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WO2025208012A1 - Molécules hétérobifonctionnelles pour lier nav1.8 et méthodes de traitement d'affections médicales les utilisant - Google Patents

Molécules hétérobifonctionnelles pour lier nav1.8 et méthodes de traitement d'affections médicales les utilisant

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Publication number
WO2025208012A1
WO2025208012A1 PCT/US2025/021987 US2025021987W WO2025208012A1 WO 2025208012 A1 WO2025208012 A1 WO 2025208012A1 US 2025021987 W US2025021987 W US 2025021987W WO 2025208012 A1 WO2025208012 A1 WO 2025208012A1
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Prior art keywords
compound
bond
pain
independently
certain embodiments
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PCT/US2025/021987
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English (en)
Inventor
Brandon James TURUNEN
Jeremy Roy DUVALL
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Solu Therapeutics Inc
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Solu Therapeutics Inc
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Publication of WO2025208012A1 publication Critical patent/WO2025208012A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention provides heterobifunctional cotinine-containing compounds, pharmaceutical compositions, and methods of using same to treat medical conditions, such as pain.
  • pain persists beyond its usefulness.
  • Such unnecessary suffering from pain can impair a subject’s physical mobility, mental performance, and even contribute to depression.
  • Such unnecessary suffering from pain can be due to acute pain and/or chronic pain.
  • Such pain can also be characterized according to whether the pain is neuropathic pain or nociceptive pain.
  • Substantial resources have been devoted over the years to researching the causes of various types of pain and to the development of medicine to attenuate pain experienced by a patient.
  • Exemplary classes of common pain-relief medications include opioids, non-steroidal anti- inflammatory agents, corticosteroids, and centrally acting agents such as anti -depressants and anti- epileptics.
  • existing therapies for treating pain are not effective for all patients and/or can have adverse side effects.
  • Voltage-gated sodium channel Na v 1.8 is expressed in the dorsal root ganglion, in unmyelinated, small-diameter sensory neurons called C-fibres, and is involved in nociception. Molecules that inhibit Na v 1.8 have been reported for treatment of pain. See, for example, P.T. Nguyen et al. in Front. Pharmacol. (2022) vol. 13, article 842032; Ruangsri et al. in J. Biol. Sciences (2011) vol. 286, pages 39,836-39,847; and US Patent Application Publication 2021/0387966.
  • Another aspect of the invention provides a collection of heterobifunctional cotinine- containing compounds represented by Formula II: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional cotinine- containing 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 heterobifunctional cotinine- containing compounds represented by Formula III: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional cotinine- containing 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 or preventing pain in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein such as a compound of Formula I, II, or III
  • an anti-cotinine antibody, or antigen-binding fragment thereof such as a compound of Formula I, II, or III
  • Another aspect of the invention provides a method of increasing antibody-dependent cell cytotoxicity (ADCC) of voltage-gated sodium channel Navl.8-expressing cells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • ADCC antibody-dependent cell cytotoxicity
  • Another aspect of the invention provides a method of depleting voltage-gated sodium channel Na v l 8-expressing cells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein such as a compound of Formula I, II, or III
  • Another aspect of the invention provides a combination comprising a heterobifunctional compound described herein (such as a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • 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.
  • 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 ort/zo-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.
  • 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 Ci-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-2/7-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci-s saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent Ci-s (or Ci-e) 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.
  • halogen means F, Cl, Br, or I.
  • 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
  • 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, 4// quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • 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, 3H -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.
  • R* is C1-6 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 C1-4 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.
  • 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, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, 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, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)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 or R configuration as defined by the IUPAC 1974 Recommendations.
  • 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 C1-C6 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 2 -methyl- 1 -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.
  • a cyclopentane susbstituted 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 H2O.
  • the terms “subject” and “patient” are used interchangeably 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.
  • 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.
  • X 1 is -(CH 2 CH2)-N(H)-'P, wherein T is a bond to L. In certain embodiments, X 1 is -(CH 2 )-N(H)- T, wherein 'P is a bond to L.
  • X 1 is a C5-10 bivalent saturated straight hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by -N(H)- or -O-. In certain embodiments, X 1 is -(C2-3 alkylene)-O-(C2-3 alkylene)-N(H)-T, wherein T is a bond to L.
  • X 1 is -(propylene)-O-(propylene)-N(H)- v P, -(CH 2 CH 2 )-O- (CH 2 CH 2 CH 2 )-N(H)-T, -(CH 2 CH 2 )-O-(CH 2 CH 2 )-N(H)-'P, or -(CH 2 )-N(H)-(CH 2 CH 2 )-O- (CH 2 CH 2 )-N(H)-'I / , wherein T is a bond to L.
  • X 1 is -(propylene)-O- (propylene)-N(H)- v P, wherein T is a bond to L.
  • X 1 is -(C1-3 alkylene)- N(H)-(C 2 -3 alkylene)-O-(C2-3 alkylene)-N(H)-T, wherein T is a bond to L.
  • X 1 is -(CH 2 )-N(H)-(CH 2 CH 2 )-O-(CH 2 CH 2 )-N(H)-'I', wherein 'P is a bond to L.
  • X 1 is -O-(C2-4 alkylene)-N(H)-'P or -O-(C2-3 alkylene)-O-(C2-6 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is -O-(C 2 -4 alkylene)-N(H)-'P, wherein T is a bond to L. In certain embodiments, X 1 is -O-(CH 2 CH 2 CH 2 )-N(H)- V P, wherein 'P is a bond to L. In certain embodiments, X 1 is -O-(C 2 -3 alkylene)-O-(C 2 -6 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is -O-(CH2CH 2 )-O-(CH 2 CH2CH2)-N(H)-'I ; , wherein T is a bond to L.
  • X 1 is -(C2-3 alkylene)-O-(C2-4 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is -(C ⁇ CFbJ-O-iCFhC ⁇ CFhJ-NfH)- 1 !', wherein T is a bond to L.
  • X 1 is a Ci-6 bivalent saturated straight hydrocarbon chain wherein (i) one or two methylene units of the chain are independently replaced by -N(H)-, - N(CHs)-, -O-, or -C(O)-, and (ii) one methylene unit of the chain is replaced by piperidinylene or piperazinylene.
  • X 1 is , wherein the piperazinyl nitrogen is attached to L.
  • X 1 is , wherein the piperidinyl nitrogen is attached to L.
  • X 1 is a covalent bond. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Tables 1 and 1-A, below.
  • X 2 is $-(Ci-5 alkylene)-N(H)- or a covalent bond, wherein $ is a bond to L.
  • X 2 is $-(Ci-s alkylene)-N(H)-.
  • X 2 is $-CH2CH2-N(H)-.
  • X 2 is $-C(H)(CH3)-N(H)-.
  • X 2 is a covalent bond.
  • X 2 is selected from the groups depicted in the compounds in Table 1, below.
  • X 2 is selected from the groups depicted in the compounds in Tables 1 and 1-A, below.
  • Y 1 is one of the following:
  • Y 1 certain embodiments, Y 1 is
  • Y 1 is
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is
  • Y 1 is In certain embodiments,
  • Y 1 is one of the following: [0098] In certain embodiments, certain embodiments, In certain embodiments, Y 1 is
  • Y 1 is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, Y 1 is selected from the groups depicted in the compounds in Tables 1 and 1-A, below.
  • R 2 is methyl
  • R 3 is trifluorom ethyl; and R 4 is methyl.
  • x is 0, and y is 0.
  • L 11 is a bond, C1.12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L 31 represents a covalent bond to NH
  • L 2 ' is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN
  • L 31 is a bond or -C(O)-; wherein Z 1 is C, CH, or N; each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N; L lj is -NH-,
  • L 2j is C1-6 linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L lj ; and I' represents a single bond or a double bond; wherein Ring A is phenylene or a 5- or 6- membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z 1 and Z 2 is independently CH or N; L lk is a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L 2k is a C3-8 straight chain alkylene or , wherein n is 1, 2, or 3, and represents a covalent bond to L lk ; (L-m) wherein Z 1 is CH or N; m is 1 or 2; p is 1 or
  • L lm is a bond, -C(O)-, - C(O)NH-, -NHC(O)-, -S(O) 2 NH-, or -NHS(O) 2 -; and L 2m is C3-6 linear alkylene, C3-6 *** cycloalkylene, or , wherein n is 1 or 2, and represents a covalent bond to
  • L lp is a bond, -C(O)-, - C(O)NH-, -NHC(O)-, -S(O) 2 -, -S(O) 2 NH-, or -NHS(O)2-; and L 2p is -(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-;
  • Ring C, and Ring D are each independently C4-6 cycloalkylene;
  • L lq and L 3q are each independently C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or - NR a -;
  • each R a is independently hydrogen or C1-3 alkyl;
  • L 2q and L 3q are each independently - O-, -NHC(O)-, or -CH2-O-; or
  • a and Ring B are each independently C4-6 cycloalkylene;
  • L la is C3-5 linear alkylene, wherein 1 or
  • each R a is independently hydrogen or C1-3 alkyl; and L is -O- or -CH2-O-; wherein represents a covalent bond to X , and represents a covalent bond to X 2 .
  • L is selected from the groups depicted in the compounds in Table 1, below. In certain embodiments, L is selected from the groups depicted in the compounds in Tables 1 and 1-A, below. Further description and embodiments for variable L are provided below in, for example, Part C.
  • the compound of Formula I is represented by Formula Ta or a pharmaceutically acceptable salt thereof: wherein the variables are as defined in embodiments described herein in connection with Formula I and L.
  • the compound is a compound of Formula la.
  • the compound of Formula I is represented by Formula lb or a pharmaceutically acceptable salt thereof: wherein the variables are as defined in embodiments described herein in connection with Formula I and L. In certain embodiments, the compound is a compound of Formula lb. [0136] In certain embodiments, the compound of Formula I is represented by Formula Ic or a pharmaceutically acceptable salt thereof: wherein the variables are as defined in embodiments described herein in connection with
  • the compound is a compound of Formula Ic.
  • R 2 and R 4 are independently C1-3 alkyl
  • R 3 is C1-3 haloalkyl
  • R 5 is C1-4 alkoxyl, -O-(C3-6 cycloalkyl), or C1-4 alkyl;
  • R 6 represents independently for each occurrence fluoro or chloro
  • R 7 , R 9 , and R 10 are independently hydrogen or C1.4 alkyl; or R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a 4 to 6 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted by 0, 1, or 2 substituents independently selected from C1-4 alkyl;
  • L 11 is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L 31 and represents a covalent bond to NH
  • L 21 is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN
  • L 31 is a bond or -C(O)-
  • Z 1 is C, CH, or N
  • each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N
  • L 1 ' is -NH-, -C(O)NH-, -NHC(O)-, or -O-
  • L 2 ' is Ci-6 linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L lj ; and II represents a single bond or a double bond;
  • the compound is a compound of Formula I*.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , x, y, z, and L is one of the embodiments described above in connection with Formula I. Additionally, further description and embodiments for variable L are provided below in, for example, Part C.
  • One aspect of the invention provides a compound represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein:
  • X 2 is cf>-(C 1-5 alkylene)-N(H)- or a covalent bond, wherein is a bond to L;
  • R 3 represents independently for each occurrence hydrogen, chloro, or fluoro
  • R 4 represents independently for each occurrence fluoro, chloro, C1-3 haloalkoxyl, C1.3 haloalkyl, -OH, Ci-4 alkoxyl, or C1-4 alkyl;
  • R 5 is hydrogen or C1-4 alkyl; each of which is substituted with 0 or 1 occurrence of C1-4 alkyl;
  • R 6 is
  • Y n is N or C(R 3 ). In certain embodiments, Y n is N. In certain embodiments, Y n is C(R 3 ). In certain embodiments, Y 11 is C(H). In certain embodiments, Y n is selected from the groups depicted in the compounds in Table 2, below. In certain embodiments, Y n is selected from the groups depicted in the compounds in Tables 2 and 2-A, below.
  • Z 11 is -O- or -CH2-.
  • Z n is -O-.
  • Z n is -CH2-.
  • Z n is selected from the groups depicted in the compounds in Table 2, below.
  • Z n is selected from the groups depicted in the compounds in Tables 2 and 2-A, below.
  • x is 1 or 2. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is selected from the values depicted in the compounds in Table 2, below. In certain embodiments, x is selected from the values depicted in the compounds in Tables 2 and 2-A, below.
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • Y 1 is one of the following:
  • the compound of Formula II is represented by Formula Ila or a pharmaceutically acceptable salt thereof: wherein the variables are as defined in embodiments described herein in connection with
  • R 111 ’ 1 represents independently for each occurrence halo
  • R 111 ’ 1 represents independently for each occurrence halo. In certain embodiments, R 111 ’ 1 represents independently for each occurrence chloro or fluoro. In certain embodiments, R 111 1 is chloro or fluoro. In certain embodiments, R 111 1 is chloro. In certain embodiments, R 111 ’ 1 is fluoro. In certain embodiments, R 111 ' 1 is selected from the groups depicted in the compounds in Table 3, below.
  • R IV ’ 3 if present, is hydrogen
  • R IX -l represents independently for each occurrence halo.
  • R R _1 represents independently for each occurrence fluoro or chloro.
  • R IV-1 is chloro.
  • R IV1 is selected from the groups depicted in the compounds in Table 4, below.
  • R IV2 , R IV-3 , R IV-4 , and R IV :5 are independently hydrogen or C1-4 alkyl; or R 1V ' 2 and R 1V ’ 3 or R 1V4 and R 1V ' 5 are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, or piperidinyl ring.
  • R IV ' 2 is hydrogen or Ci-4 alkyl. In certain embodiments, R IV ' 2 is hydrogen or -CH3. In certain embodiments, R IV ' 2 is hydrogen. In certain embodiments, R IV ' 2 is C1-4 alkyl. In certain embodiments, R IV ’ 2 is -CH3. In certain embodiments, R IV ' 2 is selected from the groups depicted in the compounds in Table 4, below.
  • R IV ' 3 is hydrogen or C1-4 alkyl. In certain embodiments, R IV ' 3 is hydrogen or -CH3. In certain embodiments, R IV-3 is hydrogen. In certain embodiments, R IV-3 is C1-4 alkyl. In certain embodiments, R IV ’ 3 is -CH3. In certain embodiments, R IV ’ 3 is selected from the groups depicted in the compounds in Table 4, below.
  • R IV ' 5 is hydrogen or C1.4 alkyl. In certain embodiments, R IV ' 5 is hydrogen or -CH3. In certain embodiments, R IV ’ 5 is hydrogen. In certain embodiments, R IV ' 3 is C1-4 alkyl. In certain embodiments, R IV ' 3 is -CH3. In certain embodiments, R IV ' 5 is selected from the groups depicted in the compounds in Table 4, below.
  • R 11 is a bond to X 1 .
  • R 11 replaces R IV ' 3 .
  • R 11 replaces R IV ' 5 .
  • R 11 occurs on the pyridine ring of Y 1 .
  • R 11 occurs on the phenyl ring of Y 1 .
  • the position of R 11 on Y 1 is selected from the positions depicted in the compounds in Table 4, below.
  • X 1 is -(C0-3 alkylene)-N(H)-'P or -(C2-3 alkylene)-O-(C 2 -3 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is -CH 2 -N(H)-'P, - (CH 2 ) 2 -N(H)-T, -(CH 2 ) 3 -N(H)-T, -(CH 2 )2-O-(CH 2 )2-N(H)-T, -(CH 2 )2-O-(CH 2 )3-N(H)-T, or - (CH 2 )3-O-(CH 2 )3-N(H)-T, wherein T is a bond to L.
  • X 1 is -(C0-3 alkylene)-N(H)-T, wherein T is a bond to L.
  • X 1 is -CH 2 -N(H)-T, - (CH 2 ) 2 -N(H)-T, or -(CH 2 )3-N(H)-T, wherein T is a bond to L.
  • X 1 is - (C2-4 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is - (CH2CH2CH2)-N(H)-T, wherein T is a bond to L.
  • X 1 is -(C2-3 alkylene)-O-(C 2 -3 alkylene)-N(H)-'P, wherein T is a bond to L.
  • X 1 is - (CH 2 ) 2 -O-(CH2)2-N(H)-T, -(CH 2 )2-O-(CH 2 )3-N(H)-T, or -(CH 2 ) 3 -O-(CH 2 )3-N(H)-T, wherein T is a bond to L.
  • X 1 is selected from the groups depicted in the compounds in Table 2, below. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Tables 2 and 2-A, below. Tn certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 3, below. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 4, below. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Tables 2, 2-A, 3, and 4, below.
  • X 2 is 4>-(C 1-5 alkylene)-N(H)- or a covalent bond, wherein (f> is a bond to L.
  • X 2 is $-(Ci-5 alkylene)-N(H)-.
  • X 2 is ⁇ -CH2CH2-N(H)-.
  • X 2 is ⁇
  • X 2 is a covalent bond.
  • X 2 is selected from the groups depicted in the compounds in Table 2, below.
  • X 2 is selected from the groups depicted in the compounds in Tables 2 and 2-A, below. In certain embodiments, X 2 is selected from the groups depicted in the compounds in Table 3, below. In certain embodiments, X 2 is selected from the groups depicted in the compounds in Table 4, below. In certain embodiments, X 2 is selected from the groups depicted in the compounds in Tables 2, 2-A, 3, and 4, below.
  • Y’-X 1 - is one of the following: [0220] In certain embodiments, Y ⁇ X 1 - is one of the following:
  • Y ⁇ X 1 - is one of the following:
  • Y ⁇ X 1 - is one of the following:
  • Y ⁇ X 1 - is selected from the groups depicted in the compounds in Table 2, below. In certain embodiments, Y ⁇ X 1 - is selected from the groups depicted in the compounds in Tables 2 and 2 -A, below. In certain embodiments, Y ⁇ X 1 - is selected from the groups depicted in the compounds in Table 3, below. In certain embodiments, Y’-X 1 - is selected from the groups depicted in the compounds in Table 4, below. In certain embodiments, Y ⁇ X 1 - is selected from the groups depicted in the compounds in Tables 2, 2-A, 3, and 4, below.
  • L is a divalent linker selected from:
  • L 4h is a bond, -C(O)-, -CH 2 C(O)-, or -C(O)CH 2 -; and m is 1, 2, or 3;
  • Ring C, and Ring D are each independently C4-6 cycloalkylene;
  • L lq and L 3q are each independently C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or - NR a -;
  • each R a is independently hydrogen or C1-3 alkyl;
  • L 2q and L 3q are each independently - O-, -NHC(O)-, or -CH2-O-; or
  • Ring A and Ring B are each independently C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L 3r is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein each represents a covalent bond to X 1 , and each represents a covalent bond to X 2 .
  • L is selected from the groups depicted in the compounds in Table 2, below. In certain embodiments, L is selected from the groups depicted in the compounds in Tables 2 and 2-A, below. In certain embodiments, L is selected from the groups depicted in the compounds in Table 3, below. In certain embodiments, L is selected from the groups depicted in the compounds in Table 4, below. In certain embodiments, L is selected from the groups depicted in the compounds in Tables 2, 2-A, 3, and 4, below. Further description and embodiments for variable L are provided below in, for example, Part C.
  • Another aspect of the invention provides a compound represented by Formula (II*): or a pharmaceutically acceptable salt thereof, wherein:
  • Y 1 is defined by Formula II- 1 that is substituted by one occurrence of R 11 , wherein
  • Formula II- 1 is represented by: wherein
  • R 4 represents independently for each occurrence fluoro, chloro, or Ci-4 alkyl
  • R 5 is hydrogen or C1-4 alkyl; occurrence of Ci-4 alkyl;
  • L is a divalent linker selected from:
  • L-c (L-c) wherein L lc is C2.10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L 2c is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • L-d is C 12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;
  • L 21 is a bond, C 1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN; and L 31 is a bond or -C(O)-; and Z ⁇ is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N; L lj is -NH-, -C(O)NH-, -NHC(O)-, or -O-; L 2 ' is Ci-6 linear alkylene or
  • variables in Formula II* 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 II*.
  • Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene
  • L lb is -CH2-NH-C(0)-, -NHC(O)-, or -C(O)NH-
  • L 2b is Ce-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR lb -, - wherein n is 1, 2, 3, or 4, and represents a covalent bond to L lb
  • each R lb is independently hydrogen or C1-3 alkyl
  • L-d is C 12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;
  • Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms
  • L lg is a bond, -CH2-, -NH-, or -O-
  • L 2g is wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L lg
  • each Z 1 is independently N or CH
  • L lh is a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-
  • L 2h is C2-10 linear alkylene > **** wherein n is 1, 2, 3, or 4, and represents a covalent bond to L lh and ’ represents a covalent bond to L 31 ’
  • L 311 is a bond, -C(O)CH2-, -O-(Cs-6 cycloalkylene)-O-, or -
  • L 4h is a bond, -C(O)-, -CH 2 C(O)-, or -C(O)CH 2 -; and m is 1, 2, or 3;
  • L 2j is Ci- 6 linear alkylene or , wherein n is 1 or 2, I I and represents a covalent bond to L 1 '; and I' represents a single bond or a double bond; wherein Ring A is phenylene or a 5- or 6- membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z 1 and Z 2 is independently CH or N; L lk is a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L 2k is a C3-8 straight chain alkylene ***
  • L lm is a bond, -C(O)-, -
  • L 2m is C3-6 linear alkylene, C3-6 cycloalkylene, or , wherein n is 1 or 2, and represents a covalent bond to
  • L-n-iv 0, 1, or 2 hydrogen atoms are replaced with F
  • L lp is a bond, -C(O)-, -C(O)NH- , -NHC(O)-, -S(O) 2 -, -S(O) 2 NH-, or -NHS(O)2-
  • L 2p is -(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-;
  • Ring C, and Ring D are each independently C4-6 cycloalkylene;
  • L lq and L 3q are each independently C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or - NR a -;
  • each R a is independently hydrogen or C1-3 alkyl;
  • L 2q and L 3q are each independently - O-, -NHC(O)-, or -CH2-O-; or
  • Ring A and Ring B are each independently C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L 3r is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein each represents a covalent bond to X 1 , and each represents a covalent bond to X 2 .
  • L 2f is a bond, -NHC(O)-, -C(O)NH-, or a Ci-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z 1 and Z 2 is independently N or CH; o (L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L lg is a bond, -CH 2 -, -NH-, or -O-; and L 2g is wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L lg ; wherein each Z 1 is independently N or CH; L lh is a bond, -C(O)-, -C(O)-NH-, or -NHC(O)
  • n 1, 2, 3, or 4
  • • represents a covalent bond to L lh and ’ represents a covalent bond to L 3h
  • L 3h is a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -
  • L 411 is a bond, -C(O)-, -CH 2 C(O)-, or -C(O)CH 2 -; and m is 1, 2, or 3; , , , , , , nd to L 31 and represents a covalent bond to NH; L 2 ' is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN; and L 31 is a bond or -C(O)-; wherein Z 1 is C, CH, or N; each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N; L lj is -NH-,
  • L 2j is Ci-6 linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L lj ; and I' represents a single bond or a double bond; wherein Ring A is phenylene or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z 1 and Z 2 is independently CH or N; L lk is a bond, -C(O)-, -C(O)NH- or -NHC(O)-; and L 2k is a C3-8 straight chain alkylene or , wherein n is 1, 2, or 3, and represents a covalent bond to L lk ; (L-m) wherein Z 1 is CH or N; m is 1 or 2; p is 1 or
  • L-n-iv (L-n-iv); or , , , C(O)NH-, -NHC(O)-, -S(O)2NH- or -NHS(O)2-; and L 2p is -(4-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen oxygen, and sulfur)-C(O))-;
  • L la of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 NH-, - (CH 2 ) 3 NH-, -(CH 2 ) 4 NH-, -(CH 2 ) 2 NHCH 2 -, -(CH 2 ) 3 NHCH 2 -, -(CH 2 ) 2 NH(CH 2 ) 2 -, -CH 2 NHCH 2 -, - CH 2 NH(CH 2 ) 2 -, -CH 2 NH(CH 2 ) 3 -, -CH 2 NHCH 2 NH-, or -CH 2 NHCH 2 NHCH 2 -.
  • L lb is -CH 2 -NH-C(O)-, -NHC(O)-, or -C(O)NH-;
  • L 2b is C 6 -12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR lb -, - C(O)NR lb -, or -NR lb C(O)-; or
  • L 2b is , wherein n is 1, 2, 3, or 4, and represents a covalent bond to L lb ; and each R lb is independently hydrogen or C1-3 alkyl; h wherein represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • L is a divalent linker of Formula (L-b-i): )NH-;
  • L 2b is C 6 -12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR lb -, - C(O)NR lb -, or -NR lb C(O)-; or
  • L 2b of Formula (L-b) or (L-b-i) is selected from ; wherein: j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the sum of j and k is 5, 6, 7, 8, 9, 10, or 11; q is 1, 2, 3, 4, 5, 6, 7, 8, or 9; r is 1, 2, 3, 4, 5, 6, 7, 8, or 9; s is O, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of q, r, and s is 4, 5, 6, 7, 8, 9, or 10; t is 1, 2, 3, 4, 5, 6, or 7; u is 1, 2, 3, 4, 5, 6, or 7; v is 1, 2, 3, 4, 5, 6, or 7; w is 0, 1, 2, 3, 4, 5, or 6; the sum of t, u, v, and w is 3, 4, 5, 6, 7, 8, or 9; a is 1, 2, 3, 4, or 5; b is 1, 2, 3, 4, or 5; c is 1, 2, 3, 4, or 5; d is 1, 1, 2, 3, 4, or 5;
  • X 1A X 2A , X 3A , and X 4A are independently -O-, -NR lb -, -C(O)NR lb -, or -NR lb C(O)-; and each R lb is independently hydrogen or C1-3 alkyl;
  • L is a divalent linker of Formula (L-b) selected from the group consisting of: .
  • the point of attachment indicated on the cycloalkyl-bound carbonyl group is the attachment point to X 1 .
  • L is divalent linker of Formula (L-c): wherein:
  • L lc is C 2 -10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene
  • L 2C is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; _ wherein represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • Ring A of Formula (L-c) is
  • L is a divalent linker of Formula (L-c-i): wherein:
  • L lc is C 2 -10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • L 2e is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • L lc of Formula (L-c) or (L-c-i) is selected from j is 1, 2, 3, 4, 5, 6, 7, 8, or 9; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of j and k is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 1, 2, 3, 4, 5, 6, or 7; r is 1, 2, 3, 4, 5, 6, or 7; s is 0, 1, 2, 3, 4, 5, or 6; the sum of q, r, and s is 2, 3, 4, 5, 6, 7, or 8; t is 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, or 5; v is 1, 2, 3, 4, or 5; w is 0, 1, 2, 3, or 4; the sum of t, u, v, and w is 3, 4, 5, 6, or 7; and
  • L is a divalent linker of Formula (L-c) selected from the group consisting of:
  • L is a divalent linker of Formula (L-d): wherein:
  • L ld is C 12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;
  • L is a divalent linker of Formula (L-e): wherein: n is an integer of 3 to 50; wherein » represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • L lf is a bond; Ci-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH- , or -C(O)-; or -(C3-6 cycloalkylene)-NHC(O)-;
  • L is selected from the group consisting of: attachment indicated on the carbonyl group is the attachment point to X 1 .
  • L 2g is wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L lg ; _ wherein represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • L lh is a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-;
  • L 211 is C2-10 linear alkylene or , wherein n is 1, 2, 3, or 4, and represents a covalent bond to L lh and represents a covalent bond to L 311 ;
  • L 3h is a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-;
  • L is a divalent linker of Formula (L-h) selected from the group consisting of:
  • the point of attachment indicated on the carbonyl group or cyclic group is the attachment point to X 1 .
  • L 11 is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L 31 and represents a covalent bond to NH;
  • L 21 is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN;
  • L 31 is a bond or -C(O)-; _ wherein represents a covalent bond to X 1 , and represents a covalent bond to X 2 .
  • L is a divalent linker of Formula (L-i) selected from the group consisting of: In certain embodiments, the point of attachment indicated on the carbonyl group is the attachment point to X 1 . [0282] In certain embodiments, L is divalent linker of Formula (L-j): each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N;
  • L lj is -NH-, -C(O)NH-, -NHC(O)-, or -O-;
  • L 2 ' is Ci-6 linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L lj ;
  • L is a divalent linker of Formula (L-j) selected from the group consisting of: .
  • the point of attachment indicated on the carbonyl group is the attachment point to X 1 .
  • L is a divalent linker of Formula (L-q-i): L 3q, L 4q, — , and — are as defined for Formula (L-q); and each p and m is independently for each occurrence 1 or 2.
  • step 1 of Scheme 1-1 P-keto ester 1 is converted to a-diazo keto compound 2 via diazo transfer from a diazo transfer agent.
  • the diazo transfer agent is / -ABSA (4-acetamidobenzenesulfonyl azide).
  • the diazo transfer may be achieved under basic conditions (e.g., 1.2 eq. /?-ABSA, 1.5 eq. EtsN, CH3CN, 0 °C to RT, 8 h).
  • step 2 a-diazo keto compound 2 is converted into silyl enol ether intermediate A by treatment with TMSOTf (e.g., 1.2 eq. TMSOTf, 1.4 eq.
  • step 3 silyl enol ether intermediate A is reacted with trifluoromethyl acetone 3 under Lewis Acid conditions (e.g, 1.5 eq. 3, 1.5 eq. TiCL, DCM, -78 °C, 2 h) to provide diazo alcohol 4.
  • step 4 diazo alcohol 4 is cyclized with Rh(OAc)2 (e.g., toluene, 100 °C, 30 min) to provide a racemic mixture of P-keto ester tetrahydrofuranyl compound 5.
  • Rh(OAc)2 e.g., toluene, 100 °C, 30 min
  • step 5 the P-keto ester tetrahydrofuranyl compound 5 is reacted with triflic anhydride (e.g., Tf O, DIPEA, DCM, -78 °C, 1.5 h) to form silyl enol ether intermediate B.
  • silyl enol ether intermediate B is reacted with aryl boronic ester 6 under Suzuki coupling conditions (e.g, Pd(PPha)4, K3PO4, toluene, 100 °C, 2 h) to provide aryl substituted dihydrofuran compound 7.
  • Suzuki coupling conditions e.g, Pd(PPha)4, K3PO4, toluene, 100 °C, 2 h
  • step 7 removal of the methyl ether from compound 7 (e.g., BBr?, DCM, 0 °C to RT, 2h) and cyclization (TFA, DCM, 45 °C, 12 h) provides a racemic mixture of tricyclic compound 8.
  • step 8 reductive hydrogenation of compound 8 (e.g., Pd(OH)2/C, 40 psi H2, MeOH, RT, 24 h) provides phenoxy-substituted tetrahydrofuran compound 9.
  • step 9 equilibration of phenoxy-substituted tetrahydrofuran compound 9 under basic conditions (e.g, KO-/Bu, THF, RT, 2 h) results in formation of the more favorable epimer and hydrolysis of the methyl ester to provide phenoxy carboxylic acid 10.
  • phenoxy carboxylic acid 10 is dimethylated (e.g, CH3I, K2CO3, CH3CN, RT, 12 h) to form anisole methyl ester 11.
  • saponification of anisole methyl ester 11 e.g., LiOH, H2O, MeOH, 12 h
  • step 12 carboxylic acid intermediate C is converted to amide intermediate 13 by reaction with amino pyridinyl methyl ester 12 (e.g, oxalyl chloride, DCM, DMF, EtsN).
  • amino pyridinyl methyl ester 12 e.g, oxalyl chloride, DCM, DMF, EtsN.
  • amide intermediate 13 may be purified (e.g., via supercritical fluid chromatography or SFC) if desired.
  • step 13 amide intermediate 13 is saponified (e.g, LiOH, H2O, MeOH, RT, 8 h) to provide pyridinyl carboxylic acid compound 14.
  • step 14 pyridinyl carboxylic acid compound 14 is converted to amide 15 by reaction with mono-protected a,co- diamino compound 16 (e.g, HATU, DIPEA) followed by BOC deprotection (e.g, HC1, dioxane).
  • mono-protected a,co- diamino compound 16 e.g, HATU, DIPEA
  • BOC deprotection e.g, HC1, dioxane
  • amide 15 is reacted with (17?,4r)-4-(4-(((15',4A)-4-(2-((25',35)-l- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-l-carboxylic acid 17 (e.g., HATU, DIPEA) to form compound 18.
  • 17 e.g., HATU, DIPEA
  • step 1 of Scheme 1-2 silyl enol ether intermediate B, which may be synthesized as described above in reference to Scheme 1-1, is reacted with aryl boronic ester 19 under Suzuki coupling conditions (e.g., Pd(PPh3)4, K3PO4, toluene, 100 °C, 6 h) to provide aryl substituted dihydrofuran compound 20.
  • Suzuki coupling conditions e.g., Pd(PPh3)4, K3PO4, toluene, 100 °C, 6 h
  • step 2 hydrogenation of aryl substituted dihydrofuran compound 20 (e.g., Pd(OH)2/C, 60 psi H2, EtOH, RT, 24 h) provides aryl-substituted tetrahydrofuran compound 21.
  • step 5 ammonolyis of pyridinyl methyl ester-amide intermediate 23 (e.g., 7N NH3, MeOH) provides BOC-protected pyridinyl amide 24.
  • BOC-protected pyridinyl amide 24 may be purified (e.g., via SFC) if desired.
  • step 6 BOC-protected pyridinyl amide 24 is deprotected (e.g., TFA, DCM, RT) to form amino compound 25.
  • step 7 amino compound 25 is reacted with (lA,4r)-4-(4-(((lS,4A)-4-(2-((25,35 Y )-l-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy) cyclohexyl)oxy) butanamido) cyclohexane-1 -carboxylic acid 17 (e.g, HATU, DMF, RT) to form the compound 26.
  • (lA,4r)-4-(4-(((lS,4A)-4-(2-((25,35 Y )-l-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy) cyclohexyl)oxy) butanamido) cyclohexane-1 -carboxylic acid 17 e.g, HATU, DMF, RT
  • step 1 of Scheme 1-3 ammonolyis (e.g., 7N NH3, MeOH, RT, 12 h) of amide intermediate 13, which may be synthesized as described above in reference to Scheme 1-1, provides pyridinyl amide compound 27.
  • pyridinyl amide compound 27 is converted to amino compound 28 by (a) converting the methyl ether to a phenol (e.g, BBn), (b) performing a Mitsunobu reaction with a BOC-protected alcohol (e.g., PPh3, DEAD), and (c) removing the BOC protecting group (e.g., HC1, dioxane).
  • a BOC-protected alcohol e.g., PPh3, DEAD
  • step 3 amino compound 28 is reacted with (17?,4r)-4-(4-(((l ⁇ S',4J?)-4-(2-((25,35)-l-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane- 1 -carboxylic acid 17 (e.g., HATU, DIPEA, DMF, RT) to form compound 29.
  • 17 e.g., HATU, DIPEA, DMF, RT
  • step 5 amino compound 33 is reacted with (17?,4r)-4-(4-(((lS,47?)-4-(2-((25,3 ) )-l-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy) butanamido) cyclohexane- 1 -carboxylic acid 17 (e.g, HATU, DMF, RT) to form the compound 34.
  • 17 e.g, HATU, DMF, RT
  • step 1 of Scheme 2-1 trifluoromethyl-substituted pyridinyl carboxylic acid 35 is reacted with imino-sulfanone 36 (e.g., HATU, DIPEA) to form amide intermediate 37.
  • imino-sulfanone 36 e.g., HATU, DIPEA
  • step 2 amide intermediate 37 is converted to alkyl amino compound 39 by (a) converting the methyl ether to a phenol (e.g., BBn, DCM), (b) performing a Mitsunobu reaction with a pthalamide- protected amine compound 38 (e.g., PPhs, DEAD), and (c) removing the pthalamide protecting group (e.g., hydrazine).
  • step 1 of Scheme 3-3 compound 59 is coupled with compound 60 under standard peptide coupling conditions (e.g., HATU, DIPEA, DMF) to give compound 61.
  • compound 61 is coupled to compound 62 using SxAr conditions (e.g., potassium carbonate, DMF) to give compound 63.
  • SxAr conditions e.g., potassium carbonate, DMF
  • compound 63 is subjected to demethylation conditions (e.g., BBrs) followed by an O-alkylation using compound 65 (e.g., CH3CN, heat) to give compound 66.
  • step 5 compound 66 is oxidized (e.g., m-CPBA) to give V-oxide 67.
  • an antibody, or antigen-binding fragment thereof that binds to a cotinine moiety.
  • the term “anti-cotinine antibody or antigen-binding fragment thereof’ refers to an antibody, or antigen binding fragment thereof that binds to a cotinine moiety.
  • Cotinine has the following structure:
  • the term “cotinine moiety” refers to cotinine or an analog of cotinine.
  • Compounds of Formula (I) and (II) described herein comprise a cotinine moiety linked via a linker to a Na v l .8-binding moiety.
  • the cotinine moiety has the following structure: wherein R 1 is Ci-4 alkyl or C3.6 cycloalkyl.
  • R 1 is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, or t-butyl.
  • R 1 is methyl.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • antibody is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, 23(9): 1126-1136).
  • DAB domain antibody
  • the term, full, whole or intact antibody refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons.
  • An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment.
  • the Fab fragment is composed of the variable domain at the amino- terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CHI (heavy) and CL (light).
  • the Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions.
  • the Fc may elicit effector functions by binding to receptors on immune cells or by binding Clq, the first component of the classical complement pathway.
  • the five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, e and 5 respectively, each heavy chain can pair with either a K or X light chain.
  • the majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgGl, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antibody or antigen binding fragment thereof. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • variable domain sequences and variable domain regions within full-length antigen binding sequences are numbered according to the Kabat numbering convention.
  • CDR the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention.
  • Kabat et al. Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).
  • Table 3 represents one definition using each numbering convention for each CDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used.
  • the anti-cotinine antibody is humanized.
  • the Fc region of the anti-cotinine antibody is modified to increase ADCC activity, ADCP activity, and/or CDC activity, suitable modifications of which are provided below.
  • the Fc region of the anti-cotinine antibody is modified to increase ADCC activity.
  • Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to Clq or Fey receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (neonatal Fc receptor).
  • effector function refers to one or more of antibody- mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody- mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody dependent complement- mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • DCP complement-dependent cell-mediated phagocytosis
  • ADCML antibody dependent complement- mediated cell lysis
  • FcR Fc receptors
  • FcR Fc receptors
  • FcyRI CD64
  • FcyRII CD32
  • FcyRIII CD 16
  • FcRn FcRn
  • Clq type II Fc receptors
  • Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcyRIII, or monocytes/macrophages via FcyRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via Clq.
  • NK Natural Killer
  • an antibody, or antigen binding fragment thereof, of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay.
  • Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.
  • amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences are numbered according to the EU index numbering convention.
  • Enhanced CPC Fc engineering can be used to enhance complement-based effector function.
  • K326W/E333S; S267E/H268F/S324T; and IgGl/IgG3 cross subclass can increase Clq binding; E345R (Diebolder et al., Science, 2014, 343: 1260-1293) and E345R/E430G/S440Y results in preformed IgG hexamers (Wang et al., Protein Cell, 2018, 9(1): 63-73).
  • N325S/L328F increases FcyRIIa binding and decreases FcyRIIIa binding Wang et al., Protein Cell, 2018, 9(1): 63-73).
  • the chimeric antibody, or antigen binding fragment thereof comprises an IgGl CHI domain, an IgG3 CH2 domain, and an IgG3 CH3 domain. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgGl CHI domain, an IgG3 CH2 domain, and an IgG3 CH3 domain except for position 435 that is histidine.
  • Such methods for the production of antibody, or antigen binding fragment thereof, with chimeric heavy chain constant regions can be performed, for example, using the COMPLEGENT technology system available from BioWa, Inc. (Princeton, NJ) and Kyowa Hakko Kirin Co., Ltd.
  • the COMPLEGENT system comprises a recombinant host cell comprising an expression vector in which a nucleic acid sequence encoding a chimeric Fc region having both IgGl and IgG3 Fc region amino acid residues is expressed to produce an antibody, or antigen binding fragment thereof, having enhanced CDC activity, i.e.
  • Also provided is a method of producing an antibody, or antigen binding fragment thereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleic acid encoding the antibody, or antigen binding fragment thereof, optionally wherein the FUT8 gene encoding alpha- 1 ,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof.
  • Such methods for the production of an antibody, or antigen binding fragment thereof can be performed, for example, using the POTELLIGENT technology system available from BioWa, Inc. (Princeton, NJ) in which CHOK1SV cells lacking a functional copy of the FUT8 gene produce monoclonal antibodies having enhanced ADCC activity that is increased relative to an identical monoclonal antibody produced in a cell with a functional FUT8 gene as described in US Patent No. 7,214,775, US Patent No. 6,946,292, WO 00/61739 and WO 02/31240, all of which are incorporated herein by reference. Those of ordinary skill in the art will also recognize other appropriate systems.
  • an antibody, or antigen binding fragment thereof comprising a heavy chain constant region that comprises a both a mutated and chimeric heavy chain constant region, individually described above.
  • an antibody, or antigen binding fragment thereof comprising at least one CH2 domain from IgG3 and one CH2 domain from IgGl, and wherein the IgGl CH2 domain has one or more mutations at positions selected from 239, 332 and 330 (for example the mutations may be selected from S239D, I332E and A330L), such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g.
  • the IgGl CH2 domain has the mutations S239D and I332E. In certain embodiments, the IgGl CH2 domain has the mutations S239D, A330L, and I332E.
  • the anti-cotinine antibody, or antigen binding fragment thereof comprises a heavy chain CDR1 having SEQ ID NO: 1, a heavy chain CDR2 having SEQ ID NO: 2, a heavy chain CDR3 having SEQ ID NO: 3, a light chain CDR1 having SEQ ID NO: 4, a light chain CDR2 having SEQ ID NO: 5, and a light chain CDR3 having SEQ ID NO: 6.
  • the compound and the antibody, or antigen-binding fragment thereof are present as a combination in a molar ratio of compound to antibody, or antigen- binding fragment thereof, of about 2:1, about 1.8:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.8, about 1:2, about 2:1 to about 1.5:1, about 1.5:1 to about 1.2:1, about 1.2:1 to about 1:1, about 1 : 1 to about 1:1.2, about 1 : 1.2 to about 1:1.5, or about 1 : 1.5 to about 1 :2.
  • the compound and the antibody, or antigen-binding fragment thereof are administered at a dosage of compound of 0.0001 mg/kg to 1 mg/kg and antibody of 0.01 mg/kg to 100 mg/kg.
  • the compound is administered at a dosage of about 0.0001 mg/kg to about 0.0002 mg/kg, about 0.0002 mg/kg to about 0.0003 mg/kg, about 0.0003 mg/kg to about 0.0004 mg/kg, about 0.0004 mg/kg to about 0.0005 mg/kg, about 0.0005 mg/kg to about 0.001 mg/kg, about 0.001 mg/kg to about 0.002 mg/kg, about 0.002 mg/kg to about 0.003 mg/kg, about 0.003 mg/kg to about 0.004 mg/kg, about 0.004 mg/kg to about 0.005 mg/kg, about 0.005 mg/kg to about 0.01 mg/kg, about 0.01 mg/kg to about 0.02 mg/kg, about 0.02 mg/
  • the compound and the antibody, or antigen-binding fragment thereof are administered in a molar ratio and/or dosage as described herein once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks for a period of one week to one year, such as a period of one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months.
  • One aspect of the invention provides a method of treating or preventing a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (e.g., a compound of Formula I or II, or a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein e.g., a compound of Formula I or II, or a compound of Formula I, II, or III
  • Another aspect of the invention provides a method of treating or preventing a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I or II, or a compound of Formula I, II, or III) and an anti- cotinine antibody, or antigen-binding fragment thereof, wherein the disease or condition is selected from pain, cough, acute itch, or chronic itch.
  • a heterobifunctional compound described herein such as a compound of Formula I or II, or a compound of Formula I, II, or III
  • an anti- cotinine antibody, or antigen-binding fragment thereof wherein the disease or condition is selected from pain, cough, acute itch, or chronic itch.
  • Another aspect of the invention provides a method of treating or preventing pain in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I or II, or a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein such as a compound of Formula I or II, or a compound of Formula I, II, or III
  • the method is to treating pain. In certain embodiments, the method is to preventing pain.
  • the pain is chronic pain. In certain embodiments, the pain is acute pain. In certain embodiments, the pain is neuropathic pain. In certain other embodiments, the pain is inflammatory pain. In certain embodiments, the pain is arthritis pain. In certain embodiments, the pain is arthritis pain selected from osteoarthritis pain and rheumatoid arthritis pain.
  • the pain is pain due to cancer.
  • the pain is due to a cancer selected from the group consisting of a solid tumor, leukemia, and lymphoma.
  • the pain is due to a cancer selected from the group consisting of a bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, and uterine cancer.
  • the pain is complex regional pain syndrome. In certain embodiments, the complex regional pain syndrome is reflex sympathetic dystrophy pain. In certain other embodiments, the pain is trauma pain. In certain embodiments, the pain is due to surgery. [0397] In certain other embodiments, the pain is located in the patient’s hand, wrist, arm, shoulder, back, leg, knee, ankle, foot, toe, neck, or head. In certain embodiments, the pain is low back pain. In certain embodiments, the pain is chronic low back pain.
  • the pain is a neuropathic pain selected from the group consisting of low back pain, hip pain, leg pain, non-herpetic neuralgia, post-herpetic neuralgia, diabetic neuropathy pain, lumbosacral radiculopathy pain, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma pain, phantom limb pain, multiple sclerosis pain, root avulsion pain, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury pain, post-surgical pain, carpal tunnel syndrome pain, trigeminal neuralgia pain, post mastectomy syndrome pain, post-thoracotomy syndrome pain, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, drug-induced pain, toxin-caused nerve injury pain, chemotherapy-caused nerve injury pain, and combinations thereof.
  • AIDS acquired immune deficiency syndrome
  • the method may be further characterized according to the amount of reduction in pain intensity relative to pain observed without performing the method. Accordingly, in certain embodiments, the method is characterized by achieving at least a 20% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 40% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 60% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least an 80% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 90% reduction in pain intensity relative to pain observed without performing the method.
  • the method may be further characterized according to the duration of reduction in pain intensity. Accordingly, in certain embodiments, the reduction in pain intensity lasts for at least 1 week. In certain embodiments, the reduction in pain intensity lasts for at least 2 weeks. In certain embodiments, the reduction in pain intensity lasts for at least 4 weeks. In certain embodiments, the reduction in pain intensity lasts for at least 2 months. In certain embodiments, the reduction in pain intensity lasts for at least 3 months. In certain embodiments, the reduction in pain intensity lasts for at least 6 months.
  • the reduction in pain intensity lasts for at a duration of 2 months to six months. In certain embodiments, the reduction in pain intensity lasts for a duration of 3 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for a duration of 6 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for a duration of 6 months to 12 months.
  • Another aspect of the invention provides a method of increasing antibody-dependent cell cytotoxicity (ADCC) of voltage-gated sodium channel Na v l ,8-expressing cells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I or II) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • ADCC antibody-dependent cell cytotoxicity
  • Another aspect of the invention provides a method of depleting voltage-gated sodium channel Na v 1.8-expressing cells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I or II) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein such as a compound of Formula I or II
  • an anti-cotinine antibody, or antigen-binding fragment thereof such as a compound of Formula I or II
  • the compound and the antibody, or antigen-binding fragment thereof are administered simultaneously.
  • the compound and the antibody, or antigen-binding fragment thereof are administered sequentially.
  • the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
  • the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.
  • the anti-cotinine antibody is of IgGl isotype comprising a substitution in an Fc region to increase ADCC activity.
  • the substitution in the Fc region is S239D/I332E, wherein residue numbering is according to the EU Index.
  • the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • Another aspect of the invention provides for the use of a heterobifunctional compound described herein (such as a compound of Formula I or II, or a compound of Formula I, II, or III, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as pain.
  • Another aspect of the invention provides a combination comprising a heterobifunctional compound described herein (e.g., a compound of Formula I or II, or a compound of Formula I, II, or III) and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • a heterobifunctional compound described herein e.g., a compound of Formula I or II, or a compound of Formula I, II, or III
  • an anti-cotinine antibody, or antigen-binding fragment thereof e.g., a compound of Formula I or II, or III
  • An antibody dependent cellular cytoxocity reporter assay is conducted using the following four assay components: (i) ARM compound of Formula (I) targeting Na v 1.8 (concentrations ranging from 1 pM to 10 pM) (ii) anti-cotinine antibody having a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12 (rabbit variable region with human IgGl Fc domain containing a DE mutation (S239D/I332E)) (concentrations ranging from 0.01 pg / mL to 200 pg / mL); (iii) target cells: cells engineered to overexpress either human Na v l .8 (typically 1000-20,000 cells per well) and (iv) reporter cells: Reagents are combined in a final volume of 20 pL in a 384 - well tissue culture treated plate.
  • 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, 18, 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 compound described herein (such as a compound of Formula I or II, 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.
  • 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.
  • 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.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • 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.
  • 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.
  • 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 appropriate.
  • 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.
  • R 6 represents independently for each occurrence fluoro or chloro;
  • R 7 , R 9 , and R 10 are independently hydrogen or C1.4 alkyl; or
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a 4 to 6 membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, wherein the heterocyclic ring is substituted by 0, 1, or 2 substituents independently selected from C1-4 alkyl;
  • R 8 represents independently for each occurrence fluoro, chloro, or C1.4 alkyl
  • R 11 is a bond to X 1 ; x is 0 or 1; y is 0, 1, or 2; z is 0 or 1; is a divalent linker selected from:
  • L lc is C2.10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L 2c is -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • L 2g is wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L lg ; (L-h) wherein each Z 1 is independently N or
  • L 11 is a bond, C1.12 linear alkylene, or ** , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L 31 and represents a covalent bond to NH
  • L 21 is a bond, C1-12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN
  • L 31 is a bond or -C(0)-; wherein Z 1 is C, CH, or N; each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N;
  • L 1 ' is -NH-, -C(O)NH-, -NHC(O)-, or -O-;
  • L 2 ' is Ci-6 linear alkylene or *** I _ 11 , wherein n is 1 or 2, and « represents a covalent bond to L 1J ; and " represents a single bond or a double bond
  • L lp is a bond, - C(O)-, -C(O)NH-, -NHC(O)-, -S(O) 2 NH- or -NHS(O) 2 -; and L 2p is -(4-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen oxygen, and sulfur)-C(O))-; and wherein each represents a covalent bond to X 1 , and each represents a covalent bond to X 2 .
  • Embodiment 2 The compound of embodiment 1, wherein the compound is a compound of Formula I.
  • Embodiment 3 The compound of embodiment 1 or 2, wherein R 1 is -CHg.
  • Embodiment 4 The compound of any one of embodiments 1-3, wherein X 2 is $-(Ci-s alkylene)-N(H)-.
  • Embodiment 5 The compound of any one of embodiments 1-3, wherein X 2 is ⁇ [>- CH 2 CH 2 -N(H)-.
  • Embodiment 6 The compound of any one of embodiments 1-3, wherein X 2 is $- C(H)(CH 3 )-N(H)-.
  • Embodiment 7 The compound of any one of embodiments 1-6, wherein Y 1 is
  • Embodiment 8 The compound of any one of embodiments 1-6, wherein Y 1 is one of the following: [0495] Embodiment 9. The compound of any one of embodiments 1-6, wherein Y 1 is
  • Embodiment 10 The compound of any one of embodiments 1-6, wherein Y 1 is one of the following: [0497] Embodiment 11 . The compound of any one of embodiments 1-6, wherein Y 1 is
  • Embodiment 12 The compound of any one of embodiments 1-6, wherein Y 1 is one of the following:
  • Embodiment 13 The compound of embodiment 1, wherein the compound is represented by Formula la or a pharmaceutically acceptable salt thereof: [0500] Embodiment 14. The compound of embodiment 1, wherein the compound is represented by Formula lb or a pharmaceutically acceptable salt thereof:
  • Embodiment 15 The compound of embodiment 1, wherein the compound is represented by Formula Ic or a pharmaceutically acceptable salt thereof:
  • Embodiment 16 The compound of any one of embodiments 1-7, 9, 11, or 13-15, wherein R 2 is methyl.
  • Embodiment 17 The compound of any one of embodiments 1-7, 9, 11, or 13-16, wherein R 3 is trifluoromethyl .
  • Embodiment 18 The compound of any one of embodiments 1-7, 9, 11, or 13-17, wherein R 4 is methyl.
  • Embodiment 19 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein R 5 is Ci-4 alkoxyl.
  • Embodiment 20 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein R 5 is methoxy.
  • Embodiment 21 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein R 5 is -O-(C.3-6 cycloalkyl).
  • Embodiment 22 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein R 5 is -O-(cyclopropyl).
  • Embodiment 24 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein R 5 is methyl.
  • Embodiment 26 The compound of any one of embodiments 1-7, 9, 11, or 13-25, wherein R 6 is fluoro.
  • Embodiment 27 The compound of any one of embodiments 1-7, 9, 11, or 13-26, wherein y is 1.
  • Embodiment 28 The compound of any one of embodiments 1-7, 9, 11, or 13-26, wherein y is 2.
  • Embodiment 29 The compound of any one of embodiments 1-7, 9, 11, or 13-18, wherein x is 0, and y is 0.
  • Embodiment 30 The compound of any one of embodiments 1-7, 9, 11, or 13-29, wherein R 7 is hydrogen.
  • Embodiment 33 The compound of any one of embodiments 1-7, 9, 11, or 13-32, wherein z is 1.
  • Embodiment 41 The compound of any one of embodiments 1-34, wherein X 1 is -(Ci- 3 alkylene)-N(H)-(C2-3 alkylene)-O-(C2-3 alkylene)-N(H)-'P, wherein T is a bond to L.
  • Embodiment 44 The compound of any one of embodiments 1-34, wherein X 1 is -O- (CH2CH2CH2)-N(H)-'P, wherein T is a bond to L.
  • Embodiment 45 The compound of any one of embodiments 1-34, wherein X 1 is -O- (C2-3 alkylene)-O-(C2-6 alkylene)-N(H)-T, wherein T is a bond to L.
  • Embodiment 46 The compound of any one of embodiments 1-34, wherein X 1 is -O- (CH 2 CH 2 )-O-(CH 2 CH 2 CH 2 )-N(H)-T, wherein T is a bond to L.
  • Embodiment 47 The compound of any one of embodiments 1-34, wherein X 1 is -(C2-3 alkylene)-O-(C 2 -4 alkyl ene)-N(H)-T, wherein T is a bond to L.
  • Embodiment 48 The compound of any one of embodiments 1-34, wherein X 1 is - (CH 2 CH 2 )-O-(CH 2 CH 2 CH 2 )-N(H)-T, wherein T is a bond to L.
  • Embodiment 49 The compound of any one of embodiments 1-6, wherein Y ⁇ X 1 - is [0536] Embodiment 50.
  • X 1 is a C2 -10 bivalent saturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are independently replaced by -N(H)-, -N(CH.3)-, or -O-;
  • R 2 is C1-3 haloalkyl
  • R 4 represents independently for each occurrence fluoro, chloro, or C1.4 alkyl
  • R 5 is hydrogen or C1-4 alkyl; , each of which is substituted with 0 or
  • L is a divalent linker selected from:
  • Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene
  • L lb is -CH 2 -NH-C(O)-, -NHC(O)-, or -C(O)NH-
  • L 2b is Ce-i 2 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR lb -, -
  • L 2b is wherein n is 1 , 2, 3, or 4, and represents a covalent bond to L lb ; and each R lb is independently hydrogen or C1-3 alkyl;
  • L 2g is wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L lg ; (L-h) wherein each Z 1 is independently N or
  • L lh is a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-;
  • L 2h is C2-10 linear alkylene or _ , wherein n is 1, 2, 3, or 4, and represents a covalent bond to L lh represents a covalent bond to L 3h ;
  • L 3h is a bond, -C(0)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-;
  • L 4h is a bond, -C(0)-, -CH2C(0)-, or - C(0)CH2-; and
  • m is 1, 2, or 3;
  • (L-i) wherein L 11 is a bond, C1.12 linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L 31 and represents a covalent bond to NH;
  • L 21 is a bond, C 1-12
  • L 2p is -(4-6 membered saturated heterocyclylene containing 1 or 2 heteratoms independently selected from nitrogen oxygen, and sulfur)-C(O))-; and _ wherein each represents a covalent bond to X 1 , and each represents a covalent bond to X 2 .
  • Embodiment 51 The compound of embodiment 50, wherein the compound is a compound of Formula II.

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Abstract

L'invention concerne des composés contenant de la cotinine hétérobifonctionnels, des compositions pharmaceutiques et des méthodes d'utilisation de ceux-ci pour traiter des affections médicales, telles que la douleur.
PCT/US2025/021987 2024-03-29 2025-03-28 Molécules hétérobifonctionnelles pour lier nav1.8 et méthodes de traitement d'affections médicales les utilisant Pending WO2025208012A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161011A1 (fr) * 2014-04-17 2015-10-22 Merck Sharp & Dohme Corp. Antagonistes benzamides des récepteur cgrp
WO2018134731A1 (fr) * 2017-01-17 2018-07-26 Glaxosmithkline Intellectual Property Development Limited Molécules hétérobivalentes non peptidiques permettant le traitement de maladies inflammatoires
WO2023017483A1 (fr) * 2021-08-13 2023-02-16 Glaxosmithkline Intellectual Property Development Limited Chimères ciblant la cytotoxicité pour des cellules exprimant ccr2
WO2023017484A1 (fr) * 2021-08-13 2023-02-16 Glaxosmithkline Intellectual Property Development Limited Chimères ciblant la cytotoxicité

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161011A1 (fr) * 2014-04-17 2015-10-22 Merck Sharp & Dohme Corp. Antagonistes benzamides des récepteur cgrp
WO2018134731A1 (fr) * 2017-01-17 2018-07-26 Glaxosmithkline Intellectual Property Development Limited Molécules hétérobivalentes non peptidiques permettant le traitement de maladies inflammatoires
WO2023017483A1 (fr) * 2021-08-13 2023-02-16 Glaxosmithkline Intellectual Property Development Limited Chimères ciblant la cytotoxicité pour des cellules exprimant ccr2
WO2023017484A1 (fr) * 2021-08-13 2023-02-16 Glaxosmithkline Intellectual Property Development Limited Chimères ciblant la cytotoxicité

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