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WO2024238871A1 - Composés arylsulfonamide et leur utilisation dans le traitement d'états médicaux - Google Patents

Composés arylsulfonamide et leur utilisation dans le traitement d'états médicaux Download PDF

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WO2024238871A1
WO2024238871A1 PCT/US2024/029818 US2024029818W WO2024238871A1 WO 2024238871 A1 WO2024238871 A1 WO 2024238871A1 US 2024029818 W US2024029818 W US 2024029818W WO 2024238871 A1 WO2024238871 A1 WO 2024238871A1
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compound
certain embodiments
alkyl
nitrogen
sulfur
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Todd Bosanac
Nathan Oliver Fuller
Robert Owen Hughes
Guy Bemis
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Rectify Pharmaceuticals Inc
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Rectify Pharmaceuticals Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P27/00—Drugs for disorders of the senses
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention provides aryl sulfonamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • ATP-binding cassette (ABC) transporters are a large, phylogenetically conserved gene family with broad physiological and pathological relevance. [1,2] They are expressed throughout the body and transport a diverse range of substrates across lipid membranes. ABC transporters are transmembrane, ATP-binding proteins that use the energy released during ATP hydrolysis to move substrates from one side of a lipid membrane to the other. [2,3]
  • ABC transporters underly rare monogenic disorders with even more implicated in the predisposition to and symptomology of common and complex diseases.
  • Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery.
  • cystic fibrosis CF
  • progressive familial intrahepatic cholestasis 2 PFIC2
  • Stargardt disease STGD
  • pathogenic ABC transporter missense mutations principally their impact on protein folding leading to endoplasmic reticulum (ER) degradation (trafficking defects), or protein function, leading to decreased substrate transport (transport defects).
  • small molecule compounds may enable treatment of disease symptoms not directly caused by mutations in ABC transporter genes.
  • small molecule compounds that can positively modulate ABC transporter function and therefore be used for the treatment of diseases in which such enhancement is predicted to be of therapeutic value, either in modifying disease or in treating disease symptomology.
  • modulators that can address mutations in ABCB11, ABCB4, ABCC6, ABCA4, ABCD1, ABCA1 and ABCA7 for the treatment of PFIC2, PFIC3, PXE/GACI, STGD, X-ALD and Alzheimer’s disease, respectively.
  • the invention provides aryl sulfonamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • one aspect of the invention provides a collection of aryl sulfonamide compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of aryl sulfonamide compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a collection of aryl sulfonamide compounds represented by Formula 1-1 : or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of aryl sulfonamide compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating a disorder associated with ABC transporter dysfunction.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder, as further described in the detailed description.
  • Another aspect of the invention provides a method increasing the expression of a protein selected from ABCB11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, and ABCD2 in a subject.
  • the method comprises administering to a subject in need thereof an effective amount of a compound described herein, such as a compound of Formula I, to thereby increase expression of said protein, as further described in the detailed description.
  • the invention provides aryl sulfonamide compounds, pharmaceutical compositions, and their use in treating medical conditions.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1 -6 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as o/7/w-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: [0016]
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a C1.4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2/f-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • bivalent Ci-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH2) n - wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but 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 non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached to it (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g .
  • arylene refers to a bivalent aryl group.
  • heteroaryl and “heteroar-, ” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 > electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4J/-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it.
  • heteroarylene is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2// pyrrol yl), NH (as in pyrrolidinyl), or + NR (as in A substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3/7 indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by one or more oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • oxo-heterocyclylene refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • 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.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R* is C 1-6 aliphatic
  • R* is optionally substituted with halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2
  • each R* is independently selected from C 1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently -R : , -NR ⁇ 2 , - C(O)R f , -C(O)OR f , -C(O)C(O)R t , -C(O)CH 2 C(O)R t , -S(O) 2 R + , -S(O) 2 NR f 2 , -C(S)NR t 2 , - C(NH)NR’ : 2 , or -N(R ⁇ )S(O) 2 R t ; wherein each R : is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ taken together with their intervening atom(s) form an unsubstituted
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + ( C 1-4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S orR configuration as defined by the IUP AC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.
  • Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, /cvV-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH 2 F, -OCHF 2 , -OCF3, -OCH2CF3, -OCF2CF3, and the like.
  • a cyclopentane substituted with an oxo group is cyclopentanone.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • IC50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.
  • EC 50 is art recognized and refers to the concentration of a compound that is required to achieve a response that is 50% of the maximum target effect relative to the baseline.
  • E max is art recognized and refers to the concentration of a compound that is require to achieve maximal target effect.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result).
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed.
  • acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • One aspect of the invention provides aryl sulfonamide compounds.
  • the compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. [0068] Accordingly, one aspect of the invention provides a compound represented by
  • R 1 is -L 1 -SO 2 -R 6 , -SO 2 N(R 9 )-R 7 , or -S(NH)(O)-R 6 ;
  • R 2 represents independently for each occurrence hydrogen, hydroxyl, C 1-3 alkyl, halo, C 1-4 alkoxyl, C1.3 haloalkyl, C 1-3 hydroxyalkyl, or optionally substituted cyclopropyl;
  • R 3 and R 4 are independently hydrogen or C 1-3 alkyl
  • R 3 represents independently for each occurrence halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, -CON(R 10 ) 2 , or C 1-6 haloalkoxyl;
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, -(C0-2 alkylene)-(3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, heterocycle, and heteroaryl are substituted with m instances of R 8 ;
  • R 7 is hydrogen, C 1-4 alkyl, C3.5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 ;
  • R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl;
  • R 9 is hydrogen or C 1-3 alkyl
  • R 10 represents independently for each occurrence hydrogen, C 1-4 alkyl, or cyclopropyl
  • L 1 is -N(R 9 )- or a bond
  • A* is an 8-10 membered partially unsaturated bicyclic oxo-heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • B 1 is phenylene or a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen; m is 0, 1, or 2; n is 0, 1, 2, or 3; o is 1, 2, or 3; and p is 0, 1 or 2
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • A* is an 8-10 membered partially unsaturated bicyclic oxo-heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen.
  • A* is an 8-10 membered partially unsaturated bicyclic oxo-heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • A* is a 9-10 membered partially unsaturated bicyclic oxo-heterocyclic ring containing two heteroatoms, wherein the heteroatoms are nitrogen atoms.
  • A* is an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • A* is azaindazolene or azaindolene.
  • A* is selected from those disclosed in Table 1, below.
  • R 1 is -V-SCh-R 6 , -SO 2 N(R 9 )-R 7 ’, or -S(NH)(O)-R 6 .
  • R 1 is -L 1 -SO 2 -R 6 .
  • R 1 is -NHSO 2 -R 6 .
  • R 1 is -SO 2 -R 6 .
  • R 1 is -SO 2 N(R 9 )-R 7 .
  • R 1 is -SO 2 NH-R 7 .
  • R 1 is -S(NH)(O)-R 6 .
  • R 1 is selected from those disclosed in Table 1, below.
  • R 2 represents independently for each occurrence hydrogen, hydroxyl, C 1-3 alkyl, halo, Ci-4 alkoxyl, C 1-3 haloalkyl, C1.3 hydroxyalkyl, or optionally substituted cyclopropyl.
  • R 2 is hydrogen.
  • R 2 is hydroxyl.
  • R 2 represents independently for each occurrence C 1-3 alkyl.
  • R 2 represents independently for each occurrence halo.
  • R 2 represents independently for each occurrence Ci-4alkoxyl.
  • R 2 represents independently for each occurrence C 1-3 haloalkyl.
  • R 2 represents independently for each occurrence C 1-3 hydroxyalkyl. In certain embodiments, R 2 is optionally substituted cyclopropyl. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence C1.3 alkyl, halo, C 1-3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or optionally substituted cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or 1 -methylcyclopropyl.
  • R 2 is hydrogen, hydroxyl, C 1-3 alkyl, halo, C1.3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 is C1.3 alkyl. In certain embodiments, R 2 is halo. In certain embodiments, R 2 is Ci-4 alkoxyl. In certain embodiments, R 2 is C 1-3 haloalkyl. In certain embodiments, R 2 is C 1-3 hydroxyalkyl. In certain embodiments, R 2 is C 1-3 alkyl, halo, C 1-3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 is methyl or cyclopropyl. In certain embodiments, R 2 is selected from those disclosed in Table 1, below.
  • R 3 and R 4 are independently hydrogen or C 1-3 alkyl. In certain embodiments, R 3 and R 4 are independently C 1-3 alkyl. In certain embodiments, R 3 and R 4 are hydrogen. In certain embodiments, R 3 and R 4 are C 1-3 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is selected from those disclosed in Table 1, below.
  • R 4 is hydrogen. In certain embodiments, R 4 is C 1-3 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 3 and R 4 are independently selected from those disclosed in Table 1, below.
  • R 5 represents independently for each occurrence halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, -CON(R 10 )2, or C 1-6 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, -CON(R 10 )2, or C 1-6 haloalkoxyl.
  • R 5 represents independently for each occurrence halo, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, -CON(R 10 )2, or C 1-6 haloalkoxyl.
  • R 3 represents independently for each occurrence halo, C 1-6 alkyl, hydroxyl, C 1-6 alkoxyl, -CON(R 10 )2, or C 1-6 haloalkoxyl.
  • R 3 represents independently for each occurrence halo, C 1-6 alkyl, C 1-6 haloalkyl, Cue alkoxyl, - CONH(R 10 ), or C 1-6 haloalkoxyl.
  • R 3 represents independently for each occurrence halo, C 1-6 alkyl, Cue haloalkyl, hydroxyl, or -CONH(R 10 ), C 1-6 haloalkoxyl.
  • R 5 represents independently for each occurrence halo, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 3 represents independently for each occurrence C 1-6 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 3 represents independently for each occurrence -CONH(R 10 ). In certain embodiments, R 5 represents independently for each occurrence -CON(R 10 )2. In certain embodiments, R 5 represents independently for each occurrence C 1-6 haloalkoxyl.
  • R 5 is halo. In certain embodiments, R 3 is F. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is C 1-6 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is C 1-6 haloalkyl. In certain embodiments, R 3 is -CF3. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 5 is C 1-6 alkoxyl. In certain embodiments, R 5 is -OMe. In certain embodiments, R 5 is -CONH(R 8 ). In certain embodiments, R 5 is C 1-6 haloalkoxyl. In certain embodiments, R 3 is selected from those disclosed in Table 1, below.
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, -(C0-2 alkylene)- (3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, heterocycle, and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, or phenyl, wherein the cycloalkyl is substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl. In certain embodiments, R 6 is Z-butyl. In certain embodiments, R 6 is C 3-5 cycloalkyl, substituted with m instances of R 8 . In certain embodiments, R 6 is cyclopropyl, substituted with m instances of R 8 . In certain embodiments, R 6 is phenyl. In certain embodiments, R 6 is -(C0-2 alkylene)-(3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), substituted with m instances of R 8 .
  • R 6 is -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 .
  • R 6 is selected from those disclosed in Table 1, below.
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, or -(Co- 2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is C1.4 alkyl, C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)- (5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, phenyl, or -(C0-2 alkylene)- (5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or -(Co-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, wherein the cycloalkyl is substituted with m instances of R 8 .
  • R 7 is hydrogen. In certain embodiments, R 7 is C 1-4 alkyl. In certain embodiments, R 7 is /-butyl. In certain embodiments, R 7 is C 3-5 cycloalkyl, substituted with m instances of R 8 . In certain embodiments, R 7 is cyclopropyl, substituted with m instances ofR 8 . In certain embodiments, R 7 is phenyl. In certain embodiments, R 7 is -(Co-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 . In certain embodiments, R 7 is selected from those disclosed in Table 1, below.
  • R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence halo, C 1-3 haloalkyl, hydroxyl, C1.4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, Ci-3 haloalkyl, hydroxyl, C1.4 alkoxy, cyano, or cyclopropyl.
  • R 8 represents independently for each occurrence C 1-4 alkyl, halo, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C1.4 alkyl, halo, C 1-3 haloalkyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, cyano, or cyclopropyl.
  • R 8 represents independently for each occurrence C1.4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, or cyano.
  • R 8 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 8 represents independently for each occurrence halo. In certain embodiments, R 8 represents independently for each occurrence C 1-3 haloalkyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkoxy.
  • R 8 is C 1-4 alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is C1.3 haloalkyl. In certain embodiments, R 8 is C 1-4 alkoxy. In certain embodiments, R 8 is cyano. In certain embodiments, R 8 is Ci-4 alkyl or C 1-3 haloalkyl. In certain embodiments, R 8 is selected from those disclosed in Table 1, below.
  • R 9 is hydrogen or C 1-3 alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C 1-3 alkyl. In certain embodiments, R 9 is selected from those disclosed in Table 1, below.
  • R 10 represents independently for each occurrence hydrogen, C 1-4 alkyl, or cyclopropyl. In certain embodiments, R 10 represents independently for each occurrence hydrogen. In certain embodiments, R 10 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 10 represents independently for each occurrence cyclopropyl. In certain embodiments, R 10 represents independently for each occurrence hydrogen or C 1-4 alkyl. In certain embodiments, R 10 represents independently for each occurrence hydrogen or cyclopropyl. In certain embodiments, R 10 is selected from those disclosed in Table 1, below.
  • L 1 is -N(R 9 )- or a bond. In certain embodiments, L 1 is - N(R 9 )-. In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is selected from those disclosed in Table 1, below.
  • B 1 is phenylene or a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen.
  • B 1 is phenylene.
  • B 1 is a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen.
  • B 1 is pyridinylene, pyrimidylene, pyridazinylene, pyrazinylene, or phenylene.
  • B 1 is pyridinylene.
  • B 1 is pyrimidylene.
  • B 1 is pyridazinylene.
  • B 1 is pyrazinylene.
  • B 1 is phenylene.
  • B 1 is selected from those disclosed in Table 1, below.
  • m is 0, 1, or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • o is 1, 2, or 3. In certain embodiments, o is 2 or 3. In certain embodiments, o is 1 or 2. In certain embodiments, o is 0. In certain embodiments, o is 1. In certain embodiments, o is 2. In certain embodiments, o is 1 or 3. In certain embodiments, o is 3. In certain embodiments, o is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • p is 0, 1, or 2. In certain embodiments, p is 1 or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • Another aspect of the invention provides a compound represented by Formula 1-1 : or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 is -lASCh-R 6 , -SO 2 N(R 9 )-R 7 ’, or -S(NH)(O)-R 6 ;
  • R 2 represents independently for each occurrence hydrogen, hydroxyl, C 1-3 alkyl, halo, C 1-4 alkoxyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, or optionally substituted cyclopropyl;
  • R 3 and R 4 are independently hydrogen or C 1-3 alkyl
  • R ? represents independently for each occurrence halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl;
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, -(C0-2 alkylene)-(3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, heterocycle, and heteroaryl are substituted with m instances of R 8 ;
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 ;
  • R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl;
  • R 9 is hydrogen or C 1-3 alkyl
  • L 1 is -N(R 9 )- or a bond
  • a 1 is a 5-6 membered partially unsaturated or aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
  • B 1 is phenylene or a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen; m is 0, 1, or 2; n is 0, 1, 2, or 3; and o is 1, 2, or 3.
  • variables in Formula 1-1 above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula 1-1.
  • R 1 is -L'-SCh-R 6 , -SC>2N(R 9 )-R 7 , or -S(NH)(O)-R 6 .
  • R 1 is -iJ-SCh-R 6 .
  • R 1 is -NHSO 2 -R 6 .
  • R 1 is -SO 2 -R 6 .
  • R 1 is -SO 2 N(R 9 )-R 7 .
  • R 1 is -SO 2 NH-R 7 .
  • R 1 is -S(NH)(O)-R 6 .
  • R 1 is selected from those disclosed in Table 1, below.
  • R 2 represents independently for each occurrence hydrogen, hydroxyl, C 1-3 alkyl, halo, Ci-4 alkoxyl, C 1-3 haloalkyl, C1.3 hydroxyalkyl, or optionally substituted cyclopropyl.
  • R 2 is hydrogen.
  • R 2 is hydroxyl.
  • R 2 represents independently for each occurrence C 1-3 alkyl.
  • R 2 represents independently for each occurrence halo.
  • R 2 represents independently for each occurrence Ci-4 alkoxyl.
  • R 2 represents independently for each occurrence C 1-3 haloalkyl.
  • R 2 represents independently for each occurrence C 1-3 hydroxyalkyl. In certain embodiments, R 2 is optionally substituted cyclopropyl. In certain embodiments, R 2 is cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence C1.3 alkyl, halo, C 1-3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or optionally substituted cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or cyclopropyl. In certain embodiments, R 2 represents independently for each occurrence methyl or 1-methylcyclopropyl.
  • R 2 is hydrogen, hydroxyl, C 1-3 alkyl, halo, C 1-3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 is C1.3 alkyl. In certain embodiments, R 2 is halo. In certain embodiments, R 2 is Ci-4 alkoxyl. In certain embodiments, R 2 is C 1-3 haloalkyl. In certain embodiments, R 2 is C 1-3 hydroxy alkyl. In certain embodiments, R 2 is C 1-3 alkyl, halo, C 1-3 haloalkyl, or cyclopropyl. In certain embodiments, R 2 is methyl or cyclopropyl. In certain embodiments, R 2 is selected from those disclosed in Table 1, below.
  • R 3 and R 4 are independently hydrogen or C 1-3 alkyl. In certain embodiments, R 3 and R 4 are independently C1.3 alkyl. In certain embodiments, R 3 and R 4 are hydrogen. In certain embodiments, R 3 and R 4 are C 1-3 alkyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is C 1-3 alkyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C 1-3 alkyl. In certain embodiments, R 4 is methyl. In certain embodiments, R 3 and R 4 are independently selected from those disclosed in Table 1, below.
  • R 5 represents independently for each occurrence halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl.
  • R ? represents independently for each occurrence C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl.
  • R 5 represents independently for each occurrence halo, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl.
  • R 5 represents independently for each occurrence halo, C 1-6 alkyl, hydroxyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl. In certain embodiments, R represents independently for each occurrence halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, or C 1-6 haloalkoxyl. In certain embodiments, R? represents independently for each occurrence halo, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, or C 1-6 haloalkoxyl. In certain embodiments, R represents independently for each occurrence halo, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
  • R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence C 1-6 alkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R ? represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 1-6 haloalkoxyl.
  • R 5 is halo. In certain embodiments, R 5 is F. In certain embodiments, R 5 is cyano. In certain embodiments, R 3 is C 1-6 alkyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is C 1-6 haloalkyl. In certain embodiments, R 5 is -CF3. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 5 is C 1-6 alkoxyl. In certain embodiments, R 5 is -OMe. In certain embodiments, R 5 is C 1-6 haloalkoxyl. In certain embodiments, R 5 is selected from those disclosed in Table 1, below.
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, -(C0-2 alkylene)- (3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl, heterocycle, and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl, C 3-5 cycloalkyl, or phenyl, wherein the cycloalkyl is substituted with m instances of R 8 .
  • R 6 is C 1-4 alkyl. In certain embodiments, R 6 is /-butyl.
  • R 6 is C 3-5 cycloalkyl, substituted with m instances of R 8 . In certain embodiments, R 6 is cyclopropyl, substituted with m instances of R 8 . In certain embodiments, R 6 is phenyl. In certain embodiments, R 6 is -(C0-2 alkylene)-(3-7 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), substituted with m instances of R 8 . In certain embodiments, R 6 is -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 . In certain embodiments, R 6 is selected from those disclosed in Table 1, below.
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, or -(Co- 2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is C1.4 alkyl, C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)- (5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 3-5 cycloalkyl, phenyl, or -(C0-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, phenyl, or -(C0-2 alkylene)- (5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or -(Co-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cycloalkyl and heteroaryl are substituted with m instances of R 8 .
  • R 7 is hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, phenyl, wherein the cycloalkyl is substituted with m instances of R 8 .
  • R 7 is hydrogen. In certain embodiments, R 7 is C 1-4 alkyl. In certain embodiments, R 7 is /-butyl. In certain embodiments, R 7 is C 3-5 cycloalkyl, substituted with m instances of R 8 . In certain embodiments, R 7 is cyclopropyl, substituted with m instances of R 8 . In certain embodiments, R 7 is phenyl. In certain embodiments, R 7 is -(Co-2 alkylene)-(5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl is substituted with m instances of R 8 . In certain embodiments, R 7 is selected from those disclosed in Table 1, below.
  • R 8 represents independently for each occurrence Ci-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence halo, C 1-3 haloalkyl, hydroxyl, C1.4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, Ci-3 haloalkyl, hydroxyl, C1.4 alkoxy, cyano, or cyclopropyl.
  • R 8 represents independently for each occurrence C 1-4 alkyl, halo, hydroxyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C1.4 alkyl, halo, C 1-3 haloalkyl, C 1-4 alkoxy, cyano, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, cyano, or cyclopropyl.
  • R 8 represents independently for each occurrence C1.4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, or cyclopropyl. In certain embodiments, R 8 represents independently for each occurrence C 1-4 alkyl, halo, C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, or cyano.
  • R 8 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 8 represents independently for each occurrence halo. In certain embodiments, R 8 represents independently for each occurrence C 1-3 haloalkyl. In certain embodiments, R 8 represents independently for each occurrence C1.4 alkoxy.
  • R 8 is C 1-4 alkyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is C1.3 haloalkyl. In certain embodiments, R 8 is C 1-4 alkoxy. In certain embodiments, R 8 is cyano. In certain embodiments, R 8 is C 1-4 alkyl or C 1-3 haloalkyl. In certain embodiments, R 8 is selected from those disclosed in Table 1, below.
  • R 9 is hydrogen or C 1-3 alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C1.3 alkyl. In certain embodiments, R 9 is selected from those disclosed in Table 1, below.
  • L 1 is -N(R 9 )- or a bond. In certain embodiments, L 1 is - N(R 9 )-. In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is selected from those disclosed in Table 1, below. [0117] As defined generally above, A 1 is a 5-6 membered partially unsaturated or aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 is a 5 membered partially unsaturated or aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • a 1 is a 5 membered aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 is a 5 membered partially unsaturated ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 is a 5 membered partially unsaturated or aromatic ring containing 1 or 2 heteroatoms independently selected from nitrogen. In certain embodiments, A 1 is a 6 membered partially unsaturated or aromatic ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, A 1 is selected from those disclosed in Table 1, below.
  • B 1 is phenylene or a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen.
  • B 1 is phenylene.
  • B 1 is a 6-membered monocyclic heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen.
  • B 1 is pyridinylene, pyrimidylene, pyridazinylene, pyrazinylene, or phenylene.
  • B 1 is pyridinylene.
  • B 1 is pyrimidylene.
  • B 1 is pyridazinylene.
  • B 1 is pyrazinylene.
  • B 1 is phenylene.
  • B 1 is selected from those disclosed in Table 1, below.
  • m is 0, 1, or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 3. In certain embodiments, n is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. [0121] As defined generally above, o is 1, 2, or 3. In certain embodiments, o is 2 or 3. In certain embodiments, o is 1 or 2. In certain embodiments, o is 0. In certain embodiments, o is 1. In certain embodiments, o is 2. In certain embodiments, o is 1 or 3. In certain embodiments, o is 3. In certain embodiments, o is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • the compound of Formula 1-1 is further defined by Formula I- A or a pharmaceutically acceptable salt thereof
  • the compound is a compound of Formula I-A.
  • compound has the following formula or a pharmaceutically acceptable salt thereof
  • the compound of Formula 1-1 is further defined by Formula I- B, I-C, I-D, I-E, or I-F, or a pharmaceutically acceptable salt thereof
  • the compound is a compound of Formula I-B, I-C, I-D, I-E, or I-F.
  • the compound of Formula 1-1 is further defined by Formula I-
  • the compound is a compound of Formula I-G.
  • the compound of Formula 1-1 is further defined by Formula I-
  • the compound is a compound of Formula I-H, I-I, I-J, I-K, I- L, I-M, or I-N.
  • the compound of Formula 1-1 is further defined by Formula I- O, I-P, I-Q, or I-R, or a pharmaceutically acceptable salt thereof:
  • the compound is a compound of Formula I-O, I-P, I-Q, or I-
  • the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1.
  • the present invention provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.
  • the present invention provides a compound set forth in Table
  • the present invention provides a compound set forth in Table 1, above.
  • the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a method of treating a disorder in which enhanced ABC transporter function is of clinical benefit.
  • a disorder is one in which ABC transporter dysfunction is etiological for disease.
  • correction of one or more underlying mutations associated with ABC transporter dysfunction is rationalized.
  • methods of the present invention provide enhancement of one or more non-mutated forms of an ABC transporter.
  • the invention provides a method of treating a disorder in which enhanced ABC transporter function is of clinical benefit, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder in which enhanced ABC transporter function is of clinical benefit.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula l is a compound defined by one of the embodiments described in Section I, above.
  • the invention provides a method of treating a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.
  • the invention provides a method of treating a disorder described herein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder.
  • the present invention provides a method of alleviating one or more symptoms of a disorder associated with ABC transporter dysfunction, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the disorder associated with ABC transporter dysfunction.
  • a compound described herein such as a compound of Formula I
  • the particular compound of Formula l is a compound defined by one of the embodiments described in Section I, above.
  • the disorder associated with ABC transporter dysfunction is characterized by dysfunction in a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4 , ABCG5, ABCG8, ABCG1, and ABCG4.
  • a transporter selected from one or more of ABCA1, ABCA2, ABCA3, ABCA4, ABCA5, ABCA7, ABCA12, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, ABCB10, ABCB11, ABCC1, ABCC2, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC12, ABCD1, ABCD2, ABCD3, ABCD4 , ABCG5, ABCG8, ABCG1, and ABCG4.
  • the present invention provides methods of treating a disorder selected from Tangier disease, Surfactant metabolism dysfunction pulmonary 3, autosomal recessive Ichthyosis congenital 4A (ARCI), Bare lymphocyte syndrome type I, Bare lymphocyte syndrome type I due to TAP2 deficiency, Dyschromatosis universalis hereditaria 3, X-linked sideroblastic anemia with ataxia, Dubin-Johnson Syndrome, Cystic fibrosis (CF), Familial Hyperinsulinemic Hypoglycemia 1, Intellectual disability Myopathy Syndrome, Congenital bile acid synthesis defect 5, Methylmalonic aciduria and homocystinuria cblJ type, Sitostrolemia, Stargardt disease, PFIC3, PFIC2, Pseudoxanthoma Elasticum, X-linked adrenoleukodystrophy (ALD), Cholestasis, Hyperbilirubinemia, Intrahepatic cholestasis of pregnancy
  • ARCI autosomal
  • the disorder associated with ABC transporter dysfunction is cystic fibrosis (CF).
  • the present invention provides a method of treating cystic fibrosis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I. In some such embodiments, the method further comprises administering one or more additional therapeutic agents, described further below and herein.
  • the disorder associated with ABC transporter dysfunction is cholestasis.
  • the present invention provides a method of treating cholestasis, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I.
  • a compound described herein such as a compound of Formula I.
  • the cholestasis is intrahepatic.
  • the cholestasis is extrahepatic.
  • the cholestasis is any of those described above and herein.
  • Another aspect of the invention provides a method increasing the expression of a protein selected from ABCB11, ABCB11 E297G, ABCC6, ABCB4, ABCA4 P1380L, and ABCD2 in a subject, wherein the method comprises administering to a subject in need thereof an effective amount of a compound described herein, such as a compound of Formula I, to thereby increase expression of said protein.
  • the protein is ABCB 11. In certain embodiments, the protein is ABCB 11 E297G. In certain embodiments, the protein is ABCC6. In certain embodiments, the protein is ABCB4. In certain embodiments, the protein is ABCA4 P1380L. In certain embodiments, the protein is ABCD2.
  • the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as a disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as disorder associated with ABC transporter dysfunction. Exemplary such disorders are described above and herein.
  • Another aspect of the invention provides for combination therapy.
  • Compounds described herein such as a compound of Formula I, or other compounds in Section I
  • additional therapeutic agents such as an autoimmune disorder, cancer, etc.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and coadministering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.
  • the present invention provides a method of treating cystic fibrosis (CF) comprising administering a compound of the present invention with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are selected from a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a cystic fibrosis transmembrane conductance (CFTR) modulator, a nutritional agent, or any agent known to treat CF.
  • the one or more additional therapeutic agents is an S- nitrosoglutathione reductase (GSNOR) inhibitor.
  • GSNOR S- nitrosoglutathione reductase
  • the GSNOR inhibitor is selected from a GSNOR inhibitor disclosed in W02010/019903, U.S. Pat. No. 8,470,857, U.S. Pat. No.8,642,628, W02010/019910, U.S. Pat. No.8,586,624, WO2011/100433, U.S. Pat. No.US 8,481,590, W02012/048181, WO2012/083165, W02012/083171, or WO 2012/170371.
  • the one or more additional therapeutic agents is an ileal bile transport (IB AT) inhibitor.
  • the IBAT inhibitor is selected from an IBAT inhibitor disclosed in AU2011326873, US2020/0330545, WO2012/064266, W02020/167964, or Front. Pharmacol. 2018; 9: 931 (Al-Dury et al., published online August 21, 2018).
  • IBAT inhibitors include, but are not limited to odevixibat, elobixivat, maralixibat, linerixibat, GSK2330672, SHP626 (volixibat), A4250, etc.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • kits comprising a therapeutically effective amount of the compound described herein (such as a compound of Formula I, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary
  • terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as par
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be
  • 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 active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intraci sternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.
  • TAA trifluoroacetic acid
  • FFA formic acid
  • Mobile Phase A Water(10 mmol/L NH 4 HC0 3 +0.05%NH 3 H20), Mobile Phase B: ACN;
  • Mobile Phase A Water(10 mmol/L NH 4 HC0 3 +0.05%NH 3 H20), Mobile Phase B: ACN;
  • Wave Length UV 254nm and 220nm.
  • Mobile Phase A Water(0.1% FA), Mobile Phase B: ACN;
  • Mobile Phase A Water(10 mmol/L NH 4 HC03+0.05% NH3H2O), Mobile Phase B: ACN;
  • Mobile Phase A Water(10 mmol/L NH 4 HC03+0.05% NH3H2O), Mobile Phase B: ACN;
  • Step 2 To a solution of Int-1 (2.2 g, 5.46 mmol, 1.0 eq.) and 2-methylpropane-2- sulfonamide (748 mg, 5.46 mmol, 1.0 eq.) in dioxane (30 mL) were added CS2CO3 (5.33 g, 16.4 mmol, 3.0 eq.), BrettPhos Pd G3 (990 mg, 1.09 mmol, 0.2 eq.) and BrettPhos (880 mg, 1.64 mmol, 0.3 eq.). The resulting mixture was stirred at 110 °C for 16 h under N2. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step 3 A solution of Int-2 (1.0 g, 1.98 mmol, 1.0 eq.) in HC1 (cone.) / THF (10 mL/10 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in NH3.H2O (10 mL) and the resulting mixture was stirred at room temperature for 0.5 h whereupon, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Method 1) to afford Compound 1-16 (450 mg, 61%) as a white solid.
  • Step 1 To a solution of Int-1 (50 mg, 0.12 mmol, 1.0 eq.) and methanesulfonamide (12 mg, 0.12 mmol, 1.0 eq.) in dioxane (5 mL) were added CS2CO3 (78 mg, 0.24 mmol, 2.0 eq.), BrettPhos Pd G3 (990 mg, 24 pmol, 0.2 eq.) and BrettPhos (19 mg, 36 pmol, 0.3 eq ). The resulting mixture was stirred at 1 10 °C for 16 h under N2. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step 2 A solution of Int-3 (26 mg, 56 qmol, 1.0 eq.) in HC1 (con.) / THF (1 mL/1 mL) was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure the residue was dissolved in NH3.H2O (2 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by prep-HPLC (Method 1) to afford Compound 1-10 (10 mg, 53%) as a white solid.
  • Step 1 A mixture of 5-bromo-6-chloropyridin-2-amine (R-3, 3 g, 14.461 mmol, 1 equiv), cyclopropylboronic acid (2.48 g, 28.922 mmol, 2 equiv), Na2COs (3.07 g, 28.922 mmol, 2 equiv) and Pd(dppf)Ch (2.12 g, 2.892 mmol, 0.2 equiv) in THF (50 mL) and H2O (10 mL) was stirred for 16h at 80°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1) to afford Int-4 (2 g, 82.02%) as a brown solid.
  • Step 2 A mixture of Int-4 (100 mg, 0.593 mmol, 1 equiv), R-4 (prepared based on procedures in WO 2018/188047) (381.01 mg, 0.889 mmol, 1.5 equiv), Pd(PPh3)4 (137.06 mg, 0.119 mmol, 0.2 equiv) and Na2COs (125.71 mg, 1.186 mmol, 2 equiv) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was stirred for 4h at 100°C under N2 atmosphere. The mixture was allowed to cool down to RT.
  • Step 4 To a stirred solution of Int-6 (100 mg, 0.195 mmol, 1 equiv) in MeOH (1 mL) was added CS2CO3 (317.81 mg, 0.975 mmol, 5 equiv) at rt. The resulting reaction mixture was stirred at 50°C for Ih, then was concentrated under reduced pressure to give the crude product, which was purified by Prep-HPLC (Method 2) to afford Compound 1-20 (37.6 mg, 53.56%) as a white solid.
  • Step 3 A stirred solution of Int-8 (80 mg, 0.144 mmol, 1 equiv) in MeOH (1 mL) was treated with CS2CO3 (234.96 mg, 0.720 mmol, 5 equiv) at rt under N2 atmosphere. The reaction mixture was stirred at RT for 2 h, and then was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Method 3) to afford Compound 1-27 (18.7 mg, 32.15%) as a white solid.
  • Step 2 To a stirred solution of Int-9 (100 mg, 0.181 mmol, 1 equiv) in MeOH (1 mL) was added CS2CO3 (88.43 mg, 0.271 mmol, 1.5 equiv) at room temperature. The resulting reaction mixture was stirred at rt for 2 h, then was concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC (Method 4) to afford Compound 1-17 (20.5 mg, 28.40%) as a pink solid. NMR (400 MHz, DMSO-d6) 8 12.07 (s, 1H), 10.35 (s, 1H), 7.50
  • Step 1 To a stirred solution of 6H-thieno[2,3-c]pyridin-7-one (R-5, 1 g, 6.615 mmol, 1 equiv) in DMF (12 mL) was added NBS (1412.77 mg, 7.938 mmol, 1.20 equiv) dropwise at rt, and the resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was then diluted with water, then was extracted with EA (3 x 6mL). The combined organic layers were washed with brine (3xl0mL), and then dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH (20/1) to afford Int-10 (780 mg, 51.25%) as a yellow solid. LC-MS: M+H found: 231.9.
  • LC-MS LiHMDS
  • Step 5 To a stirred solution of Int-13 (230 mg, 0.796 mmol, 1 equiv) and Int-12 (371.03 mg, 1.274 mmol, 1.6 equiv) in dioxane (3 mL) and H2O (0.6 mL) were added K2CO3 (220.14 mg, 1.592 mmol, 2 equiv) and Pd(dppf)C12.CH2C12 (64.88 mg, 0.080 mmol, 0.1 equiv) in portions at rt, and the resulting reaction mixture was stirred at 80°C under N2 atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure.
  • K2CO3 220.14 mg, 1.592 mmol, 2 equiv
  • Pd(dppf)C12.CH2C12 64.88 mg, 0.080 mmol, 0.1 equiv
  • Step 1 A solution of Int-4 (500 mg, 2.965 mmol, 1 equiv) and cyclopropanesulfonyl chloride (2.08 g, 14.825 mmol, 5 equiv) in pyridine (5 mL) was stirred for 16 h at 50°C, whereupon the desired product could be detected by LCMS.
  • the reaction mixture was allowed to cool down to RT, then was concentrated under reduced pressure.
  • the resulting crude mixture was extracted with EA (3 x 8ml). The combined organic layers were washed with brine (2x10ml), and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product Int-14 was used in the next step directly without further purification.
  • LCMS: m/z 273 [M+H],
  • Step 2 A mixture of Int-14 (670 mg, 2.456 mmol, 1 equiv) and NaH (117.90 mg, 4.912 mmol, 2 equiv) in DMF (7 mL) was stirred for 1 h at RT. To the reaction mixture was then added Mel (383.53 mg, 2.702 mmol, 1.1 equiv) dropwise at RT. The resulting reaction mixture was stirred for an additional 1 h at RT, whereupon the desired product could be detected by LCMS. The reaction was then quenched with H2O at RT. The resulting crude reaction mixture was extracted with EA (3 x 10ml).
  • Step 3 To a stirred mixture of Int-15 (430 mg, 1 .499 mmol, 1 equiv) and R-4 (prepared based on procedures in WO 2018/188047) (963.35 mg, 2.248 mmol, 1.5 equiv) in THF (5 mL) and H2O (1 mL) were added Na2COa (317.85 mg, 2.998 mmol, 2 equiv) and XPhos Pd G3 (253.85 mg, 0.300 mmol, 0.2 equiv) in portions at RT under N2 atmosphere.
  • Step 1 To a solution of R-6 (300 mg, 1.47 mmol, 1.0 eq.) and phenylmethanethiol (219 mg, 1.76 mmol, 1.2 eq.) in toluene (10 mL) were added DIEA (569 mg, 4.41 mmol, 3.0 eq.), Pd(OAc)2 (24 mg, 147 pmol, 0.1 eq.) and XantPhos (170 mg, 294 pmol, 0.2 eq.). The resulting reaction mixture was stirred at 90 °C for 4 h, whereupon the reaction mixture was concentrated under reduced pressure.
  • Step 2 To a solution of Int-17 (210 mg, 0.84 mmol, 1.0 eq.) in H2SO4 (con. 5 mL) was added NaClO (1 mL, 20 wt% in H2O) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 1 h, whereupon the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step 3 To a solution of t-BuNEE (45 mg, 0.62 mmol, 1.0 eq.) and TEA (188 mg, 1.86 mmol, 3.0 eq.) in DCM (5 mL) was added Int-18 (140 mg, 0.62 mmol, 1.0 eq.) at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 0.5 h, whereupon the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Int-18 140 mg, 0.62 mmol, 1.0 eq.
  • Step 1 To a mixture of R-l (100 mg, 0.49 mmol, 1.0 eq.) and hexamethyldistannane (161 mg, 0.49 mmol, 1.0 eq.) in dioxane (2 mL) was added Pd(dppf)Ch (18 mg, 25 pmol, 0.05 eq.). The resulting reaction mixture was stirred at 100 °C for 48 h under N2, whereupon the reaction mixture was concentrated under reduced pressure to afford Int-21 (100 mg, quant.) as an oil, which was taken on to the next step without further purification.
  • LCMS (ESI): m/z 291 [M+H] + .
  • Step 2 To a solution of 5-bromo-7-methyl-l,7-naphthyridin-8(7H)-one (as prepared in J. Med. Chem. 2016, 59, 10, 4462-4475) (100 mg, 0.42 mmol, 1.0 eq.) and Int-21 (100 mg, crude) in dioxane (5 mL) were added Cui (16 mg, 84 pmol, 0.2 eq.) and CsF (255 mg, 1.68 mmol, 4.0 eq.). The resulting reaction mixture was stirred at 100 °C for 2 h under N2, whereupon the reaction mixture was concentrated under reduced pressure.
  • Step 3 To a solution of Int-22 (25 mg, 88 pmol, 1.0 eq.) and 2-methylpropane-2- sulfonamide (14 mg, 106 pmol, 1.2 eq.) in dioxane (2 mL) were added CS2CO3 (86 mg, 264 pmol, 3.0 eq.), BrettPhos Pd G3 (16 mg, 18 pmol, 0.2 eq.) and BrettPhos (14 mg, 26 pmol, 0.3 eq.). The resulting reaction mixture was stirred at 100 °C for 1 h under N2, whereupon the reaction mixture was concentrated under reduced pressure.
  • CS2CO3 86 mg, 264 pmol, 3.0 eq.
  • BrettPhos Pd G3 16 mg, 18 pmol, 0.2 eq.
  • BrettPhos 14 mg, 26 pmol, 0.3 eq.
  • Step 1 To a solution of Int-11 (50 mg, 0.21 mmol, 1.0 eq.) and Int-21 (50 mg, crude) in dioxane (2 mL) were added Cui (8 mg, 41 pmol, 0.2 eq.) and CsF (128 mg, 0.84 mmol, 4.0 eq.). The resulting mixture was stirred at 100 °C for 2 h under N2. After completion, the reaction mixture was concentrated under reduced pressure. Then the reaction mixture was concentrated under reduced pressure.
  • Step 2 To a solution of Int-23 (15 mg, 52 pmol, 1.0 eq.) and 2-methylpropane-2- sulfonamide (8 mg, 62 pmol, 1.2 eq.) in dioxane (2 mL) were added CS2CO3 (51 mg, 156 pmol, 3.0 eq.), BrettPhos Pd G3 (9 mg, 10 pmol, 0.2 eq.) and BrettPhos (8 mg, 16 gmol, 0.3 eq.). The resulting mixture was stirred at 100 °C for 1 hr under N2. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step 1 A mixture of R-l (500 mg, 2.422 mmol, 1 equiv) and (methyl sulfanyl) sodium (203.65 mg, 2.906 mmol, 1.2 equiv) in DMSO (5 mL) was stirred for 3h at RT. The resulting mixture was quenched with water (20 mL), extracted with EA (3 x 20 ml), and the combined organic layers were then washed with saturated brine (2x50 ml), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 A solution of Int-24 (330 mg, 1.900 mmol, 1 equiv) in DCM (3 mL) was treated with m-CPBA (2623.28 mg, 15.200 mmol, 8 equiv) in portions at RT. The resulting mixture was stirred for 3h at RT, whereupon the reaction was quenched by the addition of Na2SzO3 solution (20 ml) at RT. The resulting mixture was extracted with DCM (3 x 30 ml), and the combined organic layers were washed with saturated NaHCOa solution (2x30 ml), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 3 A mixture of Int-25 (150 mg, 0.729 mmol, 1 equiv), R-4 (374.87 mg, 0.875 mmol, 1.2 equiv), Pd(PPh.a)4 (168.57 mg, 0.146 mmol, 0.2 equiv) and Na2COs (154.61 mg, 1.458 mmol, 2 equiv) in dioxane (2 mL) and H2O (0.4 mL) was stirred for 2h at 80°C under N2 atmosphere. The reaction mixture was allowed to cool down to RT, then was extracted with EA (3 x 10 ml).
  • LCMS (ESI): m/z 318 [M+H] + .
  • Step 2 A mixture of Int-24 (150 mg, 0.688 mmol, 1 equiv), (acetyloxy )(phenyl)- lambda3-iodanyl acetate (664.55 mg, 2.064 mmol, 3 equiv) and ammonium carbamate (134.23 mg, 1.720 mmol, 2.5 equiv) in MeOH (2 mL) was stirred for 2h at room temperature under N2 atmosphere. The reaction mixture was then concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (eluted with DCM/MeOH (15: 1)) to afford Int-27 (130 mg, 92.36%) as a yellow oil.
  • LCMS (ESI): m/z 204 [M+H] + .
  • Step 3 A mixture of Int-27 (120 mg, 0.586 mmol, 1 equiv), R-2 (284.52 mg, 0.703 mmol, 1.2 equiv), Pd(PPh.3)4 (135.51 mg, 0.117 mmol, 0.2 equiv) and Na2COs (124.28 mg, 1.172 mmol, 2 equiv) in dioxane (2 mL) and H2O (0.4 mL) was stirred for 1.5 h at 80°C under N2 atmosphere.
  • Step 1 A mixture of R-7 (200 mg, 1.145 mmol, 1 equiv), R-2 (555.70 mg, 1.374 mmol, 1.2 equiv), Na2C0.3 (242.74 mg, 2.290 mmol, 2 equiv) and Pd(PPhs)4 (264.66 mg, 0.229 mmol, 0.2 equiv) in dioxane (5 mL) and H2O (1 mL) was stirred for 2 h at 80°C under N2 atmosphere. The mixture was then allowed to cool down to RT, then was extracted with EA (3 x 20 ml).
  • Step 2 A mixture of Int-29 (390 mg, 0.936 mmol, 1 equiv), (acetyloxy )(phenyl)- lambda3-iodanyl acetate (904.55 mg, 2.808 mmol, 3 equiv) and ammonium carbamate (182.71 mg, 2.340 mmol, 2.5 equiv) in MeOH (5 mb) was stirred for 2 h at RT under N2 atmosphere. The reaction mixture was then allowed to cool down to RT, and was extracted with EA (3 x 20 ml). The combined organic layers were washed with saturated brine (3x50 ml), dried over anhydrous ISfeSCU, and filtered.
  • Step 3 A stirred solution of Int-30 (380 mg, 0.849 mmol, 1 equiv) in DCM (3 mL) was treated with TFA (3 mL, 40.389 mmol, 47.58 equiv) dropwise at RT. The resulting reaction mixture was stirred for 2 h at RT, then was concentrated under reduced pressure to afford Int-31, which was then treated with NHs(g) in MeOH (3 mL, 7M). The resulting reaction mixture was stirred for 2 h at RT, then was concentrated under reduced pressure. The resulting crude residue was purified by prep-HPLC (Method 9) to provide Compound 1-99 (52.0 mg, 19.30%) as yellow solid.
  • ABCB11 E297G an assay for measuring the expression of the E297G variant of human ABCB11 (henceforth referred to as ABCB11 E297G) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCB1 1 E297G.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCB11 E297G by calculating an E max and EC 50 value.
  • HEK-293 cells stably expressing E297G (HEK-293/E297G cells) were used for this assay and were maintained at 37°C (5% CO 2 , humidified) in Eagle's Minimum Essential Medium supplemented with 10% fetal bovine serum and 1% Glutamine.
  • the HEK-293/E297G cells were seeded in black/transparent- bottom 384-well plates at 20,000 cells/well in 22.5 pl Opti-MEM (Thermofisher, product # 11058021) media supplemented with 2.7% of fetal bovine serum (Gibco, product # 16000044) and allowed to settle for 4 hours at 37°C (5% CO 2 , humidified).
  • Compound serial dilutions are prepared in Opti-MEM as four times (4x) the final concentration and using a dilution factor of 2.15. After the four h incubation period, 7.5 pL of the 4x dilutions are transferred to the assay plate.
  • Dose response curves include eight doses with the top final concentration at 25 ⁇ M in 0.75% DMSO.
  • Liquid handling is performed in a robotic device equipped with a 384-tip head (Analytik Jena - CyBio Vario). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO 2 , humidified). After the 24-hour treatment, plates are allowed to equilibrate for 30 minutes at room temperature. Using the Analytik Jena - CyBio Vario instrument, the volume of each well is reduced to 15 pl and 15 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added back to each well. The plates are incubated at room temperature for additional 30 minutes and luminescent signal is acquired using a Hamamatsu FDSS 7000 EX plate-reader (20 reads, exposure time 0.2 seconds, gain 200).
  • Results are presented below in Table 4 for ABCB11 E297G.
  • Compounds having an activity designated as "A” provided an ECso ⁇ l ⁇ M, E max >1.2; compounds having an activity designated as "B” provided an EC 50 1-10 ⁇ M, E m ax >1 2; compounds having an activity designated as "C” provided an EC 50 10-25 ⁇ M, E max >1.2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • Results are presented below in Table 5 for ABCB 11 WT.
  • Compounds having an activity designated as "A” provided an ECso ⁇ l ⁇ M, E max >1.2; compounds having an activity designated as "B” provided an ECso 1-10 ⁇ M, E m ax >1 2; compounds having an activity designated as "C” provided an EC 50 10-25 ⁇ M, E max >1.2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • Table 5
  • ABCC6 WT an assay for measuring the expression of the wild type of human ABCC6 (henceforth referred to as ABCC6 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCC6 WT.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCC6 WT by calculating an E max and EC 50 value.
  • HEK-293 cells transiently expressing ABCC6 WT (HEK-293/ABCC6 WT) were used for this assay and were cultured at 37°C (5% CO 2 , humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product #11965-092) supplemented with 10% fetal bovine serum.
  • DMEM Dulbecco's Modified Eagle Medium
  • HEK-293 cells were transfected with 4.5pg carrier DNA and 0.24 pg/10 cm plate of cDNA encoding HiBit-tagged ABCC6 wild-type using Lipofectamine 3000 (Thermo Fisher, product # L3000-015). Twenty -four hours after transfection, the HEK- 293/ABCC6 WT cells were seeded in white/opaque 384-well plates (Corning, product #3570) at 10,000 cells/well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO 2 , humidified). Compound serial dilutions are prepared in growth medium as ten times (lOx) the final concentration and using a dilution factor of 2. After the four-hour incubation period, 2.2 pL of the lOx dilutions are transferred to the assay plate.
  • lOx ten times
  • Dose response curves include eleven doses with the top final concentration at 30 ⁇ M in 0.3% DMSO.
  • Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO 2 , humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3050), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).
  • Results are presented below in Table 6 for ABCC6 WT.
  • Compounds having an activity designated as "A” provided an ECsoM ⁇ M, E m ax >1 2; compounds having an activity designated as “B” provided an EC 50 1-10 ⁇ M, E max >1.2; compounds having an activity designated as "C” provided an EC 50 10-25 ⁇ M, E m ax >1 2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • ABCB4 WT an assay for measuring the expression of the wild type of human ABCB4 (henceforth referred to as ABCB4 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCB4 WT.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCB4 WT by calculating an E max and EC 50 value.
  • HEK-293 cells stably expressing ABCB4 WT (HEK-293/ABCB4 WT) were used for this assay and were maintained at 37°C (5% CO 2 , humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product # 12100) supplemented with 10% fetal bovine serum (Biosera product # FB-1058/500), 1% PenStrep (HDB product # 15140-122), and 0.5 mg/mL puromycin (Gibco product # Al 1138-03).
  • DMEM Dulbecco's Modified Eagle Medium
  • Biosera product # FB-1058/500 fetal bovine serum
  • PenStrep HDB product # 15140-122
  • puromycin Gibco product # Al 1138-03
  • the HEK-293/ABCB4 WT cells were seeded in white/opaque 384-well plates (Corning product # 3570) at 10,000 cells/well in 20 ⁇ l growth medium and allowed to settle for 4 hours at 37°C (5% CO 2 , humidified).
  • Compound serial dilutions are prepared in DMSO as three hundred times (333x) the final concentration and using a dilution factor of 3 using Bravo (Agilent). After the four-hour incubation period, 60 nL of DMSO solutions are transferred to the assay plate.
  • Dose response curves include eleven doses with the top final concentration at 30 ⁇ M in 0.3% DMSO.
  • Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO 2 , humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 ⁇ l of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).
  • Results are presented below in Table 7 for ABCB4 WT.
  • Compounds having an activity designated as "A” provided an EC 50 ⁇ l ⁇ M, Em ax >1 .2; compounds having an activity designated as “B” provided an EC 50 1-10 ⁇ M, E m ax >1.2; compounds having an activity designated as "C” provided an EC 50 10-25 ⁇ M, E max >1.2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • ABCA4 P1380L an assay for measuring the expression of the P1380L variant of human ABCA4 (henceforth referred to as ABCA4 P1380L) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCA4 P1380L.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCA4 P1380L by calculating an E max and EC 50 value.
  • HEK-293 cells cells transiently expressing ABCD2 WT (HEK-293/ABCD2 WT) were used for this assay and were cultured at 37°C (5% CO 2 , humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product #11965-092) supplemented with 10% fetal bovine serum.
  • DMEM Dulbecco's Modified Eagle Medium
  • HEK-293 cells were transfected with 0.24 ⁇ g/10 cm plate of cDNA encoding HiBit-tagged ABCD2 wild-type using Lipofectamine 3000 (Thermo Fisher, product # L3000-015).
  • HEK-293/ABCD2 WT cells were seeded in white/opaque 384-well plates (Coming, product #3570) at 10,000 cells/well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO 2 , humidified).
  • Compound serial dilutions are prepared in growth medium as ten times ( 10x) the final concentration and using a dilution factor of 2. After the four-hour incubation period, 2.2 ⁇ L of the lOx dilutions are transferred to the assay plate.
  • Dose response curves include eleven doses with the top final concentration at 30 ⁇ M in 0.3% DMSO.
  • Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO 2 , humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).
  • Results are presented below in Table 8 for ABCA4 P1380L.
  • Compounds having an activity designated as "A” provided an ECsoM ⁇ M, E max >1.2; compounds having an activity designated as "B” provided an EC 50 1-10 ⁇ M, E max >L2; compounds having an activity designated as "C” provided an EC 50 10-25 ⁇ M, E m ax >1 2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • ABCD2 WT an assay for measuring the expression of the wild type of human ABCD2 (henceforth referred to as ABCD2 WT) and the use of this assay to measure the efficacy of compounds to increase the expression of ABCD2 WT.
  • the assay was designed to characterize the efficacy and potency of compounds to increase the expression of ABCD2 WT by calculating an E max and EC 50 value.
  • HEK-293 cells stably expressing ABCD2 WT (HEK-293/ABCD2 WT) were used for this assay and were maintained at 37°C (5% CO 2 , humidified) in Dulbecco's Modified Eagle Medium (DMEM, Gibco product # 12100) supplemented with 10% fetal bovine serum (Biosera product # FB-1058/500), 1% PenStrep (1TDB product # 15140-122), and 0.5 mg/mL puromycin (Gibco product # Al 1138-03).
  • DMEM Dulbecco's Modified Eagle Medium
  • Biosera product # FB-1058/500 fetal bovine serum
  • PenStrep (1TDB product # 15140-122
  • puromycin Gibco product # Al 1138-03
  • the HEK-293/ABCD2 WT cells were seeded in white/opaque 384-well plates (Corning product # 3570) at 10,000 cells/well in 20 pl growth medium and allowed to settle for 4 hours at 37°C (5% CO 2 , humidified).
  • Compound serial dilutions are prepared in DMSO as three hundred times (333x) the final concentration and using a dilution factor of 3 using Bravo (Agilent). After the four-hour incubation period, 60 nL of DMSO solutions are transferred to the assay plate.
  • Dose response curves include eleven doses with the top final concentration at 30 ⁇ M in 0.3% DMSO.
  • Liquid handling is performed with ECHO 550 Acoustic Liquid Handler (Labcyte). After addition of compound treatment, cells are incubated for 24 hours at 37°C (5% CO 2 , humidified). After the 24-hour treatment, plates are allowed to equilibrate to room temperature for 10 minutes. Using Dragonfly Automated Liquid Handler (TTP LabTech), 20 pl of HiBit lytic assay reagent (Promega, product # N3040), which is prepared according to manufacturer’s instructions, is added to each well. The plates are rotated at room temperature for 2 minutes and incubated for 1 hour at 25 °C before luminescent signal is acquired using an EnVision Multimode Plate Reader (PerkinElmer).
  • Results are presented below in Table 9 for ABCD2 WT.
  • Compounds having an activity designated as "A” provided an ECso ⁇ l ⁇ M, Em ax >1 .2; compounds having an activity designated as “B” provided an EC 50 1-10 ⁇ M, E max >1.2; compounds having an activity designated as "C” provided an ECso 10-25 ⁇ M, E max >1 2; compounds having an activity designated as "D” provided an EC 50 >25 ⁇ M, E max ⁇ 1.2.
  • Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment. Sci Rep 11, 19810. 10.1038/s41598-021 -99184- 1
  • ABCA1 is the cAMP -inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem 275, 34508-34511 .
  • Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 13, 340-347. 10.1038/nml546 53. Wang, N. et al. (2000) Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem 275, 33053- 33058. 10.1074/jbc.M005438200
  • liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem 280, 4079- 4088. 10.1074/jbc.M411420200

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Abstract

L'invention concerne des composés arylsulfonamide, des compositions pharmaceutiques et leur utilisation dans le traitement d'états médicaux.
PCT/US2024/029818 2023-05-18 2024-05-17 Composés arylsulfonamide et leur utilisation dans le traitement d'états médicaux Pending WO2024238871A1 (fr)

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EP1854792A1 (fr) * 2005-02-22 2007-11-14 Chugai Seiyaku Kabushiki Kaisha Dérivé de 1-(2h)-isoquinolone
WO2013097601A1 (fr) * 2011-12-30 2013-07-04 Abbvie Inc. Inhibiteurs de bromodomaine
WO2013132253A1 (fr) * 2012-03-07 2013-09-12 Institute Of Cancer Research: Royal Cancer Hospital (The) Composés 3-aryl -5-substitué-isoquinolin -1-one et leur utilisation thérapeutique
WO2013142390A1 (fr) * 2012-03-21 2013-09-26 Gtx, Inc. Inhibiteurs de la sous-famille 1c3 d'aldo-céto réductase (akr1c3)
WO2015058160A1 (fr) * 2013-10-18 2015-04-23 Quanticel Pharmaceuticals, Inc. Inhibiteurs de bromodomaine
WO2016139361A1 (fr) * 2015-03-05 2016-09-09 Boehringer Ingelheim International Gmbh Nouvelles pyridinones et isoquinolinones utilisées comme inhibiteurs du bromodomaine brd9

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EP1854792A1 (fr) * 2005-02-22 2007-11-14 Chugai Seiyaku Kabushiki Kaisha Dérivé de 1-(2h)-isoquinolone
WO2013097601A1 (fr) * 2011-12-30 2013-07-04 Abbvie Inc. Inhibiteurs de bromodomaine
WO2013132253A1 (fr) * 2012-03-07 2013-09-12 Institute Of Cancer Research: Royal Cancer Hospital (The) Composés 3-aryl -5-substitué-isoquinolin -1-one et leur utilisation thérapeutique
WO2013142390A1 (fr) * 2012-03-21 2013-09-26 Gtx, Inc. Inhibiteurs de la sous-famille 1c3 d'aldo-céto réductase (akr1c3)
WO2015058160A1 (fr) * 2013-10-18 2015-04-23 Quanticel Pharmaceuticals, Inc. Inhibiteurs de bromodomaine
WO2016139361A1 (fr) * 2015-03-05 2016-09-09 Boehringer Ingelheim International Gmbh Nouvelles pyridinones et isoquinolinones utilisées comme inhibiteurs du bromodomaine brd9

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Title
BENNETT MICHAEL J., WU YIQIN, BOLOOR AMOGH, MATUSZKIEWICZ JENNIFER, O'CONNELL SHAWN M., SHI LIHONG, STANSFIELD RYAN K., DEL ROSARI: "Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 28, no. 10, 1 June 2018 (2018-06-01), Amsterdam NL , pages 1811 - 1816, XP093241055, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.04.016 *
SHEPPARD, G.S. ET AL.: "Discovery of N-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)- 5-( 1-hydroay-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo [2,3-c]pyridine-2- carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 10, 2020, pages 5585 - 5623, XP055716907, DOI: 10.1021/acs.jmedchem.0c00628 *
THIRUPATAIAH, B. ET AL.: "CuCl2-catalyzed inexpensive, faster and ligand/additive free synthesis of isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy: Evaluation of a new class of compounds as potential PDE4 inhibitors.", BIOORGANIC CHEMISTRY, vol. 115, 2021, pages 105265, XP086782990, DOI: 10.1016/j.bioorg.2021.105265 *

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