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WO2025240895A1 - Inhibiteurs cycloalkyle et hétérocycloalkyle substitués de nav1.8 pour le traitement de la douleur - Google Patents

Inhibiteurs cycloalkyle et hétérocycloalkyle substitués de nav1.8 pour le traitement de la douleur

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Publication number
WO2025240895A1
WO2025240895A1 PCT/US2025/029820 US2025029820W WO2025240895A1 WO 2025240895 A1 WO2025240895 A1 WO 2025240895A1 US 2025029820 W US2025029820 W US 2025029820W WO 2025240895 A1 WO2025240895 A1 WO 2025240895A1
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Prior art keywords
substituted
compound
alkyl
pharmaceutically acceptable
ring
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Inventor
John Mulcahy
Jie Zhu
Lee Dunlap
Brian Bear
Guoliang Zhang
Ryan LE
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SiteOne Therapeutics Inc
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SiteOne Therapeutics Inc
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Publication of WO2025240895A1 publication Critical patent/WO2025240895A1/fr
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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Voltage-gated sodium channels are large integral membrane protein complexes present in neurons and excitable tissues where they contribute to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4) 365-77). They have been identified as a primary target for the treatment of pain.
  • Genes encoding for nine distinct mammalian isoforms of NaV channels (NaV isoforms 1.1-1.9) have been sequenced.
  • Nav1.8 is selectively expressed in dorsal root ganglion (DRG) neurons, a type of pseudo-unipolar neuron that project both centrally and peripherally, which are implicated in nociception.
  • DRG dorsal root ganglion
  • NaV1.8 is particularly important in the pathophysiology of pain.
  • the design of a drug which selectively inhibits NaV 1.8 over the other Na V channels is therefore desirable.
  • Such a drug design is challenging given the high structural homology (75-96%) of the mammalian Na V isoforms.
  • Isoform-selective selective inhibitors have been sought by a number of research groups and certain compounds have advanced to clinical development.
  • Also provided herein are methods of treating pain and/or conditions modulated by voltage-gated sodium channels in a subject comprising administering a therapeutically or prophylactically effective amount of a compound or composition to a subject.
  • the subject is a human.
  • a compound of Formula (I) wherein W 1 is CR x ; W 2 is CH or N; L 1 is a bond or is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A; L 2 is a bond, -O-, or -C(O)-; ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10- membered heterocyclic ring or N-oxide thereof; ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or ring B is a 5- to 10-membered heterocycloalkylene ring; R x is H, F, or C 1 -C 6 alkyl; R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, or ring C; ring C is a 3- to 10-membere
  • C 2 haloalkyl, C 3 haloalkyl, or C4 haloalkyl e.g. C(CH 3 )2CF 3 ); cyano; aryl wherein the aryl is optionally substituted with 1 or 2 halo, in some embodiments, phenyl wherein the phenyl is optionally substituted with 1 or 2 halo; C 3 -C 6 cycloalkyl, in some embodiments, cyclopropyl; C 1 -C 3 alkoxy, in some embodiments methoxy; deutero- C 1 -C 3 alkoxy, in some embodiments, deutero-methoxy; halo-C 1 -C 3 alkoxy, in some embodiments, halo-C 1 alkoxy or halo-C 2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in
  • compositions, single unit dosage forms, and kits suitable for use in treating pain and/or conditions modulated by voltage-gated sodium channels which comprise a therapeutically or prophylactically effective amount of a compound provided herein, e.g., of Formula (I′), (I), or (P-I), of some or any of the embodiments, and of compounds 1-297.
  • a method of treatment of condition associated with voltage-gated sodium channels function, including Na ⁇ 1.8, in a subject comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound provided herein, e.g., of some or any of the embodiments, of Formula (I′), (I).
  • a method of inhibiting voltage-gated sodium channels function comprising contacting Na ⁇ 1.8 with a compound provided herein, e.g., of Formula (I′), (I), or (P-I), of some or any of the embodiments, and compounds 1-297.
  • the inhibition is done by contacting a subject or a sample with the compound.
  • BRIEF DESCRIPTION OF FIGURES [0013] None.
  • DETAILED DESCRIPTION Provided herein are compounds, methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in the treatment of pain and/or conditions modulated by voltage-gated sodium channels, in particular NaV 1.8.
  • Also provided herein are methods of treating pain in a subject comprising administering a therapeutically or prophylactically effective amount of a compound or composition to a subject.
  • the subject is a human.
  • a substituted alkyl group can be substituted, for example, with a cycloalkyl group, and the cycloalkyl group is not further substituted unless specified otherwise.
  • Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • the alkyl group is a primary, secondary, or tertiary hydrocarbon.
  • the alkyl group includes one to ten carbon atoms, i.e., C 1 -C 10 alkyl.
  • the alkyl is a C 1- C 6 alkyl.
  • the alkyl is a C 1- C 3 alkyl.
  • the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the alkyl group is selected from the group consisting of methyl, ethyl, tert-butyl, and neopentyl.
  • the alkyl group is methyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon, containing a carbon-carbon double bond.
  • the alkenyl group is cis or trans.
  • the alkenyl group is in an internal or terminal position.
  • the alkenyl group includes two to ten carbon atoms, i.e., C 2 -C 10 alkenyl.
  • the alkenyl group includes two to four carbon atoms, i.e., C 2 -C 4 alkenyl.
  • the alkenyl is C2-C3 alkenyl.
  • the alkenyl group is vinyl.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon, containing a carbon-carbon triple bond. In some or any embodiments, the alkynyl group is in an internal or terminal position. In some or any embodiments, the alkynyl group includes two to ten carbon atoms, i.e., C 2 -C 10 alkynyl. In some or any embodiments, the alkynyl group includes two to four carbon atoms, i.e., C 2 -C 4 alkynyl.
  • alkynyl is C2-C3 alkynyl. In some or any embodiments, the alkynyl group is ethynyl.
  • alkoxy refers to the group –OR′ where R′ is alkyl, as defined herein.
  • Alkoxy includes, in some or any embodiments, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.
  • alkoxy is C 1 -C 6 alkoxy.
  • alkoxy is C 1- C 3 alkoxy.
  • C 1 -C 6 alkoxycarbonyl refers to -C(O)OR′ where R′ is C 1 -C 6 alkyl as defined herein. In some embodiments, C 1 -C 6 alkoxycarbonyl is methoxycarbonyl or ethoxycarbonyl.
  • amino means –NH 2 .
  • amino-C 1 -C 6 alkyl means a C 1 -C 6 alkyl, as provided herein, substituted with one or two amino groups, as defined herein.
  • amino-C 1 -C 6 alkyl is aminomethyl, 1-aminoethyl, 2-amino-ethyl, or 2-amino-prop-2-yl.
  • aryl refers to phenyl or naphthyl. In some or any embodiments, aryl is phenyl. In some or any embodiments, aryl is naphthyl.
  • cycloalkyl refers to a monovalent, saturated, monocyclic hydrocarbon or bicyclic (fused, bridged, or spirocyclic) ring.
  • the terms “fused cycloalkyl,” “spirocycloalkyl,” and “bridged cycloalkyl” are embodiments of the cycloalkyl group.
  • the cycloalkyl group includes three to six carbon atoms, i.e., C3 to C6 cycloalkyl, or three to ten carbon atoms, i.e., C3 to C10 cycloalkyl.
  • the cycloalkyl has 3, 4, or 5 (C3-5); 3 or 4 (C 3-4 ); 3 (C 3 ); 4 (C 4 ); or 5 (C 5 ) carbon atoms.
  • the cycloalkyl has 5, 6, 7, or 8 (C5-8); 7 or 8 (C7-8); 5 or 6 (C5-6); 5 (C5); 6 (C6); 7 (C7); or 8 (C8) carbon atoms.
  • the cycloalkyl group is C 3 -C 6 cycloalkyl.
  • the cycloalkyl group is C 6 -C 8 cycloalkyl.
  • the cycloalkyl group is C3-C5cycloalkyl.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In some or any embodiments, the cycloalkyl group is cyclopropyl. In some or any embodiments, the cycloalkyl group is cyclobutyl. In some or any embodiments, the cycloalkyl group is cyclopentyl.
  • the cycloalkyl group is cyclohexyl. In some or any embodiments, the cycloalkyl group is cycloheptyl. In some or any embodiments, the cycloalkyl group is cyclooctyl.
  • the cycloalkyl group is bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, adamantyl, bicyclo[1.1.1]pentyl, spiro[2.5]octyl, spiro[3.5]nonanyl, and spiro[3.3]heptanyl.
  • cycloalkylene refers to a divalent cycloalkyl, as otherwise defined above.
  • 3- to 10-membered cycloalkylene refers to a saturated, monocyclic hydrocarbon or bicyclic (fused, bridged, or spirocyclic) ring where L 1 and L 2 (in Formula (I′), (I), or (P-I) and embodiments thereof) are attached at adjacent carbon atoms of ring B.
  • the terms “fused cycloalkylene,” “spirocycloalkylene,” and “bridged cycloalkylene” are embodiments of the 3- to 10-membered cycloalkylene group.
  • the 3- to 10-membered cycloalkylene group includes three to six carbon atoms, i.e., C 3 to C 6 cycloalkylene.
  • the 3- to 10-membered cycloalkylene has 3, 4, or 5 (C3-5); 3 or 4 (C3-4); 3 (C3); 4 (C4); or 5 (C5) carbon atoms.
  • the 3- to 10-membered cycloalkylene has 5, 6, or 7 (C 5-7 ); 5 or 6 (C 5-6 ); 5 (C 5 ); 6 (C 6 ); or 7 (C 7 ) carbon atoms.
  • the 3- to 10-membered cycloalkylene is monocyclic.
  • the 3- to 10- membered cycloalkylene group is cycloprop-di-yl, cyclobut-1,2-di-yl, cyclopent-1,2-di-yl), cyclohex-1,2-di-yl, or cyclohept-1,2-di-yl.
  • the 3- to 10- membered cycloalkylene group is cycloprop-di-yl cyclobut-12-di-yl cyclopent-12-di-yl or cyclohex-1,2-di-yl. In some or any embodiments, the 3- to 10-membered cycloalkylene group is cycloprop-di-yl. In some or any embodiments, the 3- to 10-membered cycloalkylene group is cyclobut-1,2-di-yl. In some or any embodiments, the 3- to 10-membered cycloalkylene group is cyclopent-1,2-di-yl.
  • the 3- to 10-membered cycloalkylene group is cyclohex-1,2-di-yl. In some or any embodiments, the 3- to 10-membered cycloalkylene group is cyclohept-1,2-di-yl. In some or any embodiments, the 3- to 10- membered cycloalkylene is bicyclic. In some or any embodiments, the bicyclic cycloalkylene has 7, 8, 9, or 10 (C7-10); 7 or 8 (C7-8); 7 (C7); 8 (C8); 9 (C9); or 10 (C10) carbon atoms.
  • the 3- to 10-membered cycloalkylene group is bicyclo[4.1.0]hept-di-yl (in some embodiments, bicyclo[4.1.0]hept-2.3-di-yl (where L 1 and L 2 are attached to the 2- and 3-positions, respectively, of ring B or are attached to the 3- and 2- positions, respectively, of ring B), bicyclo[4.1.0]hept-3,4-di-yl (where L 1 and L 2 are attached to the 3- and 4-positions, respectively, of ring B or are attached to the 4- and 3-positions, respectively, of ring B), bicyclo[4.1.0]hept-4,5-di-yl) (where L 1 and L 2 are attached to the 4- and 5-positions, respectively, of ring B or are attached to the 5- and 4-positions, respectively, of ring B)) bicyclo[4.2.0]octan-di-yl (in some embodiments, bicyclo[4.2.0]oc
  • 3- to 10-membered cycloalkylene when fused to benzo, as used herein for Ring B refers to 3- to 10-membered cycloalkylene as defined above (including embodiments thereof), fused to a benzo group.
  • 3- to 10-Membered cycloalkylene fused to benzo can be substituted on any atom of the ring system with (R 2 )p, valency rules permitting.
  • the 3- to 10-membered cycloalkylene fused to benzo is 1,2,3,4- tetrahydronaphthalenyl (where L and ring C are attached to the 2- and 3-positions, respectively, of ring B or are attached to the 3- and 2-positions, respectively, of ring B).
  • cycloalkenyl refers to a monovalent monocyclic unsaturated cyclic hydrocarbon that is not aromatic.
  • cycloalkenyl is C5-C6 cycloalkenyl, including, but not limited to cyclohexenyl.
  • cycloalkylalkyl refers to an alkyl group, as defined herein, substituted with cycloalkyl, as defined herein.
  • cycloalkylalkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, or cyclooctylmethyl.
  • C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl refers to a C 1 -C 6 alkyl substituted with a C 3 -C 6 cycloalkyl.
  • C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.
  • deutero-alkyl refers to alkyl, as defined herein, where one or more of the hydrogen atoms is replaced with deuterium and the deuterium composition of the atom or atoms is other than the naturally-occurring isotopic composition.
  • the deutero-alkyl is deutero-C 1-2 alkyl.
  • Deutero-alkyl includes, in some or any embodiments, -CH 2 -D.
  • deutero-alkoxy refers to –OR′ where R′ is alkyl, as defined herein, where one or more of the hydrogen atoms is replaced with deuterium and the deuterium composition of the atom or atoms is other than the naturally- occurring isotopic composition.
  • the deutero-alkoxy is deutero-C 1 -C 3 alkoxy.
  • Deutero-alkoxy includes, in some or any embodiments, methoxy-d 3 , ethoxy-d5, and the like.
  • haloalkyl refers to an alkyl group substituted with 1, 2, 3, 4 or 5 halo groups
  • the haloalkyl is a halo-C 1- C 6 alkyl.
  • the haloalkyl is a halo-C 1- C 3 alkyl.
  • the haloalkyl is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CF 2 CH 3 , or -C(CH 3 )2CF 3 .
  • haloalkoxy refers to an -OR′ group where R′ is halo-C 1 -C 10 alkyl as defined herein. In some or any embodiments, the haloalkoxy is a halo-C 1 -C 6 alkoxy. In some or any embodiments, the haloalkoxy is a halo- C 1- C 3 alkoxy.
  • the haloalkoxy is -OCF 3 , -OCH 2 F, -OCHF 2 , - OCH 2 CF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCF 2 CH 3 , or -OC(CH 3 )2CF 3 .
  • halogen and “halo,” as used herein, and unless otherwise specified, are synonymous and refer to chloro, bromo, fluoro or iodo.
  • heteroaryl refers to a monocyclic aromatic ring system or bicyclic aromatic ring system wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms is a heteroatom independently selected from O, S(O)0-2, NH, and N, and the remaining ring atoms are carbon atoms, and where the ring may be optionally substituted as described herein.
  • the heteroaryl group is bonded to the rest of the molecule through any atom in the ring system, valency rules permitting.
  • each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, from 5 to 6 ring atoms, or from 5 to 10 ring atoms. When heteroaryl is substituted, it can be substituted on any ring.
  • heteroaryl is , , , , of the heteroaryl to the rest of the molecule.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl pyrimidinyl pyrrolyl thiadiazolyl thiazolyl thienyl (thiophenyl), tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothienyl, benzotriazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, or
  • heteroaryl is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout the specification.
  • Heteroaryl, in some embodiments of Ring A can be pyridinyl, pyridinyl when substituted with hydroxy), pyridazinyl, (i.e.
  • heterocycloalkyl refers to a monovalent, monocyclic or bicyclic saturated or partially unsaturated (but not aromatic) ring system; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms is a heteroatom independently selected from O, S(O)0-2, and N, and the remaining ring atoms are carbon atoms.
  • the heterocycloalkyl comprises one or two heteroatom(s) which are independently selected from nitrogen and oxygen.
  • the heterocycloalkyl comprises one or two heteroatom(s) which are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described herein).
  • heterocycloalkyl is bicyclic and comprises one or two heteroatoms in the same ring.
  • the heterocycloalkyl has from 3 to 6, 5 to 7, 5 to 6, or 6 to 7 ring atoms.
  • the heterocycloalkyl may be a bridged or non-bridged, spirocyclic or not spirocyclic, and/or fused or not fused group.
  • One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, one or more of the carbon atoms may be optionally replaced with .
  • the heterocycloalkyl 3- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, tetrahydropyranyl, or 7-oxabicyclo[2.2.1]heptanyl,.
  • heterocycloalkylene refers to a divalent heterocycloalkyl which is otherwise as defined above.
  • 5- to 10-membered heterocycloalkylene refers to a monocyclic or bicyclic saturated or partially unsaturated (but not aromatic) ring system; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms is a heteroatom independently selected from O, S(O)0-2, and N, and the remaining ring atoms are carbon atoms; and wherein L 1 and L 2 (in Formula (I′), (I), or (P-I) and embodiments thereof) are attached at adjacent atoms of ring B.
  • the 5- to 10-membered heterocycloalkylene comprises one or two heteroatom(s) which are independently selected from nitrogen and oxygen. In some or any embodiments, the 5- to 10-membered heterocycloalkylene comprises one or two heteroatom(s) which are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described herein). In some or any embodiments, 5- to 10-membered heterocycloalkylene is bicyclic and comprises one or two heteroatoms in the same ring. In some or any embodiments, the 5- to 10- membered heterocycloalkylene has from 5 to 7, 5 to 6, or 6 to 7 ring atoms.
  • the 5- to 10-membered heterocycloalkylene may be a bridged or non-bridged, spirocyclic or not spirocyclic, and/or fused or not fused group.
  • One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, and/or one or more of the carbon atoms may be optionally replaced with .
  • the 5- to 10-membered heterocycloalkylene is piperidin-1,2-diyl (where L 1 and L 2 are attached to the 1- and 2-positions, respectively, of ring B or are attached to the 2- and 1-positions, respectively, of ring B), piperidin-2,3-diyl (where L 1 and L 2 are attached to the 2- and 3-positions, respectively, of ring B or are attached to the 3- and 2-positions, respectively, of ring B), piperidin-3,4-diyl (where L 1 and L 2 are attached to the 3- and 4- positions, respectively, of ring B or are attached to the 4- and 3-positions, respectively, of ring B), morpholin-2,3-di-yl (where L 1 and L 2 are attached to the 2- and 3-positions, respectively, of ring B or are attached to the 3- and 2-positions, respectively, of ring B), tetrahydropyran- 3,4-di-yl (where L 1 and L 2 are attached to the 3-
  • heterocyclic refers to a monovalent monocyclic, saturated or partially unsaturated (but not aromatic) ring system, (e.g. heterocycloalkyl) or a monovalent bicyclic ring system that contains at least one non-aromatic ring (e.g.
  • the heterocyclic ring comprises one or two heteroatom(s) which are independently selected from nitrogen and oxygen.
  • the heterocyclic ring comprises one or two heteroatom(s) which are oxygen. In some or any embodiments, the heterocyclic ring comprises one or two heteroatom(s) which are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described herein). In some or any embodiments, heterocyclic is bicyclic and comprises one heteroatom in a non- aromatic ring, or comprises one heteroatom in an aromatic ring, or comprises two heteroatoms in an aromatic ring, or comprises two heteroatoms where one is in an aromatic ring and the other is in a non-aromatic ring.
  • the heterocyclic group unless specified otherwise, has from 3 to 20, 3 to 15, 5 to 10, 3 to 10, 3 to 8, 4 to 7, 5 to 6, or 4 to 6 ring atoms.
  • the heterocyclic is monocyclic.
  • the heterocyclic is bicyclic.
  • the heterocyclic group may be a bridged or non-bridged, spirocyclic or not spirocyclic, and/or fused or not fused multicyclic group.
  • One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, one or more of the carbon atoms may be optionally replaced with .
  • heterocyclic is heterocycloalkyl, as defined above.
  • the monocyclic and bicyclic heterocyclic rings may be attached to the main structure at any heteroatom or carbon atom which results in a stable compound.
  • the bicyclic heterocyclic may be attached to the main structure through any of its rings, including any aromatic or nonaromatic ring, regardless of whether the ring contains a heteroatom.
  • heterocyclic When heterocyclic is substituted, it can be substituted on any ring, i.e. on any aromatic or nonaromatic ring comprised by heterocyclic.
  • such heterocyclic includes, but are not limited to, azepinyl, azetidinyl, benzodioxanyl, benzodioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H- benzo[b][1,4]dioxepinyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl, benzopyranonyl, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothienyl, 2,2-dioxo-1,3- dihydrobenzo[c]thienyl, benzothiopyranyl, benzoxazinyl, chromanyl, chromonyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiaziny
  • heterocyclic is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout the specification, including in some or any embodiments with group(s) independently selected from halo, alkyl, and phenyl.
  • heterocycloalkyl is pyrrolidinyl.
  • heterocycloalkyl is an N-linked heterocycloalkyl.
  • Ring A the 5- to 10-membered heterocyclic ring or N-oxide thereof, in some embodiments, the nitrogen is not hydrogen or halo, the nitrogen is not hydrogen or halo, where R 3a on the nitrogen is not hydrogen or halo, where R 3a on the nitrogen is not hydrogen or halo, or or N-oxide thereof; where each ring is substituted with R 3 and (R 3a )q, unless context dictates otherwise.
  • hydroxyalkyl refers to an alkyl, as defined herein, comprising an alcohol (hydroxy). In one or more embodiments, the alcohol group is a primary, secondary, or tertiary alcohol.
  • the hydroxyalkyl group includes one to ten carbons, i.e., C 1 -C 10 hydroxyalkyl. In one or more embodiments, the hydroxyalkyl group includes one or two alcohol (hydroxy) groups, provided that they are not on the same carbon. In one or more embodiments, the hydroxyalkyl group is hydroxyC 1- C 6 alkyl. In one or more embodiments, the hydroxyalkyl group is hydroxyC 1- C 3 alkyl. In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl.
  • the hydroxyalkyl group is a C 1- C 6 hydroxyalkyl. In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, and 2-hydroxyprop-2-yl.
  • a substituent is oxo
  • two hydrogens on the atom are replaced.
  • an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring.
  • a pyridyl group substituted by an oxo group is a pyridonyl.
  • pyridonyl, 2,4(1H,3H)-dioxo-pyrimidinyl, 3(2H)-oxo-pyridazinyl, 4-oxo- 1,4-dihydro-1,6-naphthyridinyl, and 3-oxo-1,2-dihydro-3H-indazolyl can exist in tautomeric form, e.g. hydroxypyridinyl, 2,4-dihydroxypyrimidinyl, hydroxy-pyridazinyl, 4-hydroxy-1,6- naphthyridinyl, and 3-hydroxy-1H-indazolyl, respectively.
  • Compounds of Formula (I′), (I), or (P-I) substituted with CH in the W 2 position can exist as the cis-isomer, the trans-isomer, or a mixture thereof with respect to positions W 1 and W 2 as indicated by the solid and/or dashed rectangles.
  • the cis-isomer the trans-isomer
  • a mixture thereof with respect to positions W 1 and W 2 as indicated by the solid and/or dashed rectangles.
  • solid and dashed rectangles are equivalent to solid and dashed wedges, respectively (Brecher, J. Pure Appl. Chem., Vol.78, 10, pp-1897-1970, 2006).
  • the solid and dashed rectangles denote relative stereochemistry, including in, for example, compounds 4A and 4B: unless context dictates otherwise.
  • the labelled stereochemistry indicates absolute stereochemistry.
  • DMB 2,4-dimethoxybenzyl group.
  • pharmaceutically acceptable salt refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise desirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art.
  • Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-to
  • Pharmaceutically acceptable salts further include, in some or any embodiments, and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts and the like.
  • a basic functionality salts of non-toxic organic or inorganic acids such as hydrohalides, e.g.
  • the term “substantially free of” or “substantially in the absence of” stereoisomers with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in some or any embodiments 95%, 98%, 99% or 100% by weight, of a designated stereoisomer of a compound in the composition. In some or any embodiments, in the methods and compounds provided herein, the compounds are substantially free of stereoisomers.
  • the term “isolated” with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of a specified compound, the remainder comprising other chemical species or stereoisomers.
  • isotopic composition refers to the amount of each isotope present for a given atom
  • “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom.
  • Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms.
  • the atoms of the compounds recited herein are meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.
  • isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance.
  • deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position.
  • isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • mass spectrometry and nuclear magnetic resonance spectroscopy.
  • nuclear magnetic resonance spectroscopy refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom [0060]
  • the term “local anesthetic” means a drug which provides local numbness or pain relief.
  • local anesthetic includes aminoacylanilide compounds (in some or any embodiments, lidocaine, prilocaine, bupivacaine, ropivacaine, and mepivacaine) and related local anesthetic compounds having various substituents on the ring system or amine nitrogen; aminoalkyl benzoate compounds (in some or any embodiments, procaine, chloroprocaine, propoxycaine, hexylcaine, tetracaine, cyclomethycaine, benoxinate, butacaine, and proparacaine) and related local anesthetic compounds; cocaine; amino carbonate compounds (in some or any embodiments, diperodon); N-phenylamidine compounds (in some or any embodiments, phenacaine); N-aminoalkyl amide compounds (in some or any embodiments, dibucaine); aminoketone compounds (in some or any embodiments, falicaine and dyclonine); and amino ether compounds (in some or any or any
  • alkyl,” “hydroxyalkyl,” “carbocyclic,” “cycloalkyl,” “aryl,” “alkoxy,” “heterocycloalkyl,” and “heterocyclic” groups optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.
  • alkyl, “hydroxyalkyl,” “carbocyclic,” “cycloalkyl,” “aryl,” “alkoxy,” “heterocycloalkyl,” “heterocyclic” groups optionally comprise carbon-13 at an amount other than the natural isotopic composition.
  • the term “sample” is obtained or derived from a subject, as defined herein.
  • the sample is a biological sample, and in some embodiments, the biological sample is obtained from a subject selected from the group consisting of a mammal, microorganism, cells, and cell culture. In some embodiments, the biological sample is obtained from cells, cell culture, a microorganism a mammalian organ mammalian tissue or a mammalian bodily fluid.
  • cells may include, without limitation, cell cultures and cell samples.
  • cell cultures may include, without limitation, HEK cells and CHO cells.
  • mammalian bodily fluids include, without limitation, serum, plasma, cell lysates, and whole blood.
  • subject refers to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and in some or any embodiments, a human.
  • a non-primate e.g., a cow, pig, horse, cat, dog, rat, and mouse
  • a primate e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human
  • the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat).
  • the subject is a human.
  • the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof.
  • the term “therapeutic agent” includes a compound provided herein.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.
  • “Therapeutically effective amount” refers to an amount of a compound or composition that, when administered to a subject for treating a condition, is sufficient to effect such treatment for the condition.
  • a “therapeutically effective amount” can vary depending on, inter alia, the compound, the condition and its severity, and the age, weight, etc., of the subject to be treated.
  • “Treating” or “treatment” of any condition or disorder refers, in some or any embodiments, to ameliorating a condition or disorder that exists in a subject, including prophylactically.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the condition or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying the onset of the condition or disorder. In yet another embodiment, “treating” or “treatment” includes the reduction or elimination of either the condition (e.g. pain) or one or more symptoms (e.g. pain) of the condition (e.g. sciatica), or to retard the progression of the condition (e.g. pain) or of one or more symptoms (e.g. pain) of the condition (e.g. sciatica), or to reduce the severity of the condition (e.g. pain) or of one or more symptoms (e.g. pain) of the condition (e.g. sciatica). In yet another embodiment, “treating” or “treatment” includes administering a compound described herein prophylactically.
  • the terms “prophylactic agent” and “prophylactic agents” refer to any agent(s) which can be used in the prevention of a condition or one or more symptoms thereof and/or which prevents or impedes the onset, development, progression and/or severity of a condition.
  • the term “prophylactic agent” includes a compound provided herein.
  • the term “prophylactic agent” does not refer a compound provided herein.
  • the agent is administered prophylactically, for example before surgery to prevent or impede the onset, duration, progression and/or severity of pain (e.g., post surgical pain).
  • prophylactically effective amount refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a condition, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
  • a therapy e.g., prophylactic agent
  • another therapy e.g., another prophylactic agent
  • Compounds Provided herein are compounds that can modulate the activity of voltage-gated ion channels (e.g., voltage-gated sodium channels). The compounds can be formed as described herein and used for the treatment of conditions associated with voltage-gated sodium channel function.
  • the condition associated with voltage-gated sodium channel function is pain or a condition associated with pain. In some or any embodiments, the condition associated with voltage-gated sodium channel function is a condition associated with pain. In some or any embodiments, the condition associated with voltage-gated sodium channel function is pain, itch, cough, epilepsy, Parkinson’s disease, a mood disorder, psychosis, amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity disorders and obsessive compulsive disorder. In some or any embodiments, the condition associated with voltage-gated sodium channel function is pain (in some embodiments, subacute pain or chronic pain).
  • the pain associated with voltage-gated sodium channel function includes pain and/or discomfort associated with dry eye syndrome, pain associated with (acute) corneal injuries or abrasions, acute ocular pain, chronic ocular pain, pain associated with corneal infections, pain associated with Parkinson’s disease, pain associated with ALS, and pain associated with surgery (in some embodiments, ocular surgery).
  • the aspects and embodiments described herein include the recited compounds as well as a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • Included herein, if chemically possible, are all stereoisomers of the compounds, including diastereomers and enantiomers.
  • compounds drawn as a specific enantiomer, racemate, or diastereomer in Table A also exist as all corresponding enantiomers, racemates, or diastereomers, including compounds where all bonds are flat.
  • a compound of Table A or a pharmaceutically acceptable salt and/or an isomer thereof wherein all the bonds in the compound are flat.
  • mixtures of possible stereoisomers in any ratio including, but not limited to, racemic mixtures. Unless indicated otherwise (for example, stereochemistry is explicitly indicated in a structure at a particular atom), the structure is intended to embrace all possible stereoisomers of the compound depicted.
  • this ring depicts 0-3 R 1a groups on a bicyclic ring; these R 1a groups may be on a carbon in the cyclopentyl portion of the bicyclic ring and/or in the cyclopropyl portion of the bicyclic ring.
  • a compound of Formula (I′) wherein W 1 is CR x ; W 2 is CH or N; L 1 is a bond or is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A; L 2 is a bond, -O-, or -C(O)-; ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10- membered heterocyclic ring or N-oxide thereof; ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or ring B is a 5- to 10-membered heterocycloalkylene ring; R x is H, F, or C 1 -C 6 alkyl; R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, or ring C; ring C is a 3- to 10-membere
  • C2 haloalkyl, C 3 haloalkyl, or C 4 haloalkyl e.g. C(CH 3 ) 2 CF 3 ); cyano; aryl wherein the aryl is optionally substituted with 1 or 2 halo, in some embodiments, phenyl wherein the phenyl is optionally substituted with 1 or 2 halo; C 3 -C 6 cycloalkyl, in some embodiments, cyclopropyl; C 1 -C 3 alkoxy, in some embodiments methoxy; deutero-C 1 -C 3 alkoxy, in some embodiments, deutero-methoxy; halo-C 1 -C 3 alkoxy, in some embodiments, halo-C1 alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic,
  • a compound of Formula (P-I) wherein W 1 is CR x ; W 2 is CH or N; L 1 is a bond or is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A; L 2 is a bond or -O-; ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10- membered heterocyclic ring or N-oxide thereof; ring B is a 3- to 10-membered cycloalkylene or a 5- to 10-membered heterocycloalkylene ring; R x is H, F, or C 1 -C 6 alkyl; R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, or ring C; ring C is a 3- to 10-membered cycloalkyl; C 3 -C 6 cyclo
  • Embodiment A-1 In one or more embodiments, the compound is according to Formula (V), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (VI), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (X), or a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • the compound is according to Formula (XI), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (XII) wherein L 1 is bond, or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (L), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (LI), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (LII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • the compound is according to Formula (LIII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (LIV), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (C), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (CI), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (CII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • the compound is according to Formula (CIII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (CIV), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (CV), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (D), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (DI), or a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • the compound is according to Formula (DII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof. In one or more embodiments, the compound is according to Formula (DIII), or a pharmaceutically acceptable salt thereof and/or an isomer thereof.
  • Embodiment B Provided herein is a compound of Formula (I) (including any embodiments thereof) or a pharmaceutically acceptable salt thereof and/or an isomer thereof, where R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl and either (1) R 3 is -S(O) 2 NHR or (2) ring A is a 5- to 10-membered heteroaryl or N-oxide thereof or a 5- to 10-membered heterocyclic or N- oxide thereof.
  • Embodiment C Provided herein is a compound of Formula (I) (including any embodiments thereof) or a pharmaceutically acceptable salt thereof and/or an isomer thereof, where L 1 is bond and ring designates attachment to L 1 .
  • Embodiment E Provided herein is a compound of Formula (I) (including any embodiments thereof) or a pharmaceutically acceptable salt thereof and/or an isomer thereof, R 3 is C 1 -C 6 alkyl, -OH or -NH 2 and p is 2. In some embodiments, R 3 is C 1 -C 6 alkyl, -OH or - NH 2 , p is 2, and R 1a is independently selected from halo. In some embodiments, R 3 is C 1 -C 6 alkyl, -OH or -NH 2 , p is 2, and R 1a is fluoro.
  • Embodiment F In some or any embodiments, provided herein is a compound of Formula (I′), (I), or (P-I) or a pharmaceutically acceptable salt thereof and/or an isomer thereof, wherein ring A is phenyl substituted with R 3 , pyridyl or an N-oxide thereof substituted with R 3 , pyridazinyl substituted with R 3 , benzoisoxazolyl substituted with R 3 , pyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , naphthyridinyl substituted with R 3 , naphthyridinonyl (i.e.
  • R 3a is oxo substituted with R 3 , isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , indazolyl substituted with R 3 , indazolonyl (i.e. where one R 3a is oxo) substituted with R 3 , benzoisothiazolyl substituted with R 3 ; or thiophenyl substituted with R 3 ; where ring A is substituted with (R 3a )q; in some embodiments, R 3 is not -H;
  • R 1a is selected from C 1 -C 6 alkyl, in some embodiments, methyl, propyl, or tert-butyl; deuterium; halo, in some embodiments, fluoro, chloro, or bromo; C 1 -C 6 haloalkyl, in some embodiments, C 1 haloalkyl, (e.g. CF 3 ), C 2 haloalkyl, C 3 haloalkyl, or C4 haloalkyl (e.g.
  • Embodiment G In some or any embodiments, provided herein is a compound of Formula (P-I) or a pharmaceutically acceptable salt thereof and/or an isomer thereof, wherein ring A is phenyl substituted with R 3 , pyridyl or an N-oxide thereof substituted with R 3 , pyridazinyl substituted with R 3 , benzoisoxazolyl substituted with R 3 , pyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , naphthyridinyl substituted with R 3 , naphthyridinonyl (i.e.
  • R 3a is oxo substituted with R 3 , isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , indazolyl substituted with R 3 , indazolonyl (i.e. where one R 3a is oxo) substituted with R 3 , or benzoisothiazolyl substituted with R 3 ; where ring A is substituted with (R 3a )q; in some embodiments, R 3 is not -H;
  • R 1a is selected from C 1 -C 6 alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C 1 -C 6 haloalkyl, in some embodiments, C 1 haloalkyl or C 4 haloalkyl; cyano; aryl, in some embodiments, phenyl; C 3 -C 6 cycloalkyl, in some embodiments, cyclopropyl; C 1 -C 3 alkoxy, in some embodiments methoxy; deutero-C 1 -C 3 alkoxy, in some embodiments, deutero-C1 alkoxy; halo-C 1 -C 3 alkoxy, in some embodiments, halo-C 1 alkoxy or halo-C 2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to
  • the compound can be according to Formula (I′) or (I), or a pharmaceutically acceptable salt and/or an isomer thereof.
  • the compound can be according to Formula (I′), (I), or (I-P), or a pharmaceutically acceptable salt and/or an isomer thereof, provided that “Embodiments A to H” is replaced with “Embodiment A.”
  • Embodiment 1 In some or any embodiments, including Embodiments A to H, provided herein is a compound of Formula (I′), (I), or (P-I) wherein one R 1a is C 1 -C 6 alkyl. In some or any embodiments, including Embodiments A to H, one R 1a is halo. In some or any embodiments, including Embodiments A to H, one R 1a is C 1 -C 6 haloalkyl. In some or any embodiments, including Embodiments A to H, one R 1a is cyano. In some or any embodiments, including Embodiments A to H, one R 1a is aryl.
  • one R 1a is C 3 -C 6 cycloalkyl. In some or any embodiments, including Embodiments A to H, one R 1a is C 1 -C 3 alkoxy. In some or any embodiments, including Embodiments A to H, one R 1a is deutero-C 1 -C 3 alkoxy. In some or any embodiments, including Embodiments A to H, one R 1a is halo-C 1 -C 3 alkoxy. In some or any embodiments, including Embodiments A to H, one R 1a is 4- to 6-membered heteroaryl.
  • one R 1a is C2-C3 alkenyl. In some or any embodiments, including Embodiments A to H, one R 1a is C 2 -C 3 alkynyl [0090] Embodiment 1a: In some or any embodiments, including Embodiments A to H, at least one R 1a is C 1 -C 6 alkyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is -CH 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is C 1 -C 6 alkoxy.
  • At least one R 1a is -OCH 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is C 1 -C 6 haloalkyl. In some or any embodiments, at least one R 1a is -CF 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is halo-C 1 -C 6 alkoxy. In some or any embodiments, including Embodiments A to H, at least one R 1a is -OCF 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is halogen.
  • At least one R 1a is -Cl. In some or any embodiments, including Embodiments A to H, at least one R 1a is -F. In some or any embodiments, including Embodiments A to H, at least one R 1a is C 3 -C 6 -cycloalkyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is C 3 -C 6 -cycloalkylC 1 -C 3 - alkyl. [0091] Embodiment 1a-1: In some or any embodiments, including Embodiments A to H, at least one R 1a is tert-butyl.
  • At least one R 1a is deuterium. In some or any embodiments, including Embodiments A to H, at least one R 1a is C2 haloalkyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is C3 haloalkyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is -CH 2 CF 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is C(CH 3 ) 2 CF 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is -CF 2 H.
  • At least one R 1a is aryl optionally substituted with 1 or 2 halo. In some or any embodiments, including Embodiments A to H, at least one R 1a is aryl optionally substituted with fluoro. In some or any embodiments, including Embodiments A to H, at least one R 1a is phenyl optionally substituted with 1 or 2 halo. In some or any embodiments, including Embodiments A to H, at least one R 1a is phenyl optionally substituted with fluoro. [0092] Embodiment 1b: In some or any embodiments, including Embodiments A to H, at least one R 1a is methyl or propyl.
  • At least one R 1a is propyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is n-propyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is isopropyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is fluoro, chloro, or bromo. In some or any embodiments, including Embodiments A to H, at least one R 1a is bromo. In some or any embodiments including Embodiments A to H at least one R 1a is C 1 haloalkyl.
  • At least one R 1a is C3 haloalkyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is -C(CH 3 )2CF 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is cyano. In some or any embodiments, including Embodiments A to H, at least one R 1a is phenyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is cyclopropyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is deutero-C 1 alkoxy.
  • At least one R 1a is halo-C1 alkoxy or halo-C2 alkoxy. In some or any embodiments, including Embodiments A to H, at least one R 1a is halo-C1 alkoxy. In some or any embodiments, including Embodiments A to H, at least one R 1a is halo-C 2 alkoxy. In some or any embodiments, including Embodiments A to H, at least one R 1a is oxetanyl, pyridinyl, or pyridazinyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is oxetanyl.
  • At least one R 1a is pyridinyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is pyridazinyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is vinyl. In some or any embodiments, at least one R 1a is ethynyl.
  • Embodiment 1c In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from methyl, ethyl, propyl, cyclopropyl, -F, -Cl, -Br, -OMe, -OEt, -O-propyl, -OCD3, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , -C(CH 3 )2CF 3 , phenyl, -CN, oxetanyl, pyridyl, pyridazinyl, -CHCH 2 , and -CCH.
  • At least one R 1a is ethyl. In some or any embodiments, at least one R 1a is -OEt. In some or any embodiments, including Embodiments A to H, at least one R 1a is -O-propyl. In some or any embodiments, including Embodiments A to H, at least one R 1a is -OCD 3 . In some or any embodiments, including Embodiments A to H, at least one R 1a is - OCHF 2 . In some or any embodiments, including Embodiments A to H, at least one R 1a is - OCH 2 CF 3 .
  • R 1a is oxetanyl.
  • R 1a is independently in each instance selected from -Me, -Et, -CH(CH 3 )2, -F, -Cl, -Br, -OMe, -OEt, -OCH(CH 3 ) 2 , -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , phenyl (or , , , , , -CHCH 2 , and -CCH.
  • At least one R 1 is -OCH(CH 3 ) 2 . In some or any embodiments, including Embodiments A to H, at least one R 1a is . In some or any embodiments, at least one R 1a is . In some or any embodiments, including Embodiments A to H, at least one R 1a . In some or any embodiments, including Embodiments A to H, at least one R 1a is . In some or any embodiments, at least one R 1a is .
  • Embodiment 1d-1 In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me, -Et, -t-butyl, -CH(CH 3 )2, -D, -F, -Cl, -Br, -OMe, -OEt, -OCH(CH 3 ) 2 , -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , -CH 2 CF 3, -CF 2 H, C(CH 3 ) 2 CF 3, phenyl (or , H , .
  • Embodiment 1e In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me, propyl, -F, -Cl, -OMe, -OEt, -O- propyl, -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , phenyl, -CN, -CHCH 2 , and -CCH.
  • Embodiment 1e-1 In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me, propyl, -F, -Cl, -OMe, -OEt, -O- propyl, -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , -CH 2 CF 3, -CF 2 H, phenyl, -CN, -CHCH 2 , and -CCH.
  • Embodiment 1f In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me, -CH(CH 3 ) 2 , -F, -Cl, -OMe, -OEt, - OCH(CH 3 ) 2 , -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , phenyl, -CN, -CHCH 2 , and -CCH.
  • Embodiment 1f-1 In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me, -CH(CH 3 )2, -F, -Cl, -OMe, -OEt, - OCH(CH 3 ) 2 , -OCD 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -CF 3 , -CH 2 CF 3, -CF 2 H, phenyl, -CN, - CHCH 2 , and -CCH.
  • Embodiment 1g In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -Me and -F. [00101] Embodiment 1g-1: In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and halo. In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from C 1 -C 6 haloalkyl and halo.
  • R 1a is independently in each instance selected from -CH 3 , -CF 3 , - CH 2 CF 3 , -CF 2 H, and -F. In some or any embodiments, including Embodiments A to H, R 1a is independently in each instance selected from -CF 3 and -F.
  • Embodiment 1h In some or any embodiments, including Embodiments A-G and 1 to 1g-1, one R 1a is present. In some or any embodiments, including Embodiments A-G and 1 to 1g-1, two R 1a are present. In some or any embodiments, including Embodiments A-F and 1 to 1g-1, three R 1a are present.
  • Embodiment 1i-1 In some or any embodiments, including Embodiments A to H and 1 to 1g-1, two R 1a are present and both R 1a are -F. In some or any embodiments, including Embodiments A to H and 1 to 1g-1, two R 1a are present and both R 1a are -CH 3 . In some or any embodiments, including Embodiments A to H and 1 to 1g-1, three R 1a are present and are independently in each instance selected from -Me and -F. [00104] Embodiment 1i: In some or any embodiments, including Embodiments A to H and 1 to 1g-1, one R 1a is present and R 1a is -CF 3 .
  • Embodiment 2 In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is phenyl substituted with R 3 and optionally substituted with (R 3a )q.
  • Embodiment 2a In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is a 5- to 10-membered heteroaryl or N-oxide thereof substituted with R 3 and optionally substituted with (R 3a )q. In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is a 5- to 10-membered heteroaryl substituted with R 3 and optionally substituted with (R 3a )q.
  • ring A is a 5- to 10-membered heterocyclic ring or N-oxide thereof substituted with R 3 and optionally substituted with (R 3a )q. In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is a 6- to 10-membered heterocyclic ring or N-oxide thereof substituted with R 3 and optionally substituted with (R 3a )q.
  • Embodiment 2b In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is phenyl substituted with R 3 , pyridyl or an N-oxide thereof substituted with R 3 , pyridazinyl substituted with R 3 , imidazopyridyl substituted with R 3 , benzimidazolyl substituted with R 3 , benzoisoxazolyl substituted with R 3 , oxazolopyridinyl substituted with R 3 , pyridinonyl (i.e.
  • R 3a is oxo substituted with R 3 pyrimidinonyl (ie where one R 3a is oxo) substituted with R 3 , quinolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , naphthyridinyl substituted with R 3 , or naphthyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , indazolyl substituted with R 3 , indazolonyl (i.e.
  • R 3a is oxo substituted with R 3 , benzoisothiazolyl substituted with R 3 , or thiophenyl substituted with R 3 ; where ring A is substituted with (R 3a )q; in some embodiments, R 3 is not -H. In some or any embodiments including Embodiments A- 1i, ring A is thiophenyl substituted with R 3 and optionally substituted with (R 3a )q.
  • Embodiment 2b-1 In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is phenyl substituted with R 3 , pyridyl or an N-oxide thereof substituted with R 3 , pyridazinyl substituted with R 3 , imidazopyridyl substituted with R 3 , benzimidazolyl substituted with R 3 , benzoisoxazolyl substituted with R 3 , oxazolopyridinyl substituted with R 3 , pyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , pyrimidinonyl (i.e.
  • R 3a is oxo substituted with R 3 , quinolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , naphthyridinyl substituted with R 3 , naphthyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , indazolyl substituted with R 3 , indazolonyl (i.e.
  • R 3a is oxo substituted with R 3 , or benzoisothiazolyl substituted with R 3 ; where ring A is substituted with (R 3a ) q ; in some embodiments, R 3 is not - H.
  • ring A is phenyl substituted with R 3 , pyridyl or N-oxide thereof substituted with R 3 , pyridazinyl substituted with R 3 , benzoisoxazolyl substituted with R 3 , pyridinonyl (i.e.
  • R 3a is oxo substituted with R 3 , naphthyridinyl substituted with R 3 , naphthyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 , isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 , indazolyl substituted with R 3 , indazolonyl (i.e. where one R 3a is oxo) substituted with R 3 , or benzoisothiazolyl substituted with R 3 ; where ring A is substituted with (R 3a ) q ; in some embodiments, R 3 is not - H.
  • ring A is phenyl substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is pyridyl or an N-oxide thereof substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is pyridazinyl substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is imidazopyridyl substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is benzimidazolyl substituted with R 3 .
  • ring A is benzoisoxazolyl substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is oxazolopyridinyl substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i ring A is pyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is pyrimidinonyl (i.e. where one R 3a is oxo) substituted with R 3 .
  • ring A is quinolinonyl (i.e. where one R 3a is oxo) substituted with R 3 .
  • ring A is naphthyridinonyl (i.e. where one R 3a is oxo) substituted with R 3 .
  • ring A is isoindolinonyl (i.e. where one R 3a is oxo) substituted with R 3 .
  • ring A is indazolonyl (i.e. where R 3a is oxo) substituted with R 3 .
  • R 3a is oxo
  • ring A is benzoisothiazolyl substituted with R 3 .
  • ring A is substituted with (R 3a ) q .
  • R 3 is not -H.
  • Embodiment 2c In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is substituted with R 3 , substituted with R 3 , substituted with R 3 , (i.e. where one R 3a is oxo) substituted with R 3 , (i.e. where one R 3a is oxo) substituted one R 3a is oxo) is oxo) substituted one R 3a is oxo) substituted with R 3 , substituted applicable; and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring substituted with R 3 , and where designates attachment to L 1 .
  • Embodiment 2c-1 In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is substituted with R 3 , substituted with R 3 , , (ie where one R 3a is oxo) substituted with
  • ring A is th R 3 and (R 3 substituted wi a )q, and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is substituted with R 3 and (R 3a ) q , and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is substituted with R 3 and (R 3a )q, and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is (i.e.
  • ring A is substituted with R 3 and (R 3a ) q , and where designates attachment to L 1 .
  • ring A is , designates attachment to L 1 .
  • ring A is designates attachment to L 1 .
  • Embodiments A to H and 1 to 1i ring substituted with R 3 and (R 3a ) q , and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, substituted with R 3 and (R 3a )q, and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring A is substituted with R 3 and (R 3a )q, and where designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 1i, ring (i.e.
  • R 3a is oxo substituted with R 3 and (R 3a ) q-1, and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a )q-1, and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a ) q- 1, and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a ) q-1 , and where designates attachment to L 1 .
  • ring one R 3a is oxo and another R 3a is -CH 3 ) substituted with R 3 and (R 3a ) q-2 , and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a )q-1, and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a )q-1, and where designates attachment to L 1 .
  • ring A is substituted with R 3 and (R 3a )q, and where designates attachment to L 1 .
  • ring one R 3a is oxo) substituted with R 3 and (R 3a )q-1, and where designates attachment to L 1 .
  • Embodiment 3 In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x and W 2 is CH. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CH and W 2 is CH. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x , R x is F, and W 2 is CH. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x , R x is C 1 -C 6 alkyl, and W 2 is CH.
  • W 1 is CR x , R x is CH 3 , and W 2 is CH. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x and W 2 is N. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CH and W 2 is N. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x , R x is F, and W 2 is N.
  • Embodiments A to H and 1 to 2c-1 W 1 is CR x , R x is C 1 -C 6 alkyl, and W 2 is N. In some or any embodiments, including Embodiments A to H and 1 to 2c-1, W 1 is CR x , R x is CH 3 , and W 2 is N. [00112] Embodiment 4: In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is C 1 -C 3 alkyl. In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is halogen.
  • At least one R 2 is C 1 -C 6 haloalkyl. In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is C 3 -C 6 cycloalkyl. In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is aryl optionally substituted with 1 or 2 halo.
  • Embodiment 4-1 In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is deuterium. In some or any embodiments including Embodiments A to H and 1 to 3, at least one R 2 is deutero-C 1-2 alkyl.
  • At least one R 2 is 3- to 6-membered heterocycloalkyl.
  • two R 2 groups, on the same carbon come together with the carbon to which they are attached, to form an alkylidenyl group; and the remaining R 2 , when present, are independently selected from C 1 -C 6 alkyl, in some embodiments, methyl, ethyl, or tert-butyl; deuterium; deutero-C 1-2 alkyl, is some embodiments, -CH 2 D or CD3; C 1 -C 6 alkoxy, in some embodiments, methoxy; halo, in some embodiments, fluoro or chloro; C 1 -C 3 haloalkyl, in some embodiments, C 1 -C 2 haloalkyl (CH 2 CH 2 F, CH 2 CHF 2 , CF 2 CH 3 , CH 2 CF 3 , CH 2 CF 3 ,
  • Embodiment 4a In some or any embodiments including Embodiments A to H and 1 to 3, R 2 , independently in each instance is -CH 3 -CH 2 CH 3 -C(CH 3 ) 3 -D -CH 2 D CD 3 - OCH 3 , -F, -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 F, CH 2 CHF 2 , CF 2 CH 3 , cyclopropyl, , cyclobutyl, , cyclopentyl, cyclohexyl, phenyl where the phenyl is optionally substituted with 1 or 2 halo, or .
  • R 2 is -C(CH 3 ) 3 . In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is -D. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is -CH 2 D. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is CD3. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is -CH 2 CH 2 F, CH 2 CHF 2 , or CF 2 CH 3 . In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is .
  • Embodiment 4a-1 In some or any embodiments including Embodiments A to H and 1 to 3, R 2 , independently in each instance, is -CH 3 , -CH 2 CH 3 , -F, -CF 3 , -CH 2 CF 3 , -C(CH 3 )3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl where the phenyl is optionally substituted with 1 or 2 halo.
  • R 2 independently in each instance, is -CH 3 , -CH 2 CH 3 , -F, -CF 3 , -C(CH 3 ) 3 .
  • R 2 independently in each instance, is selected from halo and C 1 -C 6 haloalkyl.
  • R 2 is -CH 3 .
  • R 2 is -C(CH 3 )3.
  • R 2 is -F.
  • R 2 is -CF 3 . In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is -CH 2 CF 3 . In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is cyclopropyl. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is cyclobutyl. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is cyclopropyl. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 is cyclopentyl.
  • Embodiment 4a-2 In some or any embodiments including Embodiments A to H and 1 to 3, R 2 , independently in each instance, is C 1 -C 6 alkyl or halo. In some or any embodiments including Embodiments A to H and 1 to 3, R 2 , independently in each instance, is -CH 3 or F.
  • Embodiment 4b In some or any embodiments, including Embodiments A to H and 1 to 4a, one R 2 is present.
  • Embodiment 4a In some or any embodiments, including Embodiments A to H and 1 to 4a, two R 2 are present. In some or any embodiments, including Embodiments A to H and 1 to 4a, three R 2 are present. [00118] Embodiment 4c: In some or any embodiments, including Embodiments A to H and 1 to 4a, two R 2 are present and both R 2 are -F. In some or any embodiments, including Embodiments A to H and 1 to 4a, two R 2 are present and both R 2 are -CH 3 . [00119] Embodiment 4d: In some or any embodiments, including Embodiments A to H and 1 to 4a, one R 2 is present and R 2 is -CH 3 .
  • Embodiment 5 In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is H. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -CN. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is halo. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -OH. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is oxo.
  • R 3 is -B(OH)2. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -COOH. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is C 1 -C 6 alkoxycarbonyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is C 1 -C 6 alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is hydroxy-C 1 -C 6 -alkyl.
  • R 3 is - S(O) 2 NHR, wherein R is C 1 -C 3 alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -S(O)2NHR, wherein R is C3-C5cycloalkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -S(O)2C 1 -C 6 -alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is .
  • R 3 is C 1 -C 6 alkoxy. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is amino-C 1 -C 6 alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is amino-C 1 -C 6 alkyl, wherein the alkyl in amino-C 1 -C 6 alkyl is optionally further substituted with 1, 2, 3, or 4 halo.
  • R 3 is amino-C 1 -C 6 alkyl, wherein the alkyl in amino-C 1 -C 6 alkyl is further substituted with 1, 2, 3, or 4 halo. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -NHC(O)C1-3alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -NHC(O)NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -NHS(O)2NH 2 .
  • R 3 is C 3 -C 6 -cycloalkyl substituted with one -NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is 3- to 6-membered heterocycloalkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is 3- to 6-membered heterocycloalkyl optionally substituted with one -NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is 3- to 6-membered heterocycloalkyl substituted with one -NH 2 .
  • Embodiment 5-1 In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -C(O)N(R)2. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -C(O)N(CH 3 )2. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is wherein each R is independently hydrogen, C 1 -C 3 alkyl, or C3-C5 cycloalkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is 5- to 6-membered heteroaryl.
  • R 3 is . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is deutero-C 1-2 alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is CD3.
  • Embodiment 5a In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is -CN, -OH, oxo, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, hydroxy- , , a o y, - , a o- a y , o - o - e e e e oa yl and wherein R each is independently hydrogen or C 3 -C 5 cycloalkyl.
  • R 3 is not -H and R 3 is -C(O)N(R) 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is -C(O)N(CH 3 ) 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is . In some or any embodiments including Embodiments A to H and 1 to 4cd, R 3 is not -H and R 3 is .
  • R 3 is not -H and R 3 is 5- to 6-membered heteroaryl. In some or any embodiments including Embodiments A to H and 1 to 4c, R 3 is not -H and R 3 .
  • R 3 is -CN, -OH, C 1 -C 6 alkoxycarbonyl, -C(O)NH 2 , -S(O)2NH 2 , -COOEt, or oxo. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is -CN. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is -OH. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is oxo.
  • R 3 is not -H and R 3 is C 1 -C 6 alkoxycarbonyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -COOEt. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is C 1 -C 6 alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is hydroxy-C 1 -C 6 -alkyl.
  • R 3 is -S(O)2NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is -S(O) 2 C 1 -C 6 - alkyl. In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is C 1 -C 6 alkoxy.
  • R 3 is not -H and R 3 is -NH 2 . In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is not -H and R 3 is amino-C 1 -C 6 alkyl.
  • Embodiment 5b In some or any embodiments including Embodiments A to H and 1 to 4d, R 3 is -CN, -OH, oxo, C 1 -C 6 alkoxycarbonyl, -C(O)NH 2 , -S(O)2NH 2 , -S(O)2C 1 -C 6 -alkyl, , or C 1 -C 6 alkoxy.
  • R 3 is -CN, -OH, oxo, -COOEt, - C(O)NH 2 , -S(O) 2 NH 2 , -S(O) 2 CH 3 , , or -OMe.
  • R 3 is -S(O)2CH 3 .
  • R 3 is .
  • R 3 is -OMe.
  • Embodiment 6 In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is hydrogen. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is oxo. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is halogen. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is C 1 -C 3 alkyl. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is C 3 -C 6 cycloalkyl.
  • Embodiment 6a In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is -H, halo, oxo, or C 1 -C 3 alkyl. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is -H, -F, oxo, or -CH 3 . In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is -F. In some or any embodiments including Embodiments A to H and 1 to 5c, at least one R 3a is -CH 3 .
  • Embodiment 6b In some or any embodiments, including Embodiments A to H and 1 to 6a, one R 3a is present. In some or any embodiments, including Embodiments A to H and 1 to 6a, two R 3a are present. In some or any embodiments, including Embodiments A to H and 1 to 6a, three R 3a are present.
  • Embodiment 6c In some or any embodiments including Embodiments A to H and 1 to 5c, R 3a is oxo and q is 1. In some or any embodiments including Embodiments A to H and 1 to 5c, R 3 is -C(O)N(R)2, R 3a is oxo, and q is 1.
  • Embodiment 7 In some or any embodiments including Embodiments A to H and 1 to 6c, ring B is a 3- to 10-membered cycloalkylene. In some or any Embodiments including Embodiments A to H and 1 to 6c, ring B is a 5- to 10-membered heterocycloalkylene ring.
  • Embodiment 7a In some or any embodiments including Embodiments A to H and 1 to 6c, ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group.
  • Embodiment 7b In some or any embodiments including Embodiments A to H and 1 to 6c, ring B is a 3- to 10-membered cycloalkylene; or a 5- or 7-membered heterocycloalkyl; where ring B is substituted with (R 2 )p.
  • ring B is a 3- to 10-membered cycloalkylene where ring B is substituted with (R 2 ) p . In some or any embodiments including Embodiments A to H and 1 to 6c, ring B is a 5- or 7-membered heterocycloalkyl where ring B is substituted with (R 2 ) p . [00132] Embodiment 7c: In some or any embodiments including Embodiments A to H and ,
  • ring B is substituted with (R 2 ) p ; and where designates attachment to L 1 , designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is or ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • Embodiment 7c-1 In some or any embodiments including Embodiments A to H and 1 to 6c, ring substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 In some or any embodiments including Embodiments A to H and 1 to 6c, ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 . [00133] Embodiment 7c-1: In some or any embodiments including Embodiments A to H , , , , , , , , , , , , , , , ,
  • ring B is substituted with (R 2 ) p ; and where designates attachment to L 1 , designates attachment to L 2 , and designates attachment to R 2 .
  • designates attachment to L 1 designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 . In some or any embodiments including Embodiments A to H and 1 to 6c, ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 . In some or any embodiments including Embodiments A to H and 1 to 6c, ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is , where ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L 1 , designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring where ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is , where ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is , where ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is here ring B is substituted with (R 2 )p; and where designates a ac e o , designates attachment to L 2 , and designates attachment to R 2 .
  • ring where ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 ) p ; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted with (R 2 )p; and where designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring ring B is substituted designates attachment to L, designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is where ring B is substituted with (R 2 ) p ; and where designates a ac e o , designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is where ring B is substituted with (R 2 )p; and where designates a ac e o , designates attachment to L 2 , and designates attachment to R 2 .
  • ring B is or where ring B is substituted with (R 2 ) p ; and where designates a ac e o , designates attachment to L 2 , and designates attachment to R 2 .
  • Embodiment 7d In some or any embodiments including Embodiments A to H and , , , , , , , , ,
  • Embodiment 7d-1 In some or any embodiments including Embodiments A to H ,
  • Embodiment 7e In some or any embodiments including Embodiments A to H and 1 to 6c, [00136] Embodiment 7e: In some or any embodiments including Embodiments A to H and and designates attachment to R 2 . [00137] Embodiment 7e-1: In some or any embodiments including Embodiments A to H designates attachment to L 2 , and designates attachment to R 2 . [00138] Embodiment 7e-2: In some or any embodiments including Embodiments A to H and 1 to 6c, ring ,
  • Embodiment 7f In some or any embodiments including Embodiments A to H and designates attachment to L 1 , designates attachment to L 2 , and designates attachment to R 2 .
  • Embodiment 7g In some or any embodiments including Embodiments A to H and and designates attachment to R 2 .
  • Embodiment 7g-1 In some or any embodiments including Embodiments A to H and 1 to 6c, ring where designates attachment to L 1 , designates attachment to L 2 , and designates attachment to R 2 .
  • Embodiment 8 In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is ring C.
  • R 1 is ring C and ring C is a 3- to 10-membered cycloalkyl substituted with (R 1a )n.
  • R 1 is ring C and ring C is a C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl wherein the C 3 -C 6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • Embodiment 8-1 In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is a 5- to 10-membered heterocyclic ring substituted with (R 1a )n.
  • Embodiment 8a In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is ring C and ring C is a 3- to 10-membered cycloalkyl substituted with (R 1a )n; a 5- to 10-membered cycloalkenyl; a 6- or 7-membered heterocycloalkyl substituted with (R 1a )n; or, a C 6 cycloalkyl-C 1 -C 6 alkyl wherein the C 6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • R 1 is ring C and ring C is a 3- to 8-membered cycloalkyl substituted with (R 1a )n; a 5- to 8-membered cycloalkenyl; a 6- or 7- membered heterocycloalkyl substituted with (R 1a )n; or, a C 6 cycloalkyl-C 1 -C 6 alkyl wherein the C6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • ring C is a 5- to 8-membered cycloalkenyl substituted with (R 1a )n.
  • Embodiment 8a-1 In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is ring C and ring C is a 3- to 10-membered cycloalkyl substituted with (R 1a )n; a 6- or 7-membered heterocycloalkyl substituted with (R 1a )n; or, a C 6 cycloalkyl- C 1 -C 6 alkyl wherein the C6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • R 1 is ring C and ring C is a 3- to 8-membered cycloalkyl substituted with (R 1a )n; a 6- or 7-membered heterocycloalkyl substituted with (R 1a )n; or, a C6 cycloalkyl-C 1 -C 6 alkyl wherein the C6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • ring C is a 3- to 8-membered cycloalkyl substituted with (R 1a )n. In some or any embodiments including Embodiments A to H and 1 to 7g-1, ring C is a 6- or 7-membered heterocycloalkyl substituted with (R 1a )n.
  • ring C is a C6 cycloalkyl-C 1 -C 6 alkyl wherein the C6 cycloalkyl is substituted with (R 1a )n and the C 1 -C 6 alkyl is optionally substituted with one or more fluoro groups.
  • Embodiment 8b In some or any embodiments including Embodiments 1 to 7g-1, , designates attachment to L 2 . In some or any embodiments including Embodiments 1 to 7g-1, R 1 is ring C and ring C is designates attachment to L 2 .
  • Embodiment 8b-1 In some or any embodiments including Embodiments 1 to 7g- embodiments including Embodiments 1 to 7g-1, R 1 is ring C and ring designates attachment to L 2 . In some or any embodiments including 2 designates attachment to L , and designates attachment to R 1a . In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is ring C and ring designates attachment to L 2 .
  • Embodiment 8c In some or any embodiments including Embodiments A to H and 2 designates attachment to L , and designates attachment to R 1a . In some or any Embodiments of Formula (I′), (I), or (P-I) L 2 .
  • Embodiment 8c-1 In some or any embodiments including Embodiments A to H designates attachment to R 1a . In some or any Embodiments of Formula (I) or (P-I) including Embodiments A to H and 1 to 7g-1, R 1 is ring C and ring
  • Embodiment 8c-2 In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is ring C and ring where designates attachment to L 2 .
  • Embodiment 8d In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is C 1 -C 10 alkyl or C 1 -C 8 haloalkyl. In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is C 1 -C 10 alkyl.
  • R 1 is methyl, tert-butyl, -CH 2 C(CH 3 )3, -CH 2 C(CH 2 CH 3 )2, or -CH(CH 2 CH 2 CH 3 ) 2 . In some or any embodiments including Embodiments A to H and 1 to 7g-1, R 1 is C 1 -C 8 haloalkyl.
  • R 1 is -CF 3 , -CH 2 CF 3 , -CH(CH 3 )CH 2 CH 2 CF 2 CH 3 , or -CH 2 CH(CH 3 )CH 2 CH 2 CF 2 CH 3
  • Embodiment 9 In some or any embodiments including Embodiments A to H and 1 to 8d, L 1 is a bond. In some or any embodiments including Embodiments A to H and 1 to 8d, L 1 is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A.
  • Embodiment 9a In some or any embodiments including Embodiments A to H and 1 to 8d, L 1 is , indicates attachment to W 1 , and indicates attachment to ring A.
  • Embodiment 10 In some or any embodiments including Embodiments A to H and 1 to 9a, L 2 is a bond. In some or any embodiments including Embodiments A to H and 1 to 9a, L 2 is -O-.
  • Embodiment 10-1 In some or any embodiments including Embodiments A to H and 1 to 9a, L 2 is C(O)-.
  • Embodiment 11 In some or any embodiments including Embodiments A to H and 1 to 10-1, R x is H.
  • R x is F. In some or any embodiments including Embodiments A to H and 1 to 10-1, R x is C 1 -C 6 alkyl. In some or any embodiments including Embodiments A to H and 1 to 10-1, R x is CH 3 .
  • Embodiment 12 In some or any embodiments including Embodiments A to H and 1 and 2 to 11, n is 0. In some or any embodiments including Embodiments A to H and 1 to 1g and 2 to 11, n is 1. In some or any embodiments including Embodiments A to H and 1 to 1g and 2 to 11, n is 2.
  • Embodiment 12a In some or any embodiments including Embodiments A to H and 1 to 1g and 2 to 11, n is 0, 1, 2, or 3.
  • Embodiment 12a-1 In some or any embodiments including Embodiments A to H and 1 to 1g and 2 to 11, n is 4 or 5.
  • Embodiment 12a-1 In some or any embodiments including Embodiments A to H and 1 to 1g and 2 to 11, n is 5.
  • Embodiment 13 In some or any embodiments including Embodiments A to H and 1 to A to 3 and 5 to 12a-1, p is 0. In some or any embodiments including Embodiments A to H and 1 to 4a and 5 to 12a-1, p is 1. In some or any embodiments including Embodiments A to H and 1 to 4a and 5 to 12a-1, p is 2. In some or any embodiments including Embodiments A to H and 1 to 4a and 5 to 12a-1, p is 3. In some or any embodiments including Embodiments A to H and 1 to 4a and 5 to 12a-1, p is 4.
  • Embodiment 13a In some or any Embodiments including Embodiments A to H and 1 to 4a and 5 to 12a-1, p is 0, 1, 2, or 3.
  • Embodiment 14 In some or any embodiments including Embodiments A to H and 1 to 5 and 7 to 13a, q is 0. In some or any embodiments including Embodiments A to H and 1 to 6a and 7 to 13a, q is 1. In some or any embodiments including Embodiments A to H and 1 to 6a and 7 to 13a, q is 2. In some or any embodiments including Embodiments A to H and 1 to 6a and 7 to 13a, q is 3.
  • Embodiment 14a In some or any embodiments including Embodiments A to H and 1 to 6a and 7 to 13a, q is 0, 1, or 2.
  • Embodiment 14a-1 In some or any embodiments including Embodiments A to H and 1 to 6a and 7 to 13a, q is 0 and R 3 is not H.
  • Embodiment 15 In some or any embodiments including Embodiments A to H and 1 to 14a to 1, n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0 or 1.
  • n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0. In some or any embodiments including Embodiments A to H and 1 to 14a to 1, n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 1.
  • Embodiment 15a In some or any embodiments including Embodiments A to H and 1 to 15, n is 0, p is 2, and q is 1; n is 1, p is 0, and q is 1; n is 1, p is 1, and q is 1; n is 1, p is 2, and q is 1; n is 2, p is 0, and q is 1; n is 2, p is 2, and q is 1; n is 3, p is 0, and q is 1; n is 3, p is 1, and q is 1; n is 3, p is 2, and q is 1; n is 3, p is 2, and q is 1; n is 3, p is 3, and q is 0; or n is 3, p is 3, and q is 1.
  • n is 0, p is 0, and q is 0; n is 0, p is 1, and q is 0; n is 0, p is 2; and q is 0; n is 0, p is 3; and q is 0; n is 1, p is 2; and q is 0; n is 2, p is 0; and q is 0; n is 2, p is 1; and q is 0; n is 2, p is 2; and q is 0; n is 2, p is 3; and q is 0; or n is 3, p is 2; and q is 0.
  • n is 0, p is 0, and q is 1; n is 0, p is 1, and q is 1; n is 0, p is 2; and q is 1; n is 0, p is 3; and q is 1; n is 1, p is 2; and q is 1; n is 2, p is 0; and q is 1; n is 2, p is 1; and q is 1; n is 2, p is 2; and q is 1; n is 2, p is 3; and q is 1; or n is 3, p is 2; and q is 1.
  • Embodiment 15a-1 In some or any embodiments including Embodiments A to H and 1 to 15, n is 4, p is 2, and q is 1.
  • Embodiment 15b In some or any embodiments including Embodiments A to H and 1 to 15, n is 1, 2, 3, 4, or 5; p is 1, 2, 3, or 4; and q is 0, 1, 2, or 3.
  • n is 0, 1, 2, 3, 4, or 5; p is 1, 2, 3, or 4; and q is 1, 2, or 3.
  • Embodiment 15c In some or any embodiments including Embodiments A to H and 1 to 15, p and n are not 0. In some or any embodiments including Embodiments A to H and 1 to 15, p and q are not 0.
  • Embodiment 15d In some or any embodiments including Embodiments A to H and 1 to 15, n is 1 or 2; p is 0, 1, 2, or 3; q is 1 or 2.
  • Embodiment 16-1 In some or any embodiments including Embodiments A to H and 1 to 15d, L 1 is bond, ring designates attachment to L 1 . In some or any embodiments including Embodiments A to H and 1 to 15d, membered cycloalkyl.
  • L 1 is bond, ring , ring B is a 5- to 8- membered cycloalkylene, and ring C a 5- to 8-membered cycloalkyl.
  • L 1 is bond, ring A is , ring B is a 5- to 8-membered cycloalkylene, ring C a 5- to 8-membered cycloalkyl, p is 0, 1, 2, or 3, and n is 1 or 2.
  • Embodiment 17 In some or any embodiments the compound is selected from any of: .
  • Embodiment 17-1 In some or any embodiments, the compound is selected from any of:
  • Embodiment 17a In some or any embodiments of, the compound is selected from any of: [00176] Embodiment 17a-1: In some or any embodiments, the compound is selected from any of: . In some further embodiments of Embodiment in some further embodiments of 17a and 17a-1, and in some further embodiments of 17a and 17a-1, [00177] Embodiment 18: In some or any embodiments of Formula , the compound is selected from any of:
  • Embodiment 18-1 In some or any embodiments of Formula (P-I), the compound is selected from any of: .
  • Embodiment 19 In some or any embodiments of Formula (I′), (I), or (P-I), the compound is selected from any of: .
  • Embodiment 19-1 In some or any embodiments, the compound is selected from any of: . In some further embodiments of Embodiment some further embodiments of Embodiment 19 and 19-1, in further some embodiments of Embodiment .
  • Embodiment 20 In some or any embodiments of Formula , the compound is selected from any of:
  • Embodiment 21 In some or any embodiments of, the compound is selected from any of: ;
  • Embodiment 22 In some or any embodiments of Formula (I), the compound is selected from any of compounds 1-297, or a pharmaceutically acceptable salt and/or an isomer thereof, from Table A.
  • Compounds drawn as trans isomers, but labelled as “mixture of enantiomers” are mixtures of trans enantiomers.
  • compounds drawn as cis isomers, but labelled as “mixture of enantiomers” are mixtures of cis enantiomers.
  • mixture of trans enantiomers and is a mixture of (1S,2R)-stereochemistry.
  • enantiomer as depicted are enantiomers with the absolute stereochemistry as drawn for the particular carbon(s). Unless indicated otherwise (for example, stereochemistry is explicitly indicated in a structure at a particular atom), the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.
  • Optically Active Compounds [00186] It is appreciated that compounds provided herein have several chiral centers and may exist in and be isolated in optically active and racemic forms. It is to be understood that any racemic, optically-active, diastereomeric, tautomeric, or stereoisomeric form, mixture, or combination thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention.
  • isomer in the phrase “a pharmaceutically acceptable salt thereof and/or an isomer thereof,” includes any optically- active, diastereomeric, tautomeric, or stereoisomeric form.
  • optically active forms in some or any embodiments, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • methods to obtain optically active materials include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated.
  • This technique can be used if crystals of the separate stereoisomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an stereoisomerically pure or enriched synthetic precursor of the desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from an a chiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the stereoisomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the stereoisomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and stereoisomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the stereoisomers are separated by virtue of preferential dissolution of one stereoisomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.
  • a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.
  • a composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight, of the designated stereoisomer, the remainder comprising other chemical species or stereoisomers.
  • isotopically Enriched Compounds [00189] Also provided herein are isotopically enriched compounds. [00190] Isotopic enrichment (in some or any embodiments, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J.
  • Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction.
  • KIE Kinetic Isotope Effect
  • DKIE Deuterium Kinetic Isotope Effect
  • the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C–H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
  • High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy.
  • tritium As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen, may lead to a similar kinetic isotope effect. [00195] For example, the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
  • the compounds described herein may be used as radiopharmaceuticals such as, for example, imaging agents.
  • radiopharmaceuticals are positron emission tomography (PET) imaging agents.
  • PET positron emission tomography
  • substitution of radionuclides (e.g., positron emitting isotopes) for atoms in the compounds allows for the syntheses of radiopharmaceuticals that can function as imaging agents.
  • radionuclides which can be substituted in the compounds described herein include, and are not limited to, 18 F, 11 C, 13 N, 15 O, 76 Br, and 124 I.
  • the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms.
  • the compound is administered as an isotopic composition.
  • the animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system.
  • enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long- term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses. [00198] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition.
  • the compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art.
  • compositions and Methods of Administration [00202]
  • the compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.
  • pharmaceutical compositions comprising a compound of Formula (I′), (I), or (P-I), as described herein in some and any embodiments, and a pharmaceutically acceptable carrier.
  • the composition is an oral or injectable composition.
  • the injectable composition is a subcutaneously injectable composition.
  • the methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including a compound of Formula (I′), (I), or (P-I) if appropriate in a salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of pain and/or conditions modulated by voltage-gated sodium channels.
  • the second agent can be formulated or packaged with the compound provided herein.
  • the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration.
  • the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
  • the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols).
  • the compound provided herein is administered orally.
  • Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
  • a lubricant such as magnesium stearate
  • Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • These compositions can also comprise substances other than diluents, in some or any embodiments, wetting, sweetening or flavoring products.
  • the compositions for parenteral administration can be emulsions or sterile solutions.
  • Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in some or any embodiments, ethyl oleate.
  • These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in some or any embodiments, using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semi- synthetic glycerides or polyethylene glycols.
  • the compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle.
  • the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, in some or any embodiments, dextran, mannitol or lactose.
  • compositions provided herein is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients.
  • prophylactic or therapeutic agents e.g., a compound provided herein, or other prophylactic or therapeutic agent
  • typically one or more pharmaceutically acceptable carriers or excipients e.g., a typically one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and more particularly in humans.
  • carrier includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • adjuvant e.g., Freund’s adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well-known to those skilled in the art of pharmacy, and in some or any embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • compositions or dosage forms Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form.
  • the composition or single unit dosage form if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, in some or any embodiments, in the U.S. Pharmacopeia (USP 36–NF 31 S2).
  • lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d.
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. In some or any embodiments, suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. [00218] Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in some or any embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, in some or any embodiments, an animal subject, such as a mammalian subject, in some or any embodiments, a human subject.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intrathecal, epidural, local or regional for peripheral nerve block, intravenous, intradermal, subcutaneous intramuscular subcutaneous oral buccal sublingual inhalation, intranasal, transdermal, topical (including administration to the eye, and in some embodiments to the cornea), transmucosal, intra-tumoral, intra-synovial, and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical (including administration to the eye, and in some embodiments to the cornea) administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.
  • suspensions e.g., aqueous or non-
  • composition, shape, and type of dosage forms provided herein will typically vary depending on their use.
  • a dosage form used in the initial treatment of pain may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • compositions are supplied either separately or mixed together in unit dosage form, in some or any embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • dosage forms can be prepared by any of the methods of pharmacy.
  • compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, in some or any embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. Delayed Release Dosage Forms [00236] Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art.
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in some or any embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
  • unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).
  • polymeric materials can be used.
  • a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:1527- 1533 (1990)).
  • the active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neo
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and poly
  • Transdermal, Topical & Mucosal Dosage Forms [00243] Also provided are transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art.
  • transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent.
  • Dosage and Unit Dosage Forms [00247] In human therapeutics, the doctor will determine the posology which the doctor considers most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the infection and other factors specific to the subject to be treated. In some or any embodiments, doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In some or any embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult.
  • dose rates of from about 50 to about 500 mg per day are also contemplated.
  • doses for subcutaneous administration are from about 1 to about 50 mg per day, or from about 1 to about 25 mg per day, or from about 1 to about 10 mg per day, or from about 1 to about 20 mg per day, or from about 5 to about 25 mg per day, or from about 5 mg to about 20 mg per day, or from about 10 to about 20 mg per day.
  • doses for oral administration are from about 5 to about 250 mg per day, from about 5 to 200 mg per day, or from about 50 mg to about 100 mg per day, or from about 75 mg to about 1125 mg per day, or from about 10 mg to about 200 mg per day.
  • the mg/day amounts are for an adult.
  • methods of treating a condition associated with voltage-gated sodium channel function and/or pain in a subject by administering, to a subject in need thereof, a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the amount of the compound or composition which will be therapeutically or prophylactically effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage administered to a subject is 0.01 mg/kg to 3 mg/kg of the subject’s body weight, or 0.10 mg/kg to 3 mg/kg of the subject’s body weight, based on weight of the active compound.
  • the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the subject’s body weight. In some embodiments, the dosage is administered subcutaneously to a subject and is between about 0.01 mg/kg to 1 mg/kg (inclusive), or between about 0.03 mg/kg to 0.5 mg/kg (inclusive) of the subject’s body weight, based on weight of the active compound.
  • the dosage is administered orally to a subject and is between about 0.10 mg/kg to 5 mg/kg (inclusive) of the subject’s body weight, or between about 0.10 mg/kg to 2 mg/kg (inclusive) of the subject’s body weight, based on weight of the active compound.
  • the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • the daily dose is administered thrice daily in equally divided doses.
  • the daily dose is administered four times daily in equally divided doses.
  • a daily dose range should be from about 0.01 mg to about 400 mg per day, from about 0.1 mg to about 250 mg per day, from about 10 mg to about 200 mg per day, in other embodiments, or from about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
  • the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
  • the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject’s body weight.
  • the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses.
  • the loading dose can be, for instance, about 6 to about 40 mg per day, or about 10 to about 20 mg per day for one day to five weeks.
  • the loading dose can be followed by one or more maintenance doses.
  • each maintenance does is, independently, about from about 1 mg to about 20 mg per day, between about 2.5 mg and about 15 mg per day, or between about 2.5 and about 8 mg per day.
  • Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.
  • a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject.
  • the steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.
  • a sufficient amount of a compound or composition provided herein is administered to achieve a steady-state concentration in blood or serum of the subject of from about 100 to about 1000 ng/mL, from about 150 to about 800 ng/mL, or from about 300 to about 600 ng/mL.
  • loading doses can be administered to achieve steady-state blood or serum concentrations of about 300 to about 2000 ng/mL, or about 400 to about 800 ng/mL for one to five days.
  • maintenance doses can be administered to achieve a steady-state concentration in blood or serum of the subject of from about 100 to about 1000 ng/mL, from about 150 to about 800 ng/mL, or from about 300 to about 600 ng/mL.
  • administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein.
  • the unit dosage comprises 1 to 1000 mg, 1 to 100 mg or 10 to 50 mg active ingredient.
  • the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient.
  • Such unit dosages can be prepared according to techniques familiar to those of skill in the art. [00255] In some or any embodiments, dosages of the second agents to be used in a combination therapy are provided herein. In some or any embodiments, dosages lower than those which have been or are currently being used to treat pain are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill in the art.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart.
  • the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In some or any embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently. [00257] In other embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart. [00258] In some or any embodiments, administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • a compound provided herein and a second agent are administered to a patient, in some or any embodiments, a subject, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the compound provided herein and the second active agent exert their effect at times which overlap.
  • Each second active agent can be administered separately, in any appropriate form and by any suitable route.
  • the compound provided herein is administered before, concurrently or after administration of the second active agent.
  • the compound provided herein and the second agent are cyclically administered to a patient Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • a first agent e.g., a first prophylactic or therapeutic agent
  • a second agent and/or third agent e.g., a second and/or third prophylactic or therapeutic agent
  • the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • the second agent can act additively or synergistically with the compound provided herein.
  • the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition.
  • a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions.
  • a compound provided herein is administered prior to or subsequent to administration of a second agent.
  • administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral.
  • the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • kits for use in methods of treatment of pain and/or a condition associated with voltage-gated sodium channel function or a pain-related disorder can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the pain or a pain-related disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • a unit dose of a compound or composition provided herein, or a second agent or composition can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 day.
  • a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.
  • suitable packaging is provided.
  • “packaging” includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject.
  • Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • plastic e.g., polyethylene, polypropylene, and polycarbonate
  • a method for treating a condition associated with voltage-gated sodium channel function and/or pain in a subject which comprises contacting the subject with a therapeutically or prophylactically effective amount of a compound of Formula (I) including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the condition is pain or the condition is associated with pain.
  • the condition is pain.
  • the condition is associated with pain.
  • the pain is nociceptive pain.
  • the pain is neuropathic pain.
  • the pain is inflammatory pain.
  • the pain is refractory to other forms of pain medications.
  • the condition is selected from the group consisting of erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, and postsurgical pain.
  • the condition is selected from the group consisting of epilepsy, Parkinson’s disease, a mood disorder, psychosis, amyotropic lateral sclerosis, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder.
  • the methods encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment pain and/or a condition associated with voltage-gated sodium channel function in combination with a second agent effective for the treatment or prevention of pain and/or a condition associated with voltage-gated sodium channel function.
  • the compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein. [00271] In some or any embodiments, provided herein are methods for treating a condition associated with voltage-gated sodium channel function in a subject. In some or any embodiments, the methods encompass the step of administering to the subject in need thereof a therapeutically or prophylactically effective amount of a compound effective for the treatment of a condition associated with voltage-gated sodium channel function in combination with a second agent effective for the treatment of a condition associated with voltage-gated sodium channel function.
  • the compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein. [00272] In some or any embodiments, provided herein is of inhibiting NA ⁇ 1.8 comprising contacting NA ⁇ 1.8 with a compound of Formula (I′), (I), or (P-I) and Compounds 1-297.
  • the pain to be reduced, ameliorated, treated, or prevented is associated with a condition or is a condition selected from acute pain, anal fissures, back pain, chronic pain, dental pain, joint pain, neck pain, neuropathic pain, obstetric pain, post-herpetic neuralgia, shingles, tension headaches, trigeminal blepharospasm, pain associated with cardiac arrythmia, focal dystonia, hyperhidrosis, muscle spasms, urinary bladder relaxation, visceral pain, sympathetically maintained pain, myositis pain, musculoskeletal pain, lower back pain, pain from sprains and strains, pain associated with functional bowel disorders, non-cardiac chest pain, pain associated with irritable bowel syndrome, pain associated with myocardial ischemia, toothache pain, pain from dysmenorrhea, erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigemin
  • the pain to be reduced, ameliorated, treated, or prevented is pain in an acute care setting, including post- surgery (post-surgical pain). In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is pain in an acute care setting, including post-surgery and the compound is administered intravenously. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is ocular pain. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is ocular pain and the compound is administered topically. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain.
  • the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain and the compound is administered subcutaneously. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain and the compound is administered orally.
  • the condition associated with voltage-gated sodium channel function is selected from itch, cough, epilepsy, Parkinson’s disease, a mood disorder, psychosis, amyotrophic lateral sclerosis (ALS), cardiac arrhythmia, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder.
  • the condition associated with voltage-gated sodium channel function is selected from pain, itch, cough, glaucoma, and ischemia. In some or any embodiments, the condition associated with voltage-gated sodium channel function is selected from pain, itch, and cough. In some or any embodiments, the condition associated with voltage-gated sodium channel function is pain. [00275] In some or any embodiments, the compounds described herein are used for delaying the onset of pain, or reducing the severity or duration of pain. In some or any embodiments, the compounds described herein are used for the reduction of the severity or duration of pain associated with voltage-gated sodium channel function. In some embodiments, the compounds described herein are used for delaying or preventing onset of pain.
  • the compounds described herein are used for prevention of pain or of a condition associated with voltage-gated sodium channel function.
  • the compounds described herein are used for treatment of pain or of a condition associated with voltage-gated sodium channel function.
  • Assay Methods Compounds can be assayed for efficacy in treating pain and/or a condition associated with voltage-gated sodium channel function according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein.
  • the compounds and compositions provided herein are useful in methods of treatment of pain and/or a condition associated with voltage-gated sodium channel function, that comprise further administration of a second agent effective for the treatment of pain and/or a pain-related disorder and/or a condition associated with voltage- gated sodium channel function.
  • the second agent can be any agent known to those of skill in the art to be effective for the treatment of pain and/or a pain-related disorder and/or a condition associated with voltage-gated sodium channel function, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States.
  • the second agent is a local anesthetic (in some or any embodiments, a steroid), an opioid, a vasoconstrictor, a glucocorticoid, adrenergic drugs (in some or any embodiments, alpha agonists or mixed central-peripheral alpha-2- agonists), vanilloids, an anti-inflammatory agent (e.g. NSAID, or an anti-inflammatory agent associated with ocular conditions, including cyclosporine and lifitegrast) or a chemical permeation enhancer.
  • the second agent is an inhibitor of NaV 1.8.
  • chemical permeation enhancers include anionic surfactants, cationic surfactants, nonionic surfactants.
  • the second agent is bupivacaine, levobupivicaine, tetracaine, ropivacaine, epinephrine, phenylephrine, clonidine, sodium lauryl sulfate, sodium octyl sulfate, dodecyltrimethylammonium bromide, octyltrimethylammonium bromide, polyoxyethylene (20) sorbitan monolaurate, and/or polyoxyethylene (20) sorbitan monooleate.
  • a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agents. [00281] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • the active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of pain and/or a pain-related disorder and/or a condition associated with voltage-gated sodium channel function.
  • another therapeutic agent in particular an agent effective in the treatment of pain and/or a pain-related disorder and/or a condition associated with voltage-gated sodium channel function.
  • effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
  • the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the pain or a pain-related disorder to be alleviated.
  • ESI electrospray ionization
  • g grams
  • mg milligrams
  • mL or ml milliliters
  • ⁇ L microliters
  • ⁇ M micromolar
  • HATU hexafluorophosphate azabenzotriazole tetramethyl uronium
  • hr or hrs hours
  • Hz Hertz
  • MHz megahertz
  • mmol millimoles
  • MS mass spectrometry
  • N normality when referring to acid
  • psi poundss per square inch
  • HPLC high pressure liquid chromatography
  • Prep-HPLC preparatory high pressure liquid chromatography
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • DMSO-d6 deuterated dimethylsulfoxide
  • Methanesulfonic anhydride (9.95 g, 35.3 mmol) was added dropwise at 0 °C and the reaction mixture was warmed to room temperature and stirred for two hours. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The combined organic extracts washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in pentane as an eluent to obtain ethyl 2-(trifluoromesyloxy)-1-cyclohexene-1-carboxylate as a pale yellow liquid.
  • reaction mixture was cooled to 0–5 °C and m-(chlorosulfonyl)nitrobenzene (5 g, 22.6 mmol) was added dropwise.
  • the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the mixture was diluted with water followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N,N-bis(2,4-dimethoxybenzyl)-3-nitrobenzenesulfonamide.
  • the mixture was diluted with water and the pH was adjusted to 4–5 using 1N hydrochloric acid and extracted with ethyl acetate.
  • the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the 4,4,4',4'-tetrafluoro-2-[bi(cyclohexyl)]carboxylic acid as a light yellow solid.
  • the resulting mixture was cooled to 0 °C and phosphoryl chloride (0.696 mL, 7.44 mmol) was added dropwise.
  • the reaction mixture was allowed to warm to 5 °C and stirred for 1 hour. After completion of the reaction, the mixture was diluted with water, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting mixture was purged with nitrogen for 10 minutes and heated at 85 °C for 16 hours. After completion of the reaction, the mixture was diluted with water and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using 2–5% ethyl acetate in hexane as an eluent to obtain methyl 2-cyclopropyl-5,5-difluorocyclohex-1-ene-1-carboxylate as pale-yellow liquid.
  • reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to obtain rac-(1R,2R)-2-cyclopropyl-5,5-difluoro-N-(2-sulfamoylpyridin-4-yl)cyclohexane-1 carboxamide and rac-(1R,2S)-2-cyclopropyl-5,5-difluoro-N-(2-sulfamoylpyridin-4- yl)cyclohexane-1-carboxamide as off white solids.
  • the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction the mixture was concentrated under reduced pressure. The residue was diluted with water, neutralized with a saturated aqueous solution of sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (2.25 mL, 13.4 mmol) was added dropwise.
  • the reaction mixture was allowed to warm up to room temperature and stirred for 16 hours.
  • the mixture was diluted with water, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was purged with nitrogen for 10 minutes and bis(triphenylphosphine)palladium(II) dichloride (288 mg, 0.409 mmol) was added.
  • the reaction was purged with nitrogen for an additional 10 minutes and stirred at 100 °C for 16 h.
  • the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (5.99 mL, 35.7 mmol) was added dropwise.
  • the reaction mixture was warmed to room temperature and stirred for another 16 hours.
  • the mixture was diluted with water, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction was purged with nitrogen for 10 minutes followed by addition of bis(triphenylphosphine)palladium(II) dichloride (68.1 mg, 96.8 ⁇ mol) and heated at 50 °C for 4 hours.
  • the reaction mixture was cooled to room temperature and methyl 5,5-difluoro-2- (((trifluoromethyl)sulfonyl)oxy)cyclohex 1 ene 1 carboxylate (628 mg 194 mmol) and disodium carbonate (1.03 g, 9.68 mmol) in water (1 mL) were added at room temperature.
  • reaction mixture was purged with nitrogen for 10 minutes followed by addition of bis(triphenylphosphine)palladium(II) dichloride (273 mg, 387 ⁇ mol).
  • the reaction was purged with nitrogen for 10 minutes and heated at 100 °C for 16 hours.
  • the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting reaction mixture was heated at 80 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure.
  • the aqueous mixture was acidified with acetic acid and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-cyclooctyl-5,5-difluorocyclohexane-1-carboxylic acid as a colorless oil.
  • reaction mixture was cooled to 0 °C and phosphoryl trichloride (331 ⁇ L, 3.54 mmol) was added dropwise. The reaction mixture was stirred at 5 °C for 1 hour. After completion of the reaction, water was added to the reaction mixture followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • reaction mixture was stirred at 70 °C for 14 hours. After completion of the reaction, water was added to the reaction mixture followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated.
  • reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, water was added to the reaction mixture followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate filtered and concentrated to get the crude mass which was adsorbed on silica gel and purified by silica gel column chromatography using 15% ethyl acetate in hexanes as an eluent to obtain N-(2-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5,5- difluorocyclohexane-1-carboxamide as a white solid.
  • the reaction mixture was stirred at 100 °C for 8 hours under nitrogen atmosphere.
  • the mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • reaction mixture was stirred at 50 °C for 3 hours.
  • the mixture was concentrated and diluted with water, followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtained methyl 5,5-difluoro-2-hydroxycyclohexane-1- carboxylate as a yellow oil.
  • the vial was capped and degassed under argon for 20 min.
  • the vial was wrapped with parafilm.
  • the reaction was stirred at room temperature under blue LED irradiation (450 nm) for 10 hours.
  • water was added followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the residue was purified by preparative HPLC using 60-80% acetonitrile in water to obtain rac-benzyl 1',4,4-trifluoro-[1,1'-bi(cyclohexane)]-2-carboxylate as a yellow oil.
  • the reaction mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere.
  • the mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate.
  • the organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the reaction mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere.
  • the mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the residue was purified by silica gel flash column chromatography using 10- 20% ethyl acetate in hexane as an eluent to obtain rac-(1S,2S)-3,3-dimethyl-2-phenyl-N- (quinolin-8-yl)cyclobutane-1-carboxamide as a yellow oil.
  • the fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 10% ruthenium on silicon dioxide (3.10 g, 3.07 mmol).
  • the H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL/min.
  • the solution 1 was pumped by Pump 1 (1 mL/min) to fixed bed (6.350 mm, 100 °C).
  • the solution 1 was flowing through fixed bed ⁇ FLR1, 5 min ⁇ to leave the reactor zone, then the reaction mixture was collected from the reactor output.
  • the mixture was concentrated to obtain rac-(1R,2S)-2-cyclohexyl-3,3-dimethylcyclobutane-1-carboxylic acid as a yellow solid.
  • the reaction mixture was stirred at 110 °C for 16 hours.
  • the mixture was concentrated to obtain a mixture of rac-methyl (1S,2R)-5-methyl-[1,1'-bi(cyclohexan)]-4-ene- 2-carboxylate and rac-methyl (1R,2R)-5-methyl-[1,1'-bi(cyclohexan)]-5-ene-2-carboxylate as a light yellow oil.
  • the sealed tube was heated at 140 °C for 3 hours under microwave irradiation.
  • the mixture was concentrated.
  • the residue was purified by silica gel flash column chromatography using 0-6% methanol in dichloromethane as an eluent to obtain rac-2-((1S,2R,5R)-5-methyl-[1,1'-bi(cyclohexan)]-2- yl)-1,6-naphthyridin-4(1H)-one as light yellow oil.
  • reaction mixture was stirred at 60 °C for 16 hours.
  • the mixture was purified by prep HPLC to obtain rac-2-((1S,2R,5R)-5-methyl-[1,1'- bi(cyclohexan)]-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide as a light yellow solid.
  • Compound 247 4-oxo-2-((1S,1's,2R,4'R)-4'-(trifluoromethyl)-[1,1'-bi(cyclohexan)]-2-yl)-1,4-dihydro-1,6- naphthyridine-5-carboxamide (Compound 247-1), 4-oxo-2-((1R,1's,2S,4'S)-4'- (trifluoromethyl)-[1,1'-bi(cyclohexan)]-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 247-2), 4-oxo-2-((1S,1'r,2R,4'S)-4'-(trifluoromethyl)-[1,1'-bi(cyclohexan)]-2-yl)- 1,4-dihydro-1,6-naphthyridine-5-carboxamide (Compound 2
  • the fixed bed (FLR1, volume 5 mL) was completely packed with granular catalyst 10% ruthenium on silicon dioxide (3.3 g).
  • the hydrogen back pressure regulator was adjusted to 3.0 MPa, and the flow rate of hydrogen was 30 mL/min.
  • the solution S1 was pumped by Pump 1 0.5 mL/min) to fixed bed (FLR1, SS, Fixed bed, 6.350 (1/4") mm, 1 mL, 135 °C).
  • the solution S1 was flowing through (FLR1, 9.3 h) to leave the reactor zone, then the reaction mixture was collected from the reactor output.
  • the mixture was concentrated to obtain methyl 2-[4- (trifluoromethyl)cyclohexyl]cyclohexanecarboxylate as a yellow oil.
  • the reaction mixture was stirred under hydrogen atmosphere (50 psi) at 50 °C for 12 hours.
  • the mixture was filtered through a pad of Celite® and the filtrate was concentrated.
  • the residue was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as an eluent to obtain methyl rac-(1S,2R)-2-(cyclohexyloxy)cyclohexane-1-carboxylate as a colorless oil.
  • reaction mixture was heated at 40 °C for 4 hours.
  • the mixture was concentrated, and the resulting aqueous solution was acidified with 1N hydrochloric acid followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtained rac-(1R,2R)-2-(cyclohexyloxy)cyclohexane-1-carboxylic acid as a yellow oil.
  • the reaction mixture was stirred at 100 °C for 8 hours under nitrogen atmosphere.
  • the mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • reaction mixture was stirred at 0 °C for 0.5 hour before ethyl cyanoformate (12.3 g, 125 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours.
  • the mixture was cooled to 0 °C, quenched with sat. ammonium chloride solution, diluted with water, followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the reaction mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere.
  • the mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
  • the residue was purified by silica gel flash column chromatography using 0-2% ethyl acetate in hexane as an eluent to obtain ethyl 4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclopent-1-ene-1-carboxylate as a yellow oil.
  • the hydrogen back pressure regulator was adjusted to 3.5 MPa, and the flow rate of hydrogen was 30 mL/min. Then solution 1 was pumped by Pump 1 (0.303 mL/min) to fixed bed (FLR1, 6.350 mm, 1 mL, 120 °C). The solution 1 was flowing through (FLR1, 12 hours) to leave the reactor zone, then the reaction mixture was collected with a bottle.
  • reaction mixture was stirred at 55 °C for 12 hours.
  • the mixture was concentrated.
  • the reaction mixture was stirred at 80 °C for 12 hours.
  • the mixture was concentrated and the resulting aqueous solution was acidified with 1N hydrochloric acid followed by extraction with ethyl acetate.
  • reaction mixture was stirred at 70 °C for 12 hours.
  • the mixture was purified by preparative HPLC to obtain rac-2-((1R,2S)-4,4-dimethyl-2-(4-(trifluoromethyl)cyclohexyl)cyclopentyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide as a white solid.
  • the reaction mixture was concentrated, diluted with water, basified with sodium bicarbonate, followed by extraction with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 0-10% methanol in dichloromethane as an eluent to obtain rac-4,5-dichloro-2-((1S,2R)- 4,4,4',4'-tetrafluoro-[1,1'-bi(cyclohexan)]-2-yl)-1,6-naphthyridine as a brown solid.
  • reaction mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was quenched with sat. ammonium chloride solution followed by extraction with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated.
  • Electrophysiology experiments were performed on Human Embryonic Kidney 293 cells (HEK) or Chinese hamster ovary cells (CHO) transfected with the full-length cDNA coding for the appropriate human NaV sodium channel ⁇ -subunit NaV 1.8.
  • experiments are performed on Human Embryonic Kidney 293 cells (HEK) or Chinese hamster ovary cells (CHO) transfected with the full-length cDNA coding for the appropriate human NaV sodium channel ⁇ -subunit, including NaV 1.7, NaV 1.6, NaV 1.5, and NaV 1.4.
  • Sodium currents were measured using the patch-clamp technique in the whole-cell configuration with a HEKA EPC 9 amplifier (HEKA Elektronik Dr. Schulze GmbH, Germany), an AxoPatch 200B (Molecular Devices), or can be measured using an IonFlux 16 automated patch clamp system (Fluxion Biosciences, South San Francisco, USA) as previously described by Moran. See, Moran O, Picollo A Conti F (2003) Tonic and phasic guanidinium toxin-block of skeletal muscle Na channels expressed in Mammalian cells, Biophys J 84(5):2999–3006.
  • borosilicate glass micropipettes (Sutter Instruments, Novato, CA) were pulled to a tip diameter yielding a resistance of 1.0–2.0 M ⁇ in the working solutions.
  • the composition of intracellular solution was (in mM): CsF 125, EGTA 10, HEPES 10, NaCl 10, and the pH was adjusted to 7.2 with CsOH.
  • the composition of extracellular solution was (in mM): NaCl 135, KCl 4.5, CaCl22, MgCl21, HEPES 10, and the pH was adjusted to 7.4 with NaOH.
  • TTX tetrodotoxin
  • Peak currents were generally between 0.5–20 nA.
  • Lyophilized stock of each test article was stored at -20 °C, solubilized in DMSO (maximum final concentration 1%) and diluted to the desired concentration with the external solution prior to recording. Current measurements were recorded under continuous perfusion, controlled by syringe pump addition.
  • the output of the EPC 9 patch-clamp amplifier was filtered with a built-in low-pass, four-pole Bessel filter having a cutoff frequency of 10 kHz and sampled at 20-50 kHz.
  • the membrane was kept at a holding potential of between - 120 and -80 mV.
  • Pulse stimulation and data acquisition were controlled with the Pulse software (HEKA Elektronik Dr. Schulze GmbH, Germany) or the IonFlux software (Fluxion Biosciences, South San Francisco, USA). All measurements were performed at room temperature (about 20–22 °C). Recordings were made at least 5 min after establishing the whole-cell and voltage-clamp configuration to allow for stabilization of the voltage-dependent properties of the channels. Currents were elicited by 10-50 ms step depolarizations from a holding potential to a value between -40 and +10 mV. Peak currents after channel activation were recorded.
  • Column 1 provides IC50 data for NaV 1.8/ ⁇ 1 as measured using the manual patch-clamp technique in the whole-cell configuration with a HEKA EPC 9 amplifier, where ++++ indicates an IC 50 of less than or equal to 20 nM (nanomolar), +++ indicates an IC 50 of greater than 20 nM but less than or equal to 100 nM, ++ indicates an IC50 of greater than 100 nM but less than or equal to 1.0 ⁇ M, and + indicates an IC50 of greater than 1 ⁇ M but less than 10 ⁇ M. ND means not detectable. NT means not tested. For Table 1A and 1B, Column 2, all data were measured in CHO cells.

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Abstract

L'invention concerne des composés, des compositions pharmaceutiques comprenant les composés, des procédés de préparation des composés, et des méthodes d'utilisation des composés et des compositions dans le traitement d'états associés à une fonction de canal sodique déclenché par la tension où les composés sont de 1 à 297.
PCT/US2025/029820 2024-05-17 2025-05-16 Inhibiteurs cycloalkyle et hétérocycloalkyle substitués de nav1.8 pour le traitement de la douleur Pending WO2025240895A1 (fr)

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