethyl (2R)-2- hydroxypropanoate with ethyl (2S)-2-hydroxypropanoate.
  • the crude residue was purified by prep-HPLC (HCl condition; column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 48%-78%, 8min).
  • Example 34 (2S)-2-[3,5-dichloro-4-[[3-(2,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (Compound 34) [0313]
  • the title compound was prepared (20 mg, 45.8% yield, white solid) using the same procedure as in the preparation of Example 32, substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(2,4-difluorophenyl)-4- methoxy-phenyl]methyl]phenol.
  • Example 35 2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl-phenyl)methyl]-2- methyl-phenoxy]acetic acid (Compound 35) [0315] Preparation of [3,5-dichloro-4-[(4-methoxy-3-phenyl- phenyl)methyl]phenyl]N,N-diethylcarbamate [0316] To a solution of 3,5-dichloro-4-[(4-methoxy-3-phenyl-phenyl)methyl]phenol (400 mg, 1.11 mmol, 1 eq) in THF (8 mL) was added NaH (89.1 mg, 2.23 mmol, 60% purity, 2 eq) under N 2 atmosphere.
  • the crude residue (118 mg) was purified by prep-HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 70%-100%, 9min) to give 3,5-dichloro-2-iodo-4-[(4-methoxy-3-phenyl-phenyl)methyl]phenol (70 mg, 30% yield) as an off-white solid.
  • Example 37 2-[3,5-dichloro-4-[[2-fluoro-4-hydroxy-5-(4-pyridyl) phenyl] methyl]phenoxy]acetic acid (Compound 37) [0331]
  • the title compound was prepared (1.8 mg, 1.93% yield, white solid) using the same procedure as in the preparation of Example 36, substituting Suzuki cross coupling reagent phenylboronic acid with 4-pyridylboronic acid.
  • the crude residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 23%-49%, 6min).
  • Example 38 2-[3,5-dichloro-4-[[2-fluoro-5-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 38) [0333]
  • the title compound was prepared (10.1 mg, 14.7% yield, white solid) using the same procedure as in the preparation of Example 36, substituting Suzuki cross coupling reagent phenylboronic acid with (4-fluorophenyl)boronic acid.
  • the crude residue was purified by pre-HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 60%-80%, 10min).
  • Example 39 2-[3,5-dichloro-4-[[5-(3,4-difluorophenyl)-2-fluoro-4- methoxy-phenyl]methyl]phenoxy]acetic acid (Compound 39) [0335] The title compound was prepared (2.4 mg, 5.0% yield, white solid) using the same procedure as in the preparation of Example 36, substituting Suzuki cross coupling reagent phenylboronic acid with (3,4-difluorophenyl)boronic acid.
  • Example 40 2-[3,5-dichloro-4-[(2-chloro-4-hydroxy-5-phenyl- phenyl)methyl]phenoxy]acetic acid (Compound 40) [0337] Preparation of [3,5-dichloro-4-[(2-chloro-4-methoxy-phenyl) methyl] phenoxy]-triisopropyl-silane B [0338] [3, 5-Dichloro-4-[(2-chloro-4-methoxy-phenyl) methyl] phenoxy]- triisopropyl-silane was prepared (920 mg, 72.8% yield, 99.5% purity, white solid) using the same procedure as in the preparation of Example 1, substituting 1-bromo-4-methoxy-benzene with 1-bromo-2-chloro-4-methoxy-benzene.
  • Example 41 2-[3,5-dichloro-4-[(2-fluoro-4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]acetic acid (Compound 41) [0346] Preparation of 2-fluoro-4-methoxy-3-phenyl-benzaldehyde [0347] A mixture of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (1.0 g, 4.29 mmol, 1 eq), phenylboronic acid (628 mg, 5.15 mmol, 1.2 eq), Na 2 CO 3 (1.14 g, 10.73 mmol, 2.5 eq) and Pd(PPh 3 ) 4 (495 mg, 0.429 mmol, 0.1 eq) in dioxane (10 mL) and H 2 O (3 mL) was degassed and purged with N 2 for 3 times, and then stirred at 80 °C for 2 h under N 2 atmosphere.
  • Example 42 2-[3,5-dichloro-4-[[2-fluoro-3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 42) [0357]
  • the title compound was prepared (71 mg, 46.7% yield, white solid) using the same procedure as in the preparation of Example 41, substituting phenylboronic acid (4- fluorophenyl)boronic acid.
  • the crude residue was purified by prep-HPLC (HCl condition; column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water(0.05%HCl)- ACN]; B%: 50%-80%, 7min).
  • Example 43 2-[3,5-dichloro-4-[[3-(3-chlorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 43) [0359] To a solution of ethyl 2-[4-[(3-bromo-4-hydroxy-phenyl)methyl]-3,5-dichloro- phenoxy]acetate (60 mg, 0.14 mmol, 1 eq) and (3-chlorophenyl)boronic acid (32.8 mg, 0.21 mmol, 1.5 eq) in dioxane (6 mL) and H 2 O (2 mL) were added Pd(PPh 3 ) 4 (16.0 mg, 0.014 mmol, 0.1 eq) and K 2 CO 3 (57.3 mg, 0.41 mmol, 3 eq).
  • Example 44 2-[3,5-dichloro-4-[(4-hydroxy-3-phenyl- phenyl)methyl]phenoxy]acetic acid (Compound 44) [0361] The title compound was prepared (9.5 mg, 16.3% yield, 96% purity, white solid) using the same procedure as in the preparation of Example 1, substituting 3- pyridylboronic acid with phenylboronic acid. The crude residue was purified by prep-HPLC (HCl condition, column: Agela ASB 150*25mm*5um; mobile phase: [water(0.05%HCl)- ACN]; B%: 56%-86%, 8min).
  • Example 45 2-[3,5-dichloro-4-[[3-(2-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 45) [0363]
  • the title compound was prepared using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with (2- fluorophenyl)boronic acid.
  • the crude residue was purified by prep-HPLC (HCl condition, column: Agela ASB 150*25mm*5um; mobile phase: [water(0.05% HCl)-ACN]; B%: 50%- 70%, 8min).
  • Example 46 2-[3,5-dichloro-4-[[4-hydroxy-3-(1H-pyrazol-3- yl)phenyl]methyl]phenoxy]acetic acid (Compound 46) [0365] Preparation of 2-[3,5-dichloro-4-[[4-hydroxy-3-(2-tetrahydropyran-2- ylpyrazol-3-yl)phenyl]methyl]phenoxy]acetic acid [0366] The title compound was prepared using the same procedure as in the preparation of Example 15, substituting (3,4-difluorophenyl)boronic acid with (2- tetrahydropyran-2-ylpyrazol-3-yl)boronic acid.
  • Example 47 2-[3,5-dichloro-4-[(4-hydroxy-3-isothiazol-5-yl- phenyl)methyl]phenoxy]acetic acid (Compound 47) [0370] Preparation of ethyl 2-(3,5-dichloro-4-(4-methoxy-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)phenoxy)acetate [0371] To a mixture of ethyl 2-[4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5-dichloro- phenoxy] acetate (500 mg, 1.12 mmol, 1 eq) in dioxane (5 mL) were added 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (850 mg, 3.
  • the resulting mixture was degassed and purged with N 2 for 3 times, and then stirred at 85 °C for 4 h under N 2 atmosphere.
  • Example 48 2-[3,5-dichloro-4-[(4-hydroxy-3-isothiazol-5-yl- phenyl)methyl]phenoxy]acetic acid (Compound 48) [0377]
  • the title compound was prepared using the same procedure as in the preparation of Example 47, substituting 4-bromoisothiazole with 5-bromoisothiazole.
  • the crude residue was purified by prep-HPLC (column: Venusil ASB Phenyl 150*30mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 50%-80%, 10min) as a brown solid.
  • Example 49 2-[3,5-dichloro-4-[[3-(1-cyclopropylpyrazol-4-yl)-4-hydroxy- phenyl]methyl]phenoxy]acetic acid (Compound 49) [0379]
  • the title compound was prepared using the same procedure as in the preparation of Example 47, substituting 4-bromoisothiazole with 1-cyclopropyl-4-iodo- pyrazole.
  • the crude residue was purified by prep-HPLC (HCl condition, column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05%HCl)-ACN]; B%: 35%-65%, 8min) a gray solid.
  • Example 50 2-[3,5-dichloro-4-[(4-hydroxy-3-isoxazol-4-yl- phenyl)methyl]phenoxy]acetic acid (Compound 50) [0381]
  • the title compound was prepared using the same procedure as in the preparation of Example 3, substituting (4-fluorophenyl)boronic acid with 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole.
  • the crude residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water (0.05%HCl)- ACN]; B%: 50%-80%, 7min) as a white solid.
  • Example 51 2-[3,5-dichloro-4-[[4-hydroxy-3-(1,2,4-triazol-1- yl)phenyl]methyl]phenoxy]acetic acid (Compound 51) [0383] Preparation of ethyl 2-[3,5-dichloro-4-[[4-methoxy-3-(1,2,4-triazol-1- yl)phenyl]methyl]phenoxy]acetate [0384] To a solution of ethyl 2-[4-[(3-bromo-4-methoxy-phenyl)methyl]-3,5- dichloro-phenoxy]acetate (100 mg, 0.22 mmol, 1 eq) in toluene (2 mL) and dioxane (0.5 mL) were added 1H-1,2,4-triazole (30.8 mg, 0.45 mmol, 2 eq) and K 3 PO 4 (94.7 mg, 0.45 mmol, 2 eq), and then added a solution
  • Example 52 2-[3,5-dichloro-4-[(4-hydroxy-3-imidazol-1-yl- phenyl)methyl]phenoxy]acetic acid (Compound 52) [0390] The title compound was prepared using the same procedure as in the preparation of Example 51, substituting 1H-1,2,4-triazole with imidazole.
  • Example 53 2-[3,5-dichloro-4-[(4-hydroxy-3-isothiazol-4-yl- phenyl)methyl]phenoxy]-N-methylsulfonyl-acetamide (Compound 53) [0392] The title compound was prepared using the same procedure as in the preparation of Example 27, substituting 2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-methoxy- phenyl]methyl] phenoxy]acetic acid with 2-[3,5-dichloro-4-[(3-isothiazol-4-yl-4-methoxy- phenyl)methyl]phenoxy]acetic acid.
  • Example 54 (2S)-2-[3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)-4- hydroxy-phenyl]methyl]phenoxy]propanoic acid (Compound 54) [0394]
  • the title compound was prepared (14.5 mg, 21.4% yield, white solid) using the same procedure as in the preparation of Example 32, substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)- 4-methoxy-phenyl]methyl]phenol.
  • Example 55 (2R)-2-[3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)-4- hydroxy-phenyl]methyl]phenoxy]propanoic acid (Compound 55) [0396]
  • the title compound was prepared (5.2 mg, 11.0% yield, white solid) using the same procedure as in the preparation of Example 32, substituting ethyl (2R)-2- hydroxypropanoate with ethyl (2S)-2-hydroxypropanoate, and substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(3-chloro-4-fluorophenyl)- 4-methoxy-phenyl]methyl]phenol.
  • Example 56 (2S)-2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (Compound 56) [0398]
  • the title compound was prepared (25.2 mg, 53.7% yield, white solid) using the same procedure as in the preparation of Example 32, substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(4-fluorophenyl)-4- methoxy-phenyl]methyl]phenol.
  • Example 57 (2R)-2-[3,5-dichloro-4-[[3-(4-fluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (Compound 57) [0400]
  • the title compound was prepared (32.2 mg, 68.3% yield, white solid) using the same procedure as in the preparation of Example 32, substituting ethyl (2R)-2- hydroxypropanoate with ethyl (2S)-2-hydroxypropanoate, and substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(4-fluorophenyl)-4- methoxy-phenyl]methyl]phenol.
  • Example 58 (2S)-2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (Compound 60) [0402]
  • the title compound was prepared (16.1 mg, 33.5% yield, white solid) using the same procedure as in the preparation of Example 32, substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(3,4-fluorophenyl)-4- methoxy-phenyl]methyl]phenol.
  • Example 59 (2R)-2-[3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4-hydroxy- phenyl]methyl]phenoxy]propanoic acid (Compound 61) [0404]
  • the title compound was prepared (16.0 mg, 35.0% yield, white solid) using the same procedure as in the preparation of Example 32, substituting ethyl (2R)-2- hydroxypropanoate with ethyl (2S)-2-hydroxypropanoate, and substituting 3,5-dichloro-4-[(4- methoxy-3-phenyl-phenyl)methyl]phenol with 3,5-dichloro-4-[[3-(3,4-difluorophenyl)-4- methoxy-phenyl]methyl]phenol.
  • Example 60 Biological Assays
  • the thyroid receptor coactivator recruitment assay was designed according to the instruction of TR-FRET Thyroid receptor alpha (beta) Coactivator Assay (Invitrogen#PV4686, PV4687). Brief procedure: [0407] The diluted compounds were transferred into the two 384-well plates in duplicate using Echo. TR-FRET Coregulator Buffer C (obtained from Thermo Fisher, China) was prepared by diluting 1 M DTT (Theromo catalog # P2325) to 5 mM DTT in buffer C. The 10 ⁇ L of the buffer was dispensed to the each well of assay plates.
  • TR alpha, Fluorescein-SRC2-2 and Tb anti-GST Antibody were diluted and mixed to a concentration of 0.8 nM, 400 nM and 4 nM in TR-FRET Coregulatory Buffer C, respectively. The 10 ⁇ L of the mixture was dispensed to each well of the assay plates.
  • the TR beta, Fluorescein-SRC2-2 and Tb anti-GST Antibody were diluted and mixed to a concentration of 2.0 nM, 400 nM and 4 nM in TR-FRET Coregulatory Buffer C. Then the 10 uL of the mixture was dispensed to the each well of another two assay plates. [0409] After incubation of the plates from the light at RT for 2 hours.
  • the signal measurement were performed on the Envision which installs a 340 nm laser, the mirror TRF D400/D505 dual/Bias, 520/25 nm filter and 495/10 nm filter.
  • the terbium labeled anti-GST antibody was excited by laser and collected using the filters of TRF Emission 520 and TRF Emission 495, respectively.
  • the TR-FRET ratio was calculated by dividing the emission signal at 520 nm for TR coactivator assay by the emission signal at 495 nm for TR coactivator assay. A binding curve was generated by plotting the emission ratio vs. the log [ligand].
  • THR- ⁇ Activity activate THR- ⁇ , THR- ⁇ , A: IC50 ⁇ 5 nM, B: 5 nM ⁇ IC50 ⁇ 20 nM; C: 20 nM ⁇ IC 50 ⁇ 100 nM; D: IC 50 >100 nM Selectivity: A: SI ⁇ 3; B: 3 ⁇ SI ⁇ 20; C: SI>20 ND: not determined [0411]

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Abstract

La présente demande concerne de nouveaux composés de formule (I) où R1, R2, R3, R4, R5, R6, R7, R8, et R11 sont tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci qui sont des agonistes du récepteur des hormones thyroïdiennes (THR), les compositions pharmaceutiques comprenant un ou plusieurs des composés et des sels de ceux-ci en tant que principe actif, et l'utilisation des composés et des sels de ceux-ci pour prévenir et/ou traiter des maladies métaboliques, des maladies du SNC, comprenant, entre autres, la SHNA, l'hyperlipidémie, l'hypercholestérolémie, l'obésité et le diabète, la sclérose en plaques, ainsi que des états associés, chez les mammifères et en particulier chez les humains.
PCT/US2023/015193 2022-03-16 2023-03-14 Agonistes du récepteur des hormones thyroïdiennes WO2023177667A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777442B2 (en) * 2001-03-12 2004-08-17 Bayer Aktiengesellschaft Diphenyl derivatives
US7109164B2 (en) * 2000-02-17 2006-09-19 Bristol-Myers Squibb Company Aniline-derived ligands for the thyroid receptor
US20080004251A1 (en) * 2004-03-22 2008-01-03 Karo Bio Ab Novel Pharmaceutical Compositions Comprising Agonists of the Thyroid Receptor
WO2018032012A1 (fr) * 2016-08-12 2018-02-15 Oregon Health & Science University Composés amides, compositions pharmaceutiques les contenant et leurs procédés d'utilisation
US20210053917A1 (en) * 2019-03-01 2021-02-25 Autobahn Therapeutics, Inc. Novel thyromimetics

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7109164B2 (en) * 2000-02-17 2006-09-19 Bristol-Myers Squibb Company Aniline-derived ligands for the thyroid receptor
US6777442B2 (en) * 2001-03-12 2004-08-17 Bayer Aktiengesellschaft Diphenyl derivatives
US20080004251A1 (en) * 2004-03-22 2008-01-03 Karo Bio Ab Novel Pharmaceutical Compositions Comprising Agonists of the Thyroid Receptor
WO2018032012A1 (fr) * 2016-08-12 2018-02-15 Oregon Health & Science University Composés amides, compositions pharmaceutiques les contenant et leurs procédés d'utilisation
US20210053917A1 (en) * 2019-03-01 2021-02-25 Autobahn Therapeutics, Inc. Novel thyromimetics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-[3,5-Dichloro-4-[(4-hydroxy-3phenylphenyl)methyl]phenoxy]aceti c acid", XP093093573, retrieved from PUBCHEM *

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