WO2024054622A2 - Composés bloquant les canaux sodiques, leurs dérivés et leurs procédés d'utilisation - Google Patents

Composés bloquant les canaux sodiques, leurs dérivés et leurs procédés d'utilisation Download PDF

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WO2024054622A2
WO2024054622A2 PCT/US2023/032280 US2023032280W WO2024054622A2 WO 2024054622 A2 WO2024054622 A2 WO 2024054622A2 US 2023032280 W US2023032280 W US 2023032280W WO 2024054622 A2 WO2024054622 A2 WO 2024054622A2
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compound
alkyl
fluoro
methyl
substituted
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WO2024054622A3 (fr
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Ashok Bajji
Michael D. Kaufman
James Michael BALKOVEC
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Latigo Biotherapeutics, Inc.
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • 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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with 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
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel NaV1.8, such as pain, itch, and cough.
  • A is aryl or heteroaryl wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo-C 1 -C 4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C 1 -C 8 alkyl, deuterated C 1 -C 4 alkyl wherein the alkyl chain may be fully or partially deuterated, C 3 -C 10 cycloalkyl, halogen, cyano, nitro, C 1 -C 8 alkoxyl, haloalkoxyl, wherein the haloalkoxy chain
  • R 9 is H, halogen, -CD 3 , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , -OCF 3 , or substituted or unsubstituted cycloalkoxy;
  • X is H, halogen, -CD 3 , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF 3 , - or OCF 3 ;
  • R 8 is H, hydroxyl, halogen, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalk
  • B is , wherein R 6 is described above; Z is CR 10 , N, or N + O-; wherein R 10 is H, halo, -CD 3 , C 1 -C 8 alkyl, haloalkyl, or alkoxy.
  • R 6 is wherein: X 1 and X 2 are both O, NH, or NR’; or X 1 is O and X 2 is either NH or NR’; R 7 is NH 2 , NHR’, NR’R”, C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl.
  • B is a phenyl ring. In another embodiment, B is a pyridine ring.
  • R 1 is H, -CH 3 , or F.
  • R 2 is chloro, -CF 3 , H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl.
  • R 3 is H, -CF 3 , or F.
  • R 4 is H.
  • R 8 is H, -CH 3 , or -O-CH 3 .
  • R 7 is -CH 3 .
  • X is F or -CN.
  • Q is N or CH.
  • W is CH and T is CH
  • Z is CR 10 and R 10 is H or F.
  • the compound is selected from a group consisting of:
  • the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein: A and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo- C 1 -C 4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C 1 -C 8 alkyl, deuterated C 1 -C 4 alkyl wherein the alkyl chain may be fully or partially deuterated, C 3 -C 10 cycloalkyl, halogen, cyano, nitro, C 1 -C 8 alkoxyl, aloalkoxyl wherein the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R 1 , R 2 , R 3 and R 4 are independently
  • the compound of the invention is a compound of Formula (II): (Formula II) wherein ring B, and groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , are described in claim 1; R 8 is H, hydroxyl, halogen, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH 2 -cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one hetero
  • the compound of the invention is a compound of Formula (III): Formula (III) wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are described above in Formula (I); R 8 , W, T, Q, and X are described above in Formula (II); Z is CH, N, CF, or N+-O- In another embodiment, X is F. In another embodiment, R 8 is -CH 3 . In another embodiment, Q is N. In another embodiment, Q is N, W is CH, and T is CH. In another embodiment, R 1 is H or F. In another embodiment, R 2 is H, chloro, or CF 3 . In another embodiment, R 3 is H or CF 3 .
  • R 4 is H.
  • R 5 is H.
  • R 7 is methyl.
  • R 6 is azetidine, pyrrolidine, -CH 2 -OH, -CH-(CH 3 )-OH, -CH- CH 2 -NH-CH 3 , -CH 2 -NH 2 , CH-(CH 3 )-NH 2 , -CH 2 -NH 2 , -C-(CH 3 ) 2 -NH 2 , or -cyclobutyl-NH 2 .
  • R 9 is H.
  • the compound of Formula (I) is selected from the group consisting of:
  • the invention provides a compound of compound of Formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C 1 -C 8 -alkyl, C 1 -C 8 fully or partially fluorinated fluoroalkyl, C 2 -C 8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R’’)-cycloalkyl, C(R’)(R’’)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycl
  • B is a 6 membered substituted or unsubstituted heteroaryl ring, comprising one or more N atoms.
  • the N atoms in the heteroaryl ring may be in the form of a N- oxide.
  • the N-oxide containing B-ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.
  • the compound is a compound of Formula (III): Formula (III) wherein Q T and W are independently N or CR 6 ;
  • R 6 is H, halogen, -CD 3 , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , - OCF 3 , or substituted or unsubstituted cycloalkoxy;
  • R 5 is H, -OH, halo, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH 2 - cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted 3-6
  • the compound is a compound of Formula (IV): Formula (IV), wherein: Z is CR 10 , N, or N + O-; wherein R 10 is H, halo, -CD 3 , C 1 -C 8 alkyl, haloalkyl, or alkoxy.
  • ring A is substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S.
  • ring A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • ring A is substituted or unsubstituted 6 membered heteroaryl having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least 2 N atoms.
  • A is: wherein Q 1 , Q 2 , Q 3 and Q 4 are independently selected from a group consisting of: N, N + O-, or CR 7 ; wherein at least two of Q 1 , Q 2 , Q 3 and Q 4 are CR 7 ; R 7 is H, -OH, halo, -CD 3 , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , -OCF 3 , substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O- cycloheteroalkyl.
  • A is: wherein, Q 2 and Q 4 are independently N or N + O- ; Q 2 is N or N + O- ; Q 4 is CR 7 ; or Q 2 is CR 7 , Q 4 is N or N + O-; R 8 and R 9 are independently selected from a group consisting of H, -OH, halo, -CD 3 , substituted or unsubstituted C1-C6 alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH 2 , NHR’, NR’R”, aryl, heteroaryl, -CF 2 CH 3 , and -CF 2 CF 3 ; In other embodiments, in the compounds of Formula (I), Formula (III), and/or Formula (IV), A is: wherein, Q 3 and Q 4 are independently N or N +
  • A is: wherein, Q 1 and Q 4 are independently N or N + O-; Q 1 is N or N + O-, and Q 4 is CR 7 ; Q 1 is CR 7 and Q 4 is N or N + O-; or Q 1 or Q 4 is CR 7 ; wherein R7, R 8 , and R 9 are defined above.
  • Q 1 and Q 4 are independently N or N + O-; Q 1 is N or N + O-, and Q 4 is CR 7 ; Q 1 is CR 7 and Q 4 is N or N + O-; or Q 1 or Q 4 is CR 7 ; wherein R7, R 8 , and R 9 are defined above.
  • Q is N or CH; R 5 is methyl or -OMe, X is F or CN. In other embodiments, in the compound of Formula (III) and/or Formula (IV), Q is CF.
  • R 7 , R 8 , and R 9 are independently selected from a group consisting of: H, methyl, fluoro, chloro, bromo, CF 3 , cyclopropyl, difluorophenyl, and dimethylpyrazole.
  • R 10 in the compound of Formula (III) and/or Formula (IV), is H or F.
  • Z in the compound of Formula (III) and/or Formula (IV), Z is N or CH.
  • R 2 is Formula (II): wherein, m and n are independently 0 or 1; and X 1 and X 2 are not both O, NH, or NR’.
  • the compound of the invention is selected from a group consisting of:
  • A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C 1 -C 8 -alkyl, C 1 -C 8 fully or partially fluorinated fluoroalkyl, C 2 -C 8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R ’ )(R ” )-cycloalkyl, C(R ’ )(R ” )-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-6 member
  • the compound is a compound of Formula (II): Formula (II) wherein: A, C, R 1 , R 2 , and R 3 are described above; Q, T and W are independently N or CR 5 ; R 5 is H, halogen, -CD 3 , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , - OCF 3 , or cycloalkoxy; R 4 is H, -OH, halo, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH 2 - cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropyl
  • the compound is a compound of Formula (III): wherein, Z is CH, N, CF, or N + O-; and A, W, T, Q, X, R 1 , R 2 , R 3 , and R 4 are described above.
  • ring A is substituted or unsubstituted 5-6 membered heteroaryl with one or more heteroatom.
  • the 5-6 membered ring heteroaryl includes N as the one or more heteroatom.
  • the heteroatom N may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of: pyridyl N-oxide, pyrazinyl N-oxide, pyridazinyl N-oxide, and pyrimidinyl N- oxide.
  • A is a 6-membered heteroaryl comprising at least one heteroatom, wherein the heteroatom is N.
  • A is a 6-membered heteroaryl comprising 2 N atoms.
  • ring A may be a substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • ring A is: wherein Q 1 , Q 2 , Q 3 and Q 4 are independently selected from a group consisting of: N, N + O-, or CR 6 ; wherein at least two of Q 1 , Q 2 , Q 3 and Q 4 are CR 6 ; R 6 is H, -OH, halo, -CD 3 , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , -OCF 3 , substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O- aryl, O-heteroaryl, O-cycloalkyl, or O-cycloheteroalkyl.
  • ring A is: wherein, Q 2 and Q 4 are independently N or N + O- ; Q 2 is N or N + O- and Q 4 is CR 6 ; or Q 2 is CR 6 and Q 4 is N or N + O-; R 7 and R8 are independently selected from the group consisting of H, -OH, halo, -CD 3 , substituted or unsubstituted C 1 -C 6 alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH 2 , NHR’, NR’R”, aryl, Heteroaryl, -CF 2 CH 3 , and -CF 2 CF 3 ; R 6 is described above.
  • ring A is: wherein, Q 3 and Q 4 are N; Q 3 is N, N + O-; Q 4 is CR 6 ; or Q 3 is CR 6 , Q 4 is N or N + O-; wherein R7 and R 8 are defined above.
  • ring A is: wherein Q 1 and Q 4 are independently N or N + O-; Q 1 is N or N + O- and Q 4 is CR 6 ; or Q 1 is CR 6 and Q 4 is N or N + O-; wherein R 6 , R 7 , and R 8 are described above.
  • ring A is: wherein Q 1 and Q 2 is N; wherein R 7 and R 8 are described above.
  • ring A is: wherein Q 1 is CR 6 , and Q 2 is N; R 6 , R 7 , and R 8 are described above.
  • ring A is: wherein, Q 1 is N; Q 2 is CR 6 ; R 6 , R 7 , and R 8 are described above.
  • R 1 is H.
  • R 3 is methyl.
  • R 2 is H, methyl, -CH 2 -NH 2 , -CH 2 -NH-CH 3 , -CH 2 -OH, -CH(NH 2 )(CH 3 ), -CH 2 -OH, - CH(OH)(CH 3 ), -CH(CF 3 )(NH 2 ), -CH 2 -O-CH 3 , amino-cycopropyl, pyrrolidine, azetidine, oxetane, tetrahydrofuran, or hydroxypyrrolidone.
  • T is N. In other embodiments, T is N, W is CH, and Q is CH. In other embodiments, in the compounds of Formula (II) and/or Formula (III), R 4 is methyl. In other embodiments, in the compounds of Formula (II) and/or Formula (III), X is F. In other embodiments, in the compounds of Formula (II) and/or Formula (III), Z is N or CH. In other embodiments, the compound of the invention is selected from a group consisting of:
  • the invention provides inhibitors of a voltage gated sodium channel NaV1.8.
  • the inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above.
  • the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above.
  • the condition may be associated with aberrant activity of voltage gated sodium channels.
  • the condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma/injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy
  • the invention provides methods of making a medicament using a compound of the invention, such as any of those described above.
  • the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of those described above, in a subject.
  • substituted refers to the ability to change one or more functional groups for another functional group or groups on a molecule, provided that the valency of all atoms is maintained.
  • substituent may be either the same or different at every position.
  • the substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions).
  • R groups such as groups R 1 , R 2 , and the like, or variables, such as “m” and “n”
  • R 1 and R 2 can be substituted alkyls, or R 1 can be hydrogen and R 2 can be a substituted alkyl and the like
  • a when used in reference to a group of substituents herein, mean at least one.
  • the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • R or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below. Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art.
  • a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
  • a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
  • a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein.
  • hydrocarbon refers to any chemical group comprising hydrogen and carbon.
  • the hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in the art, all valences must be satisfied in making any substitutions.
  • the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.
  • Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic saturated hydrocarbon group, or combination thereof, and can include di- and multivalent groups, having the number of carbon atoms designated (e.g., C1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons).
  • alkyl refers to C 1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., “straight-chain”), branched, or cyclic saturated hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers thereof.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain.
  • Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C 1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different.
  • alkyl group substituent includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.
  • substituted alkyl includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon group having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom, such as O, N, P, Si or S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR’, -NR’R”, -OR’, -SR, -S(O)R, and/or -S(O 2 )R’.
  • Cycloalkyl refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group.
  • Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • cycloalkylalkyl refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C 1-20 alkylene moiety.
  • alkylene moiety also as defined above, e.g., a C 1-20 alkylene moiety.
  • Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • carbocyclyl refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which all ring members are carbon atoms. Unless otherwise specified, a carbocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic.
  • heterocyclyl refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which at least one ring member is a heteroatom, such as N, O, or S. Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic.
  • saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiozo
  • cycloheteroalkyl and “heterocycloalkyl” refer to a saturated ring system, such as a 3- to 10-member cycloalkyl ring system, that include one or more heteroatoms.
  • the heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S).
  • heterocycloalkyl examples include, but are not limited to, 1-(1, 2,5,6-tetrahydropyridyi), 1- piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • the cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings.
  • Heterocyclic rings include those having from one to three heteroatoms, such as oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heteroatoms such as oxygen, sulfur, and nitrogen
  • examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6- membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
  • An unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double bonds or triple bonds.
  • unsaturated hydrocarbons include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkenyl refers to a monovalent group derived from a C2-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule.
  • Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.
  • cycloalkenyl refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • alkynyl refers to a monovalent group derived from a straight or branched C 2-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon- carbon triple bond.
  • alkynyl examples include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.
  • alkylene by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched, or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • heteroalkylene by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S- CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • spirocyclyl refers to a polycyclic compound in which two rings have a single atom, e.g., carbon, as the only common member of two rings.
  • a “spirocycloalkyl” refers to a cycloalkyl group with two rings having a single carbon in common
  • a “spiroheterocycloalkyl” or “spiroheterocycloalkyl” refers to a cycloheteroalkyl group with two rings having a single carbon or other atom, e.g., nitrogen, in common.
  • aryl means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to and groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzoihiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-is
  • arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively.
  • a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., “3 to 7 membered”), the term “member” refers to a carbon atom or heteroatom.
  • member refers to a carbon atom or heteroatom.
  • R’, R”, R’” and R” each may independently refer to hydrogen, halogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1 -3 halogens
  • substituents include (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, -O(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 - C10)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )alkyl-NH 2 , (C 1 - C 6 )alkyl-O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-N-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -
  • an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen.
  • each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present.
  • R’ and R are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR’R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e. g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e. g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like.
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’) q -U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH 2 ) r -B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, - S(O) 2 NR’- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’) s -X’-(C”R’”) d -, where s and d are independently integers of from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR’-.
  • the substituents R, R’, R” and R may be independently selected from halogen, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • acyl specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group.
  • aryl acyl groups such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group.
  • Specific examples of acyl groups include acetyl and benzoyl.
  • alkoxyl or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C 1 -20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like.
  • alkoxy alkyl refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • Alkyl refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • Aralkyloxyl refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplar)' aralkyloxyl group is benzyloxyl, i.e., C 6 H 5 CH 2 -O-. An aralkyloxyl group can optionally be substituted.
  • Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.
  • Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • Acyloxyl refers to an acyl-O- group wherein acyl is as previously described.
  • amino refers to the -NH 2 group and refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic groups.
  • acyl amino and “alkylamino” refer to specific N- substituted organic groups with acyl and alkyl substituent groups respectively.
  • An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups.
  • dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups.
  • trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups.
  • R’, R”, and/or R’” taken together may optionally be –(CH 2 ) k where k is an integer from 2 to 6.
  • Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine.
  • the amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom.
  • thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described.
  • “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.
  • the term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
  • cyano refers to the -CN group.
  • halo halide
  • halogen refer to fluoro, chloro, bromo, and iodo groups.
  • haloalkyl refers to an alkyl group substituted with one or more halogens.
  • haloalkyl includes monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -4)alkyl includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.
  • halocycloalky and cyclohaloalkyl refer to a cycloalkly group with one or more halogens.
  • hydroxyl refers to the -OH group.
  • hydroxy alkyl refers to an alkyl group substituted with an -OH group.
  • mercapto refers to the -SH group.
  • oxo refers to an oxygen atom that is double bonded to a carbon atom or to another element.
  • nitro refers to the -NO 2 group.
  • thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
  • sulfate refers to the - SO 4 group.
  • thiohydroxyl or thiol refers to a group of the formula -SH. More particularly, the term “sulfide” refers to compound having a group of the formula - SR.
  • sulfone refers to compound having a sulfonyl group -S(O 2 )R’.
  • sulfoxide refers to a compound having a sulfinyl group -S(O)R
  • ureido refers to a urea group of the formula -NH-CO-NH 2 .
  • Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, m terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms.
  • Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium ( 3 H), iodine-125 ( 12 5 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure may exist as salts, and particularly as pharmaceutically acceptable salts. The present disclosure includes such salts.
  • Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in art.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or m a suitable inert solvent or by ion exchange.
  • acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow' the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.
  • Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • the present disclosure provides compounds that are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • protecting group refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4- dimethoxybenzyl, while co existing amino groups may be blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • a resin to which a compound or intermediate may be attached As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • the invention provides compounds that modulate, e.g., inhibit, the activity of voltage gated sodium channels.
  • the compounds and their methods of manufacturing are provided in detail below.
  • A is aryl or heteroaryl wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo-C 1 -C 4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C 1 -C 8 alkyl, deuterated C 1 -C 4 alkyl wherein the alkyl chain may be fully or partially deuterated, C 3 -C 10 cycloalkyl, halogen, cyano, nitro, C 1 -C 8 alkoxyl, haloalkoxyl, wherein the
  • R 9 is H, halogen, -CD 3 , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , -OCF 3 , or substituted or unsubstituted cycloalkoxy;
  • X is H, halogen, -CD 3 , alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, -CF 3 , - or OCF 3 ;
  • R 8 is H, hydroxyl, halogen, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalk
  • B is , wherein R 6 is described above; Z is CR 10 , N, or N + O-; wherein R 10 is H, halo, -CD 3 , C 1 - C 8 alkyl, haloalkyl, or alkoxy.
  • R 6 is wherein: X 1 and X 2 are both O, NH, or NR’; or X 1 is O and X 2 is either NH or NR’; R 7 is NH 2 , NHR’, NR’R”, C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl , or heterocyclyl.
  • B is a phenyl ring. In another embodiment, B is a pyridine ring.
  • R 1 is H, -CH 3 , or F.
  • R 2 is chloro, -CF 3 , H, 2-pyrazoline, or 1-methyl-1H-pyrazol-4-yl.
  • R 3 is H, -CF 3 , or F.
  • R 4 is H.
  • R 8 is H, -CH 3 , or -O-CH 3 .
  • R 7 is -CH 3 .
  • X is F or -CN.
  • Q is N or CH.
  • W is CH and T is CH
  • Z is CR 10 and R 10 is H or F.
  • the compound is selected from a group consisting of:
  • the first set of compounds are prepared by methods and procedures described below.
  • the intermediates described in this section may be relied upon for preparation of first set of compounds.
  • Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted. All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized.
  • Prep Method 1 Equipment Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm; Prep Method 2 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
  • Prep Method 3 Equipment Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150x21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
  • Analytical LCMC were collected using one of following methods- Method 1 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C 18 2.7 ⁇ m, 3.0 mm ⁇ 30 mm; Mobile Phase: MeCN (0.05% HCOOH) - Water (0.05% HCOOH); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL/min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.
  • SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System (SFE-30A, LC-30ADSF, SFC-30A) using following methods: Method 1 Column: Daicel chiralpak-AS-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH [0.1% NH 3 (7M in MeOH)], CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Method 2 Column: Daicel chiralpak-OJ-H 5 um 250 * 20 mm; Mobile Phase: CO 2 /MeOH (0.1% HCOOH), CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Method 3 Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • compounds of Formula (I) may be synthesized starting from carboxylic acids A-1 by reacting with a substituted aniline or heteroaryl aniline A-2 using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA, to give intermediates of type A-3.
  • Intermediates A-3 may contain a protecting group (PG) such as Boc which may be removed by treatment with an acid such as TFA to provide compounds of Formula(I) having structure A-4.
  • PG protecting group
  • Any suitable PG such as Cbz or Fmoc may be employed and can be removed accordingly.
  • carboxylic acid A-1 may be treated with ammonia or a primary amine (R 5 NH 2 ) in the presence of an amide coupling reagent such as HATU and a base such as DIEA to give carboxamide intermediate A-5 which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compounds of type A-6 to give compounds of formula A-3.
  • an amide coupling reagent such as HATU and a base such as DIEA
  • compounds of the invention can be prepared by reacting intermediates A-1 with an amine B-1, utilizing amide coupling conditions or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl) 2 or POCl 3 and with amine B-1 and base such as DIEA or pyridine in DCM, DMF or THF to give compounds of type B-2.
  • the compounds of formula B-3 can be formed by removing a protecting group, such as Boc under acidic conditions.
  • B-3 can be separated into the corresponding R and S isomers using chiral HPLC.
  • R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine B-1 followed by deprotection.
  • compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-1 in organic solvent with either (COC1) 2 or SOCl 2 followed by addition of NH 4 OH to afford C-1.
  • Intermediate C-1 can then be brought together with materials of variously substituted Br compounds C-2, utilizing Xantphos- Pd-G2 mediated coupling conditions to deliver intermediate C-3.
  • the compounds of formula C-3 may be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to provide compounds of formula B-3.
  • PIDA diacetoxyiodo
  • B-3 was separated to the corresponding R and S isomers using chiral HPLC conditions.
  • Step 2 methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate: A solution of 5-chloro-2- fluoro-4-(trifluoromethyl)benzoic acid (2 g, 8.30 mmol) in SOCl 2 (20 mL) was heated at 80 °C for 1h. Then the mixture was concentrated in vacuum. The residue was added to MeOH (30 mL) and stirred at room temperature for 1 hour. The final mixture was concentrated under vacuum to give the crude methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (1.8 g) which was used directly in next step without further purification.
  • Step 3 methyl 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzoate: A solution of methyl 5-chloro-2-fluoro-4-(trifluoromethyl)benzoate (1.8 g, 7.03 mmol), 6-fluoro-2-methylpyridin-3-ol (982 mg, 7.73 mmol), and Cs 2 CO 3 (4.6 g, 14.06 mmol) in MeCN (40 mL) was heated at 80 °C for 16 hours. Upon completion of the reaction, the mixture was concentrated under vacuum.
  • Step 2 methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoate: A solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (400 mg, 1.8 mmol) in DMF (5 mL) Cs 2 CO 3 (1.75 g, 5.4 mmol), 6-fluoro-2-methylpyridin-3-ol (342 mg, 2.7 mmol) was added. The mixture was heated to 100 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite.
  • Step 2 methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate: A mixture of methyl 6-fluoro-2-methyl-3-nitrobenzoate (1.70 g, 7.98 mmol) and 6-fluoro-2- methylpyridin-3-ol (1.22 g, 9.57 mmol) in MeCN (30 mL) was added Cs 2 CO 3 (3.31 g, 23.93 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 hours.
  • Step 3 methyl 3-amino-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methylbenzoate: A solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-nitrobenzoate (1.70 g, 5.31 mmol) in MeOH (30 mL) and water (10 mL) was added NH 4 Cl (1.99 g, 37.16 mmol), Fe (1.48 g, 26.54 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3).
  • Step 5 methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H- pyrazol-4-yl)benzoate: A mixture of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-iodo-2- methylbenzoate (400 mg, 1.00 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (188 mg, 1.50 mmol) in 1,4-dioxane/H 2 O (4/1, 10 mL) was added potassium carbonate (413 mg, 2.99 mmol) and Pd(dppf)Cl 2 (146 mg, 0.20 mmol).
  • Step 6 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)benzoic acid: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1- methyl-1H-pyrazol-4-yl)benzoate (250 mg, 0.70 mmol) in MeOH/THF/H 2 O (1/1/1, 9 mL) was added LiOH (168 mg, 7.04 mmol) at room temperature.
  • Reagents & conditions a) methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, DMF, 120 °C; b) LiOH, THF/MeO/H 2 O, 60 °C Step 1: methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- iodo-2-methylbenzoate (500 mg, 1.25 mmol) and CuI (475 mg, 2.49 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.20 g, 6.23 mmol) dropwise at room temperature under an atmosphere of N 2 .
  • Step 2 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzoic acid: To a solution of methyl 6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate (350 mg, 1.02 mmol) in MeOH/THF/H 2 O (1/1/1, 9 mL) was added LiOH (244 mg, 10.20 mmol) at room temperature. The reaction mixture was heated at 60 °C for 12 hours. After the reaction was completed, the mixture was concentrated.
  • Step 2 methyl 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzoate: A solution of methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (300 mg, 0.99 mmol), 6-fluoro-2-methylpyridin-3-ol (253 mg, 1.99 mmol), (1S,2S)-N1,N 2 - dimethylcyclohexane-1,2-diamine (28 mg, 0.20 mmol), K 2 CO 3 (410 mg, 2.97 mmol), pyridine (235 mg, 2.97 mmol), Cu (13 mg, 0.20 mmol) and CuI (38 mg, 0.20 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 16 hours under N 2 .
  • 6-fluoro-2-methyl-3-nitrobenzoic acid A solution of 2-fluoro-6-methylbenzoic acid (3 g, 19.5 mmol) in H 2 SO 4 (2 mL) was added H 2 SO 4 /fuming HNO 3 (6/1, 7 mL) at 0 °C and stirred for 5 hours at room temperature. Then the mixture was added to ice-cold water. The precipitate was collected by filtration and dried under vacuum to obtain 6-fluoro-2-methyl-3- nitrobenzoic acid (2.5 g, 64.4%) as a yellow solid.
  • methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate A solution of methyl 3- amino-4-cyclopropyl-6-fluoro-2-methylbenzoate 6 (700 mg, 3.14 mmol) and I2 (1.19 g, 4.70 mmol) in THF (10 ml) was added t-BuONO (485.0 mg, 4.70 mmol) at room temperature. The reaction mixture was heated to 80 °C and refluxed for 2 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • methyl 4-cyclopropyl-6-fluoro-2-methyl-3-(trifluoromethyl)benzoate A solution of methyl 4-cyclopropyl-6-fluoro-3-iodo-2-methylbenzoate (650 mg, 1.95 mmol) and CuI (741.0 mg, 3.89 mmol) in DMF (10 ml) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.87 g, 9.73 mmol) at room temperature. The reaction mixture was heated at 100 °C for 5 hours under N 2 . After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3).
  • methyl 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoate A solution of methyl 4-cyclopropyl-6-fluoro-2-methyl-3- (trifluoromethyl)benzoate (500 mg, 1.81 mmol) and 6-fluoro-2-methylpyridin-3-ol (345.1 mg, 2.72 mmol) in MeCN (5 mL) was added Cs 2 CO 3 (1.75 g, 5.43 mmol) at room temperature. The reaction mixture was heated at 80 °C for 5 hours.
  • Reagents & conditions a) K 2 CO 3 , MeI, DMF; b)H 2 SO 4 , fuming HNO 3 ; c) Pd/C, H 2 , THF; d) NBS, MeCN; e) Trimethylboroxine, K 2 CO 3 , Pd(dppf)Cl 2 , 1,4-dioxane/H 2 O; f) CuCl 2 , t- BuONO, MeCN, 60 ⁇ C; g) Cs 2 CO 3 , MeCN, 80 ⁇ C; h) KOH, t-BuOH, THF/H 2 O, 80 ⁇ C Step 1.
  • methyl 5-amino-2-fluoro-4-(trifluoromethyl)benzoate A solution of methyl 2- fluoro-5-nitro-4-(trifluoromethyl)benzoate (4 g, 14.98 mmol) in THF (50 mL) was added Pd/C (600 mg) and stirred at room temperature for 16 hours under an atmosphere of H 2 . LCMS showed the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • methyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate To a flame-dried round-bottomed flask equipped with a magnetic stir bar and addition funnel under N 2 was added t-BuONO (1.22 g, 11.83 mmol), CuCl 2 (1.59 g, 11.83 mmol) and MeCN (20 mL). The solution was stirred at room temperature for 0.5 hour. A solution of methyl 3-amino-6-fluoro-2-methyl-4- (trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in MeCN (10 mL) was added dropwise at 0 °C. The reaction mixture was heated to 60 °C and stirred for 1 hour.
  • 6-fluoro-3-methoxy-2-(methyl-d3)pyridine To a 250 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 2-bromo- 6-fluoro-3-methoxypyridine (500 mg, 2.43 mmol), ZnCl 2 (4.96 g, 36.4 mmol) and Pd(dppf)Cl 2 (178 mg, 0.24 mmol) in DMF (10 mL). This was followed by the addition of CD 3 MgI (1.0 M in diethyl ether, 36.4 mL) dropwise with stirring at room temperature. The solution was heated to 100 °C and stirred for 2 hours.
  • Step 2 (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((3-(5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (110 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Reagents & conditions a) (i) SOCl 2 , 80 ⁇ C; (ii) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate, DIEA, THF; b) TFA, DCM, rt Step 1: tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: A solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzoic acid (300 mg, 0.95 mmol) in SOCl 2 (5 mL) was stirred at 80 °C for 0.5 hour.
  • Step 2 (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((3-(2- ((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (400 mg, 0.70 mmol) in DCM (5 mL) TFA (0.5 mL) was added at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(6- ((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl) (oxo)- ⁇ 6 -sulfaneylidene)carbamate (55 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH of 8-9 with saturated aqueous NaHCO 3 . The resulting solution was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • reaction solution was stirred at room temperature for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-((3-(2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (120 mg, 0.20 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was diluted with THF and added to a stirred solution of NH 3 -H 2 O (5 mL) dropwise. Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4- yl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 0.34 mmol) in 1,4-dioxane (8 mL) was added 4- bromo-2-(methylsulfinyl)pyridine (76 mg, 0.34 mmol), Cs 2 CO 3 (292 mg, 0.89 mmol) and Xantphos-Pd-G2 (61 mg, 0.07 mmol) at room temperature.
  • Step 3 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To a solution of 5-chloro-2- ((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(methylsulfinyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide (105 mg, 0.22 mmol) in MeOH (5 mL) was added PhI(OAc) 2 (173 mg, 0.54 mmol) and ammonium carbamate (50 mg, 0.65 mmol) at room temperature.
  • reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (15 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 4 (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide and (R)-5-chloro-2-((6-fluoro- 2-methylpyridin-3-yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4- (trifluoromethyl)benzamide : 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide was purified by Chiral-Prep- HPLC (Chi
  • the first eluting isomer was lyophilized to afford (S)-5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (12.7 mg) as a white solid.
  • Step 2 (R)-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide : A solution of tert-butyl (R)-((3-(6-((6- fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3-(1-methyl-1H-pyrazol-4- yl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (75 mg, 0.13 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • tert-butyl (R)-((5-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate A solution of 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-(trifluoromethyl)benzoic acid (60 mg, 0.16 mmol) and tert-butyl (R)-((5-amino-2-fluorophenyl)(methyl)(oxo)-16- sulfaneylidene)carbamate (70 mg, 0.24 mmol) in Pyridine (3 mL) was added POCl 3 (0.09 mL) at 0 °C.
  • reaction mixture was stirred at 0 °C for 10 minutes. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Example 9A Reagents & conditions: a) (i) SOCl 2 , 80 ⁇ C; (ii) DIEA, THF; b) TFA, DCM Step 1. tert-butyl (R)-((3-(4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- methyl-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A solution of 4-cyclopropyl-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-methyl-3- (trifluoromethyl)benzoic acid (100 mg, 0.27 mmol in SOCl 2 (2 ml) was heated for 1 hour at 80 °C.
  • Example 11A Reagents & conditions: a) Cs 2 CO 3 , MeCN, 80 ⁇ C; b) TFA, DCM Step 1. tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2- yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (200 mg, 0.40 mmol), 4-bromo-2-methoxyphenol (123 mg, 0.60 mmol), and Cs 2 CO 3 (393 mg, 1.21 mmol) in MeCN (5 mL) was heated to 80 °
  • Reagents & conditions a) Zn(CN) 2 , Xbuxphos-Pd-G 3 , THF/H 2 O, 50 ⁇ C; b) TFA, DCM Step 1.
  • tert-butyl (R)-((4-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate A mixture of tert-butyl (R)-((4-(2-(4-bromo-2-methoxyphenoxy)-5-chloro-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (130 mg, 0.19 mmol), Zn(CN) 2 (34 mg, 0.29 mmol) and tBuXphos-P
  • Example 13A Reagents & conditions: a) Cs 2 CO 3 , MeCN, 80 ⁇ C; b) TFA, DCM Step 1.
  • tert-butyl (R)-((4-(5-chloro-2-((6-fluoro-2-(methyl-d3)pyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate A solution of 6-fluoro-2-(methyl-d3)pyridin-3-ol (26.2 mg, 0.20 mmol), tert-butyl (R)-((4-(5-chloro-2- fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (100 mg, 0.20 mmol) and Cs 2 CO 3 (196.8 mg, 0.60 mmol) in MeCN (6 mL) was heated to 80 °C and stirred for 6 hours.
  • reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)ethyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)-2- oxoethyl)carbamate (700 mg, 1.06 mmol) in THF (10 mL) was added BH 3 -THF (0.7 mL) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 1 hour under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was quenched with saturated aqueous NaHCO 3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Example 74A Compound profiling human NaV1.8/ ⁇ 3 cell line – SyncroPatch384PE Assay
  • Compounds were tested on recombinant human Nav1.8/b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device.
  • Cells were cultured at 37°C/5% CO 2 in Ham’s F-12 supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 mg/mL streptomycin sulfate and selection antibiotics (0.01 mg/ml Blasticidin, 0.4 mg/ml Zeocin and 0.25 mg/ml Hygromycin).
  • HBSS Hank’s Balanced Salt Solution
  • the cells were washed in HBSS to remove the Accutase and re- suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl 2 , 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH.
  • Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2, 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.
  • Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid.
  • Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds.
  • Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.
  • A represents an IC 50 less than or equal to 5 nM
  • B represents an IC 50 greater than 5 nM to less than or equal to 50 nM
  • C represents an IC 50 greater than 50 nM to less than or equal to 100 nM
  • D represents an IC 50 greater than 100 nM to less than or equal to 200 nM
  • E represents an IC50 greater than 200 nM.
  • Example 75A Compound profiling human NaV1.8/ ⁇ 1 cell line – Sophion QPatch II Assay
  • Compounds were tested on recombinant human NaV1.8/ ⁇ 1 stably transfected HEK293 (Eurofins, CYL3025, St. Charles, MO) cells using the QPatch II system (Sophion Bioscience A/S, Ballerup – Denmark), an automated patch clamp device.
  • Cells were cultured at 37°C/5% CO 2 in DMEM/ F-12 supplemented with 10% fetal bovine serum, 1x Non-Essential Amino Acids, and selection antibiotics (0.625 ⁇ g/mL Puromycin, 400 ⁇ g/mL Geneticin, and 100 ⁇ g/mL Hygromycin).
  • Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl 2 , 2; EGTA, 5; HEPES, 10; pH adjusted to 7.2 with CsOH.
  • Extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl 2 , 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • 500 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents. Compounds were tested in an interleaved manner across two cohorts of wells to develop an aggregate 8-point concentration response curve.
  • Final concentrations include 0.1% DMSO and 0.03% pluronic Acid. In general, the concentration range spans a range from 0.01 – 300 nM.
  • Compounds were diluted 1:10 with extracellular solution within their respective cohort. DMSO (0.1% by volume) served as a vehicle control to ascertain assay performance.
  • Whole cell patch clamp recordings were conducted according to Sophion standard procedure for QPatch II®. Cells were held at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied to elicit inward Na + currents. Inter-sweep interval was 15 sec.
  • a and B are independently aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of halo- C 1 -C 4 alkyl wherein the haloalkyl chain may be fully or partially halogenated, substituted or unsubstituted C 1 -C 8 alkyl, deuterated C 1 -C 4 alkyl wherein the alkyl chain may be fully or partially deuterated, C 3 -C 10 cycloalkyl, halogen, cyano, nitro, C 1 -C 8 alkoxyl, aloalkoxyl wherein the haloalkyoxy chain may be fully or partially halogenated, and arylalkoxyl; R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, -OH, halogen, C 1 -C 6 -alkyl, C
  • the compound of the invention is a compound of Formula (II): (Formula II) wherein ring B, and groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , are described in claim 1; R 8 is H, hydroxyl, halogen, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, - CH 2 -cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one hetero
  • the compound of the invention is a compound of Formula (III): Formula (III) wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are described above in Formula (I); R 8 , W, T, Q, and X are described above in Formula (II); Z is CH, N, CF, or N + -O- In another embodiment, X is F. In another embodiment, R 8 is -CH 3 . In another embodiment, Q is N. In another embodiment, Q is N, W is CH, and T is CH. In another embodiment, R 1 is H or F. In another embodiment R 2 is H chloro or CF 3 In another embodiment, R 3 is H or CF 3 .
  • R 4 is H.
  • R 5 is H.
  • R 7 is methyl.
  • R 6 is azetidine, pyrrolidine, -CH 2 -OH, -CH-(CH 3 )-OH, -CH- CH 2 -NH-CH 3 , -CH 2 -NH 2 , CH-(CH 3 )-NH 2 , -CH 2 -NH 2 , -C-(CH 3 ) 2 -NH 2 , or -cyclobutyl-NH 2 .
  • R 9 is H.
  • the compound of Formula (I) is selected from the group consisting of:
  • the second set of compounds, provided herein, are prepared by methods and procedures described below.
  • the intermediates described in this section may be relied upon for preparation of second set of compounds.
  • Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted. All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized.
  • Prep Method 1 Equipment Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C 18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm; Prep Method 2 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
  • Prep Method 3 Equipment Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150x21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
  • Analytical LCMC were collected using one of following methods- Method 1 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C 18 2.7 ⁇ m, 3.0 mm ⁇ 30 mm; Mobile Phase: MeCN (0.05% HCOOH) - Water (0.05% HCOOH); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL/min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA.
  • SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System (SFE-30A, LC-30ADSF, SFC-30A) using following methods: Method 1 Column: Daicel chiralpak-AS-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH [0.1% NH 3 (7M in MeOH)], CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Method 2 Column: Daicel chiralpak-OJ-H 5 um 250 * 20 mm; Mobile Phase: CO 2 /MeOH (0.1% HCOOH), CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Method 3 Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Coupling constants, J are quoted to the nearest 0.1 Hz.
  • General synthetic schemes Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples.
  • the present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.
  • Scheme A in general, compounds of Formula (I) may be synthesized starting from carboxylic acids A-1 by reacting with a substituted aniline or heteroaryl aniline A-2 using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base such as DIEA to give intermediates of type A-3
  • Intermediates A-3 may contain a protecting group (PG) such as Boc which may be removed by treatment with an acid such as TFA to provide intermediates having structure A-4.
  • PG protecting group
  • Any suitable PG such as Cbz or Fmoc may be employed and can be removed accordingly.
  • the NH group of A-4 may be acylated using standard amide coupling reagents such as HATU in conjunction with a carboxylic acid and a base such as DIEA or the NH group may be acylated with a reactive carboxylic acid ester such as an N- hydroxysuccinimide ester, to provide compounds of Formula (I) after removal of any protecting groups.
  • a reactive carboxylic acid ester such as an N- hydroxysuccinimide ester
  • carboxylic acid A-1 may be treated with ammonia or a primary amine (R 5 NH 2 ) in the presence of an amide coupling reagent such as HATU and a base such as DIEA to give carboxamide intermediate A-5 which can undergo metal-catalyzed coupling with a halogen-substituted aryl or heteroaryl compounds of type A-6 to give compounds of formula A-3.
  • an amide coupling reagent such as HATU and a base such as DIEA
  • compounds of the invention can be prepared by reacting intermediates A-1 with an amine B-1, utilizing amide coupling conditions or by activation of an appropriately functionalized carboxylic acid A-1 with (COCl) 2 or POCl 3 and with amine B-1 and base such as DIEA or pyridine in DCM, DMF or THF to give compounds of type B-2.
  • the compounds of formula B-3 can be formed by removing a protecting group, such as Boc under acidic conditions.
  • B-3 can be separated into the corresponding R and S isomers using chiral HPLC.
  • R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine B-1 followed by deprotection.
  • the sulfoximine nitrogen of intermediate B-3 was acylated using standard amide coupling reagents such as, but not limited to, HATU, a base such as DIEA, and HO 2 C-R 6 -PG to give compounds of formula B-4.
  • B-4 contains a PG, as shown, it was removed to give a compound of formula B-5.
  • a Boc group as used to protect the sulfoximine it was removed by treatment with TFA to give compounds of formula B-5
  • Trialkylsilyl groups may be employed to protect hydroxyl groups and can be removed by treatment with aqueous acids such as acetic acid.
  • B-3 may yield compound B- 5 directly if there is no need for a protecting group.
  • Scheme C As illustrated in Scheme C, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-1 in organic solvent with either (COC1) 2 or SOCl 2 followed by addition of NH 4 OH to afford C-1. Intermediate C-1 can then be brought together with materials of variously substituted Br compounds C-2, utilizing Xantphos- Pd-G2 mediated coupling conditions to deliver intermediate C-3.
  • the compounds of formula C-3 may be treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to provide compounds of formula B-3. In some instances, B-3 was separated to the corresponding R and S isomers using chiral HPLC conditions.
  • Example 1B 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide
  • Reagents & conditions a) (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH/THF/H 2 O Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A mixture of (
  • reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (140 mg, 0.2 mmol) in THF/H 2 O/AcOH (1/3/3, 7 mL) was stirred at room temperature for 4 hours.
  • reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)- S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of (R)-N-(3-(N-(2- ((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF/H 2 O/AcOH (1/3/3, 7 mL) was stirred at room temperature for 4 hours.
  • Example 3B 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide
  • Reagents & conditions a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH/THF/H 2 O Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide: A solution of (
  • the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C 18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H 2 O containing 0.05% NH 3 .
  • reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-(2-(((3- (5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido)phenyl)(methyl) (oxo)- ⁇ 6 -6-sulfaneylidene)amino)-2-oxoethyl)carbamate (100 mg, 0.15 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • Example 5B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2-methylpyridin- 3-yl)oxy)-4-(trifluoromethyl)benzamide
  • Reagents & conditions a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl ((R)-1-(((R)-(3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate: A mixture of (R)-5-chloro-2-
  • reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-5-chloro-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert-butyl ((R)-1-(((R)-(3- (5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (120 mg, 0.18 mmol) in DCM (3 mL) was added TFA (0.5 mL)
  • reaction mixture was stirred at 50°C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert- butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamoyl) cyclobutyl)carbamate (120 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was heated at 50°C for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5- chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide : A solution of tert- butyl (R)-(1-(((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl) benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-methyl-1-oxopropan-2- yl)carbamate (100 mg, 0.15 mmol) in DCM (3 mL) was added T
  • Step 2 A solution of tert-butyl (S)-2-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamoyl)pyrrolidine-1- carboxylate (120 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3).
  • Step 2 A solution of tert-butyl ((R)-1-(((R)-(3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate (90 mg, 0.15 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours.
  • Reagents & conditions a) N-(tert-butoxycarbonyl)-N-methylglycine, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and N-(tert- butoxycarbonyl)-N-methylglycine (104 mg, 0.55 mmol) in DMF ( 5 mL) was added HATU (158 mg, 0.42 mmol) and DIEA (133 mg, 1.0 mmol).
  • Example 11B (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide
  • Reagents & conditions a) 2-((tert-butyldimethylsilyl)oxy)acetic acid, HATU, DIEA, DMF; b) TFA, DCM Step 1: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and 2-((tert- butyldimethylsilyl)oxy)acetic acid (105 mg, 0.55 mmol) in DMF ( 5 mL) was added HATU (158 mg
  • Step 2 A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (100 mg, 0.16 mmol) in THF (3 mL) was added AcOH (3 mL) and H 2 O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (20 mL) and extracted with DCM (10 mL x 3).
  • Example 12B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide
  • Reagents & conditions a) (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid, HATU, DIEA, DMF; b) AcOH, THF, H 2 O
  • Step 1 A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (150 mg, 0.32 mmol) and (S)-2- ((tert-butyldimethylsilyl)oxy)propanoic acid (112 mg, 0.
  • Step 2 A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S- methylsulfonimidoyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- (trifluoromethyl)benzamide (100 mg, 0.15 mmol) in THF (3 mL) was added AcOH (3 mL) and H 2 O (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3).
  • Example 13B 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide
  • Step 2 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)- S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of N-(3-((R)-N-((R)-2- ((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in THF (3 mL) was added CH 3 CO 2 H (3 mL) and H 2 O (1 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide : A solution of tert-butyl (R)-(2-(((3- (2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-oxoethyl)carbamate (150 mg, 0.24 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with NaHCO 3 solution (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Example 15B N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2-methylpyridin- 3-yl)oxy)-3-(trifluoromethyl)benzamide
  • Reagents & conditions a) (tert-butoxycarbonyl)-D-alanine, HATU, DIEA, DMF; b)TFA, DCM Step 1: tert-butyl ((R)-1-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-1-oxopropan-2- yl)carbamate: A mixture of (R)-2-fluoro-6-((
  • Step 2 N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide: A solution of tert-butyl ((R)-1-(((R)-(3- (2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-(2-(((3- (2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-oxoethyl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methyl-N- (methylglycyl)sulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (R)- (2-(((3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((S)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide: A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF (3 mL) and H 2 O (1 mL) was added AcOH (3 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-((R)-N-((R)-2- hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A mixture of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2- fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.18 mmol) in THF (3 mL) and H 2 O (1 mL) was added AcOH (3 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-(2-hydroxyacetyl)-S- methylsulfonimidoyl)phenyl)-3-(trifluoromethyl)benzamide : A solution of (R)-N-(3-(N-(2-((tert- butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-fluoro-6-((6-fluoro-2- methylpyridin-3-yl)oxy)-3-(trifluoromethyl)benzamide (120 mg, 0.1824 mmol) in THF (1 mL) and H 2 O (3 mL) was added AcOH (3 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 6 hours.
  • the aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Example 21B (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)pyrrolidine-2-carboxamide Reagents & conditions: a) (tert-butoxycarbonyl)-L-proline, HATU, DIEA, DMF; b) TFA, DCM Step 1: tert-butyl (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamoyl)pyrrolidine-1- carboxylate: A mixture of (R)-2-flu
  • Step 2 (S)-N-((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3-yl)oxy)-3- (trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)pyrrolidine-2- carboxamide: A solution of tert-butyl (S)-2-(((R)-(3-(2-fluoro-6-((6-fluoro-2-methylpyridin-3- yl)oxy)-3-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene) carbamoyl)pyrrolidine-1-carboxylate (120 mg, 0.17 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature.
  • Example 30B Compound profiling human NaV1.8/ ⁇ 3 cell line – SyncroPatch384PE Assay
  • Compounds were tested on recombinant human Nav1.8/b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device.
  • Cells were cultured at 37°C/5% CO 2 in Ham’s F-12 supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 mg/mL streptomycin sulfate and selection antibiotics (0.01 mg/ml Blasticidin, 0.4 mg/ml Zeocin and 0.25 mg/ml Hygromycin).
  • HBSS Hank’s Balanced Salt Solution
  • the cells were washed in HBSS to remove the Accutase and re- suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl 2 , 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH.
  • Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2, 3.8; MgCl 2 , 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.
  • Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid.
  • Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds.
  • Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.
  • A represents an IC50 less than or equal to 5 nM
  • B represents an IC50 greater than 5 nM to less than or equal to 50 nM
  • C represents an IC50 greater than 50 nM to less than or equal to 100 nM
  • D represents an IC50 greater than 100 nM to less than or equal to 200 nM
  • E represents an IC50 greater than 200 nM.
  • the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C 1 -C 8 -alkyl, C 1 -C 8 fully or partially fluorinated fluoroalkyl, C 2 -C 8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R’)(R’’)-cycloalkyl, C(R’)(R’’)-aryl, -NR’R’’, substituted or unsubstituted 3-8 membered cycloalkyl
  • B is a 6 membered substituted or unsubstituted heteroaryl ring, comprising one or more N atoms.
  • the N atoms in the heteroaryl ring may be in the form of a N- oxide.
  • the N-oxide containing B-ring is selected from pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.
  • the compound is a compound of Formula (III): Formula (III) wherein, Q, T and W are independently N or CR 6 ;
  • R 6 is H, halogen, -CD 3 , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , - OCF 3 , or substituted or unsubstituted cycloalkoxy;
  • R 5 is H, -OH, halo, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH 2 - cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, substituted or unsubstituted
  • the compound is a compound of Formula (IV): Formula (IV), wherein: Z is CR 10 , N, or N + O-; wherein R 10 is H, halo, -CD 3 , C 1 -C 8 alkyl, haloalkyl, or alkoxy.
  • ring A is substituted or unsubstituted 6 or more membered heteroaryl ring having at least one heteroatom independently selected from N, O, or S.
  • ring A is substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
  • ring A is substituted or unsubstituted 6 membered heteroaryl having at least one heteroatom, wherein the heteroatom is N. In certain embodiments, ring A is substituted or unsubstituted 6 membered heteroaryl having at least 2 N atoms.
  • A is: wherein Q 1 , Q 2 , Q 3 and Q 4 are independently selected from a group consisting of: N, N + O-, or CR 7 ; wherein at least two of Q 1 , Q 2 , Q 3 and Q 4 are CR 7 ; R 7 is H, -OH, halo, -CD 3 , alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , -OCF 3 , substituted or unsubstituted 5 or 6 membered ring heterocyclyl or heteroaryl, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl, O-heteroaryl, O-cycloalkyl, or O- cycloheteroalkyl.
  • A is: wherein, Q 2 and Q 4 are independently N or N + O- ; Q 2 is N or N + O- ; Q 4 is CR 7 ; or Q 2 is CR 7 , Q 4 is N or N + O-; R 8 and R 9 are independently selected from a group consisting of H, -OH, halo, -CD 3 , substituted or unsubstituted C 1 -C 6 alkyl, branched alkyl, alkenyl, alkylnyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH 2 , NHR’, NR’R”, aryl, heteroaryl, -CF 2 CH 3 , and -CF 2 CF 3 ; In other embodiments, in the compounds of Formula (I), Formula (III), and/or Formula (IV), A is: wherein, Q 3 and Q 4 are independently N or N or N
  • A is: wherein, Q 1 and Q 4 are independently N or N + O-; Q 1 is N or N + O-, and Q 4 is CR 7 ; Q 1 is CR 7 and Q 4 is N or N + O-; or Q 1 or Q 4 is CR 7 ; wherein R7, R 8 , and R 9 are defined above.
  • Q 1 and Q 4 are independently N or N + O-; Q 1 is N or N + O-, and Q 4 is CR 7 ; Q 1 is CR 7 and Q 4 is N or N + O-; or Q 1 or Q 4 is CR 7 ; wherein R7, R 8 , and R 9 are defined above.
  • A is: wherein Q 1 is CR 7 , Q 2 is N; R 7 , R 8 , and R 9 are defined above.
  • A is: wherein, Q 1 is N; Q 2 is CR 7 ; R 7 , R 8 , and R 9 are defined above.
  • R 2 is: wherein m and n are independently 0 or 1; X 1 is O and X 2 is NH, and R 4 is alkyl, for example, methyl.
  • Q is N or CH; R 5 is methyl or -OMe, X is F or CN. In other embodiments, in the compound of Formula (III) and/or Formula (IV), Q is CF.
  • R 7 , R 8 , and R 9 are independently selected from a group consisting of: H, methyl, fluoro, chloro, bromo, CF 3 , cyclopropyl, difluorophenyl, and dimethylpyrazole.
  • R 10 in the compound of Formula (III) and/or Formula (IV), is H or F.
  • Z in the compound of Formula (III) and/or Formula (IV), Z is N or CH.
  • R 2 is Formula (II): wherein, m and n are independently 0 or 1; and X 1 and X 2 are not both O, NH, or NR’.
  • the compound of the invention is selected from a group consisting of:
  • the third set of compounds, provided herein, are prepared by methods and procedures described below.
  • the intermediates described in this section may be relied upon for preparation of third set of compounds.
  • Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.
  • Prep Method 1 Equipment Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C 18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm; Prep Method 2 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
  • Prep Method 3 Equipment Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C 18 column, 150x21.2 mm; General gradient: 30% to 90% MeCN/H 2 O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Analytical LCMC were collected using one of following methods.
  • SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System (SFE-30A, LC-30ADSF, SFC-30A) using following methods: Analytical Method 4 Column: Daicel chiralpak-AS-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH [0.1% NH 3 (7M in MeOH)], CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Analytical Method 5 Column: Daicel chiralpak-OJ-H 5 um 250 * 20 mm; Mobile Phase: CO 2 /MeOH (0.1% HCOOH), CO 2 /MeOH ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Analytical Method 6 Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CO 2 /MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Analytical Method 7 Column: Daicel chiralpak-AD-H 5 um 250x20 mm; Mobile Phase: CO 2 /i-PrOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min.
  • Analytical Method 8 Column: Daicel chiralpak-IC 5 um 250x20 mm; Mobile Phase: CO 2 /EtOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL/min. Unless otherwise stated, 1 H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz Digital NMR Spectrometer.
  • NMR nuclear magnetic resonance spectroscopy
  • Coupling constants, J are quoted to the nearest 0.1 Hz.
  • General synthetic schemes Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples.
  • the present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.
  • Compounds of Formula (I) may be prepared from A-1 starting materials or intermediates but not limited to methyl 4,6-dichloropyridazine-3-carboxylate, 2,6-dichloro-3- (trifluoromethyl)pyridine, 2,4-dichloro-5-nitropyridine, methyl 2-hydroxy-4-methylnicotinate, 2- bromo-3,5-dichloroisonicotinic acid, methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate, methyl 5-bromo-2-chloro-4-methylnicotinate, ethyl 5-bromo-3-fluoro-2-iodoisonicotinate, 2,6- dichloro-4-methylnicotinic acid, ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate, methyl 2- chloro-5-nitronicotinate, 2-chloro-4,6-dimethylnicotinic acid, that are commercially available, synth
  • Modifications may be made to the starting materials and intermediates to prepare still other intermediates that possess alternate or additional groups such as alkyl, fluoroalkyl, trifluoromethyl, cyano, halogen, chloro, bromo, iodo, amino, nitro, aryl, heteroaryl, carboalkoxy, alkoxy, aryloxy, heteroaryloxy, and the like.
  • Methodology used to convert above starting materials into Compounds of Formula (I) are shown for each of the Examples.
  • Scheme A As illustrated in Scheme A, in general, compounds of Formula (I) may be synthesized from an A-1 starting material or intermediate. Ring A and X of A-1 may first be modified to give an intermediate A-1 suitable for subsequent modification.
  • Modifications can include, but are not limited to, exchange of a halogen for trifluoromethyl, metal-catalyzed coupling to introduce an alkyl, aromatic, or heteroaromatic group, treatment with nitric acid to introduce a nitro group, reduction of a nitro group to an amino group, or other transformations known to those skilled in the art.
  • the X group of A-1 may be displaced by various substituted phenols or heteroaromatic alcohols in the presence of base, such as K 2 CO 3 , Cs 2 CO 3 , NaH, KH or other organic bases to provide intermediates of type A-2.
  • Intermediates of type A-2 may or may not be further modified on Ring A and the carboxylate ester is subsequently hydrolyzed with KOH or LiOH in an aqueous solvent, to give the carboxylic acid intermediate A-3.
  • Intermediates A-3 may be reacted with a substituted aniline or heteroaryl aniline using standard amide coupling reagents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA, to give Compounds of Formula (I).
  • standard amide coupling reagents not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA
  • Compounds of Formula (I) may be further modified to provide additional Compounds of Formula (I).
  • Intermediate A-2 may be treated with ammonia, a primary amine (R 1 NH 2 ), or a dialkylaluminum amide to give carboxamide A-4 which can undergo metal-catalyzed coupling with a halo-substituted aniline or heteroaryl aniline to give Compounds of Formula (I).
  • Scheme B
  • compounds of the invention can be prepared by reacting substituted compound A-1 with an aryl- or heteroaryl-alcohol B using a base such as DIEA or inorganic base such as K 2 CO 3 or Cs 2 CO 3 to afford intermediate A-2.
  • Intermediate A-2 can be converted to corresponding acid A-3 by treating A-2 with base such as KOH or LiOH or NaOH in aqueous EtOH or MeOH or a mixture of MeOH/THF/H 2 O.
  • Intermediates A-5 can be formed either by treating A-3 and amine C, utilizing amide coupling conditions or by activation of appropriately functionalized carboxylic acid A- 4 with (COCl) 2 or POCl 3 and with amine C base such as DIEA or pyridine in DCM, DMF or THF.
  • the compounds of formula A-6 can be formed by removing a protecting group, such as Boc under acidic conditions.
  • A-6 can be separated to the corresponding R and S isomers using chiral HPLC.
  • R- and S-isomers also can be prepared by coupling of the acid to enantiomerically pure amine C followed deprotection.
  • compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-3 in organic solvent with either (COC1) 2 or SOCl 2 followed by addition of NH 4 OH to afford B-1.
  • Intermediate B-1 can then be brought together with materials of variously substituted Br compounds, utilizing Xantphos-Pd-G2 mediated coupling conditions to deliver intermediate B-2.
  • the compounds of formula B-2 treated with ammonium carbonate or ammonium carbamate and (diacetoxyiodo)benzene (PIDA) in methanol to deliver compound of formula B-3.
  • PIDA diacetoxyiodo
  • B-3 was separated corresponding R and S isomers using chiral HPLC conditions.
  • Reagents & conditions a) fuming HNO 3 , H 2 SO 4 , 0 to 50 °C; b) PhOPOCl 2 , 160 °C; c) Cs 2 CO 3 , MeCN, 50 °C; d) Fe, NH 4 Cl, MeOH/H 2 O, 50 °C; e) p-TsOH•H 2 O, NaNO 2 , KI, MeCN/H 2 O, rt; f) CuI, DMF, N 2 , 120 °C; g) LiOH, THF/MeOH/H 2 O, rt Step1.
  • methyl 2-hydroxy-4-methyl-5-nitronicotinate To a stirred solution of methyl 2- hydroxy-4-methylnicotinate (40 g, 0.24 mol) in H 2 SO 4 (200 mL) was added fuming HNO 3 (13 mL) dropwise at 0 °C. The mixture was heated to 50 °C for 5 hours. The resulting mixture was poured into ice water (3 L). The precipitate was collected by filtration, washed with water, and dried under vacuum to give crude methyl 2-hydroxy-4-methyl-5-nitronicotinate (26 g, 51% yield) as a yellow solid.
  • LCMS (ESI) calcd.
  • Step 2 methyl 2-chloro-4-methyl-5-nitronicotinate: A solution of methyl 2-hydroxy-4- methyl-5-nitronicotinate 5 (8.0 g, 37.8 mmol) in phenyl dichlorophosphate (40 mL) was heated to 160 °C for 2 hours. The resulting solution was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 mL x 3).
  • Reagents & conditions a) 6-fluoro-2-methylpyridin-3-ol, Cs 2 CO 3 , MeCN, 50 ⁇ C; b) Fe, NH 4 Cl, MeOH/H 2 O, 60 ⁇ C; c) t-BuoNO, CuBr, MeCN, 50 ⁇ C; d) LiOH, THF/H 2 O, rt Step 1: methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate: To a solution of methyl 2-chloro-4-methyl-5-nitronicotinate (3.6 g, 15.7 mmol) and 6-fluoro-2- methylpyridin-3-ol (2.0 g, 15.7 mmol) in MeCN (60 mL) was added Cs 2 CO 3 (10.0 g, 31.5 mmol).
  • Step 2 methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: A solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-nitronicotinate (2.5 g, 7.8 mmol) in MeOH (30 mL) and water (10 mL) was added NH 4 Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3).
  • Step 3 methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To a solution of methyl 5-amino-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (1.3 g, 4.46 mmol) and CuBr (638 mg, 4.46 mmol) in MeCN (30 mL) was added t-BuONO (459 mg, 4.46 mmol) dropwise at room temperature. The reaction solution was heated at 50 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (80 mL) and extracted with EtOAc (40 mL x 3).
  • Reagents & conditions a) 6-fluoro-2-methylpyridin-3-ol, DIEA, DMF, 100 ⁇ C; b) LiOH, THF, H 2 O, rt Step 1: methyl 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate: A mixture of methyl 3-chloro-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate (500 mg, 1.97 mmol), 6-fluoro-2-methylpyridin-3-ol (375 mg, 2.95 mmol), DIEA (381 mg, 2.95 mmol), in DMF (10 mL) was heated at 100 °C for 16 hours.
  • Step 2 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine- 4-carboxylic acid : To a solution of methyl 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6- (trifluoromethyl)pyridazine-4-carboxylate (350 mg, 1.01 mmol) in THF/H 2 O (1/1, 10 mL) was added LiOH (242 mg, 10.11 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours.
  • Step 2 methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: A solution of methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-nitronicotinate (2.5 g, 7.3 mmol) in MeOH (30 mL) and water (10 mL) was added NH 4 Cl (2.71 g, 51.1 mmol), Fe (2.04 g, 36.5 mmol). The mixture was heated to 60 °C for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3).
  • Step 3 methyl 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate: To a solution of methyl 5-amino-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinate (1 g, 3.2 mmol) and CuBr (458 mg, 3.2 mmol) in MeCN (20 mL) was added t-BuONO (391 mg, 3.8 mmol) dropwise at room temperature. The reaction solution was heated at 50 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3).
  • Reagents & conditions a) TsOH . H 2 O, Acetonitrile, 0 °C, NaNO 2 , KI, 0 °C; b) added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, DMF, 100 °C; c) LiOH.H 2 O, THF/MeOH/ H 2 O, rt Step 1: methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate: To a solution of TsOH .
  • Step 2 methyl 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate: To a stirred solution of methyl 2-(4-cyano-2-methoxyphenoxy)-5-iodo-4-methylnicotinate (380 mg, 0.89 mmol) and copper(I) iodide (341 mg, 1.79 mmol) in DMF (40 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (860 mg, 4.48 mmol) dropwise at room temperature under an atmosphere of N 2 . The mixture was heated at 120 °C for 6 hours.
  • Step 2 To a solution of methyl 6-chloro-4-(4-cyano-2-methylphenoxy)pyridazine-3- carboxylate (1000 mg, 3.29 mmol) in MeCN (10 mL) was added NaI (4939 mg , 32.92 mmol) at 0 °C. Then a solution of AcCl (568 mg, 7.24 mmol) in MeCN (5 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 6 hours. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 3 To a solution of methyl 4-(4-cyano-2-methylphenoxy)-6-iodopyridazine-3- carboxylate (800 mg, 2.02 mmol) and Cu (386 mg, 6.07 mmol) in DMF (10 mL) was added [Ph2SCF 3 ] [OTf]- (1473 mg ,3.64 mmol). The mixture was heated at 60 °C for 16 hours. Then the mixture was filtered through celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 To a solution of 3,4-difluoro-2-methoxyphenol (1.2 g, 7.49 mmol) in DMF (10 mL) was added NaH (0.36 g, 8.99 mmol, 60%). The mixture was stirred at room temperature for 30 minutes. Then the mixture was added dropwise to a solution of methyl 4,6-dichloropyridazine- 3-carboxylate (1.54 g, 7.49 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 1h. LCMS showed the reaction was completed. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL x 3).
  • Step 3 To a solution of methyl 6-chloro-4-(3,4-difluoro-2-methoxyphenoxy)pyridazine- 3-carboxylate (800 mg, 2.42 mmol) in MeCN (10 mL) was added NaI (3640 mg , 24.24 mmol) at 0 °C. Then a solution of AcCl (415 mg, 5.32 mmol) in MeCN (5 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 3 h. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3).
  • Step 4 To a solution of methyl 4-(3,4-difluoro-2-methoxyphenoxy)-6-iodopyridazine-3- carboxylate (800 mg, 1.89 mmol) and CuI (720 mg, 3.79 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2912 mg ,15.17 mmol). The mixture was heated at 120 °C for 2 hours. LCMS showed the rection was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3).
  • Step2 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine: A mixture of 3-((3- bromophenyl)thio)propanenitrile (3 g, 0.012 mol) in Et 2 O (100 mL) under N 2 at room temperature was added Titanium tetraisopropanolate (3.88 g, 0.014 mol) and ethylmagnesium bromide (5 mL, 1 mol/L in THF). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with 10% hydroxide sodium solution (100 mL) and extracted with DCM (50 mL x 3).
  • Step3 tert-butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate: A mixture of 1-((3-bromophenyl)thio)-3-ethylpentan-3-amine (1.9 g, 6.3 mmol) and Boc 2 O (4.12 g, 0.019 mol) in DCM (50 mL) was added TEA (1.91 g, 0.019 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (25 mL x 3).
  • Step4 tert-butyl (1-(3-bromophenylsulfonimidoyl)-3-ethylpentan-3-yl)carbamate: A mixture of tert-butyl (1-((3-bromophenyl)thio)-3-ethylpentan-3-yl)carbamate (1.5 g, 3.7 mmol), PhI(OAc) 2 (3.58 g, 0.011 mol) and NH 4 OAc (0.57 g, 0.0074 mol) in EtOH (30 mL) was stirred at room temperature for 6 hours.
  • Step5 tert-butyl ((3-bromophenyl)(3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(oxo)- l6-sulfaneylidene)carbamate: A mixture of tert-butyl (1-(3-bromophenylsulfonimidoyl)-3- ethylpentan-3-yl)carbamate (0.95 g, 2.19 mmol), Boc 2 O (2.39 g, 0.0109 mol), TEA (1.11 g, 0.0109 mol) and DMAP (26.78 mg, 0.22 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours.
  • tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(3-nitrophenyl)(oxo)-16- sulfaneylidene)carbamate : A mixture of (3-hydroxy-3-methylbutyl)(imino)(3-nitrophenyl)-16- sulfanone (500 mg, 1.84 m mol), (Boc) 2 O (1.60 g, 0.0073 mol) in THF (10 mL) was added DMAP (560.79 mg, 4.59 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 16 hours.
  • tert-butyl ((3-aminophenyl)(3-((tert-butoxycarbonyl)oxy)-3-methylbutyl)(oxo)-16- sulfaneylidene)carbamate A mixture of tert-butyl ((3-((tert-butoxycarbonyl)oxy)-3- methylbutyl)(3-nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (320 mg, 0.67 mmol), NH 4 Cl (108.20 mg, 2.02 mmol) in EtOH/H 2 O (4/1, 10 mL) was added Fe (263.62 mg, 4.72 mmol) at 70 °C.
  • Step 2 A solution of methyl 2-bromo-3,5-dichloroisonicotinate 2 (2 g, 7 mmol), CuI (2.76 g, 14 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (6.72 g, 35 mmol) in DMF (25 mL) was heated at 100 °C for 5 hours under N 2 . LCMS showed the rection was completed. The mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried with Na 2 SO 4 , and concentrated under vacuum.
  • Step 3 A mixture of methyl 3,5-dichloro-2-(trifluoromethyl)isonicotinate (1.5 g, 5.5 mmol), 6-fluoro-2-methylpyridin-3-ol (420 mg, 3.3 mmol) and Cs 2 CO 3 (5.38 g, 16.5 mmol) in MeCN (30 mL) was heated 80 °C for 2 hours. The mixture was cooled to room temperature, filtered through celite.
  • Step 4 To a solution of methyl 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinate 7 (290 mg, 0.80 mmol) in THF/H 2 O (1/1, 10 mL) was added LiOH (200 mg, 7.95 mmol) at 25 °C. Then the mixture was heated at 60 °C for 5 hours. After the reaction was completed, the mixture was quenched by 2N HCl and adjusted pH to 3-4. Then the solution was concentrated to remove most THF. The residue was extracted with EtOAc (50 mL x 3).
  • Reagents & conditions a) Cs 2 CO 3 , DMF, rt; b) PhI(OAc) 2 , AcONH 4 , EtOH; c) (Boc) 2 O, DMAP; d) Fe, NH 4 Cl
  • Step 1 A mixture of 3-nitrobenzenethiol (1 g, 6.4 mmol), (3-bromopropoxy)(tert- butyl)dimethylsilane (1.78 g, 7 mmol), Cs 2 CO 3 (6.26 g, 19.3 mmol) in DMF (20 mL) was stirred at room temperature for 3 hours.
  • Step 2 A mixture of tert-butyldimethyl(3-((3-nitrophenyl)thio)propoxy)silane (2 g, 6.1 mmol), PhI(OAc) 2 (5.89 g, 18.3 mmol), NH 4 OAc (0.94 g, 12.2 mmol) in EtOH (20 mL) was stirred at 50 °C for 6 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 3 A mixture of (3-((tert-butyldimethylsilyl)oxy)propyl)(imino)(3-nitrophenyl)-16- sulfanone (1.68 g, 4.7 mmol), (Boc) 2 O (1.03 g, 4.7 mmol) in THF (10 mL) was added DMAP (0.57 g, 4.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 4 A mixture of tert-butyl ((3-((tert-butyldimethylsilyl)oxy)propyl)(3- nitrophenyl)(oxo)-16-sulfaneylidene)carbamate (550 mg, 1.19 mmol), NH 4 Cl (320.03 mg, 5.98 mmol) in MeOH/H 2 O (4/1, 30 mL) was added Fe power (400.98 mg, 7.18 mmol). The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the resulting mixture was filtrated through celite. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3).
  • Step 3 (3-bromophenyl)(methyl)-16-sulfanediimine (200 mg, 0.862 mmol), t-BuOK (241 mg, 2.155 mmol) and Boc 2 O (563 mg, 2.586 mmol) in THF (10 mL) was stirred at room temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • the upper layer clear solution was added dropwise into a stirred solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-iodo-4-methylnicotinate (1.5 g, 3.73 mmol), ZnCl 2 (300 mg, 1.57 mmol) and Pd(dppf)Cl 2 (300 mg, 0.43 mmol) in THF (4 mL) under an atmosphere of N 2 .
  • the mixture was heated to 50 °C and stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and the mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3).
  • Step 2 A solution of tert-butyl methyl 5-(cyclopent-1-en-1-yl)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methylnicotinate (550 mg, 1.61 mmol) in MeOH (20 mL) was added Pd/C (100 mg) and stirred at room temperature under an atmosphere of H 2 . LCMS showed the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3).
  • Reagents & conditions a) CuCl, t-BuOK, NMP, 80 ⁇ C; b) K 2 CO 3 , MeCN, 70 ⁇ C; c) KOH, t-BuOH, THF/H 2 O, 70 ⁇ C Step 1. methyl 2-chloro-4-methyl-5-(perfluoroethyl)nicotinate: In a glove-box, a three- neck 1000ml round-bottom flask equipped with a Teflon coated magnetic stir-bar was charged with t-BuOK(34g, 0.3mol)and NMP(500ml).
  • Step 2 methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (perfluoroethyl)nicotinate: To solution of methyl 2-chloro-4-methyl-5-(perfluoroethyl)nicotinate (3.8g, 12.52mmol) in MeCN (28.5mL) was added 6-fluoro-2-methylpyridin-3-ol (1.67g, 13.15mmol) and K 2 CO 3 (5.18g, 37.54mmol).
  • Step 1 methyl 2-((6-chloro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinate: To solution of methyl 2-chloro-4-methyl-5- (trifluoromethyl)nicotinate (6.36g, 25.1mmol) in MeCN (48mL) was added 6-chloro-2- methylpyridin-3-ol (3.0g, 20.9mmol) and K 2 CO 3 (8.65g, 62.9mmol). The mixture was heated to 70°C and stirred for 16 hours.
  • Step 2 2-((6-chloro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of methyl2-((6-chloro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinate (2.04g,10.15mmol) in t-Butanol (8mL) and water(8ml) was added Tetrahydrofuran(8ml), the resulting mixture was added Potassium hydroxide (1.59g, 28.28mmol).
  • the reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combine organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 2 (R)-5-(4-(difluoromethyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (R)-((3-(5- (4-(difluoromethyl)phenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (243 mg, 0.38 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (40 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinamido)phenyl) (methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (250 mg, 0.42 mmol) and (4-cyanophenyl)boronic acid (185 mg, 1.26 mmol) in 1,4-dioxan
  • the reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combine organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 3 (R)-5-(4-cyanophenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (R)-((3-(5-(4-cyanophenyl)- 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -16- sulfaneylidene)carbamate (240 mg, 0.39 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of give tert- butyl (R)-((3-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- 4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (160 mg, 0.247 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • Reagents & conditions a) oxalyl chloride, DMF, DCM, tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate, Et 3 N; b) TFA, DCM Step1: tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: A solution of 2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (150 mg, 0.43 mmol) in DCM (5 mL) was added DMF (4 drop) and oxalyl chloride (81 mg, 0.64 mmol) at room temperature.
  • Step 2 (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide : A solution of tert-butyl (R)-((3- (2-(4-cyano-2-methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl) (oxo)- ⁇ 6 -sulfaneylidene)carbamate (120 mg, 0.19 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • Step 2 (R)-5-(3,4-difluorophenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N- (3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of give tert-butyl (R)-((3-(5-(3,4- difluorophenyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinamido)phenyl)(methyl) (oxo)- ⁇ 6 -sulfaneylidene)carbamate (150 mg, 0.24 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • Step 2 tert-butyl (R)-((3-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-((6-fluoro-2- methylpyridin-3-yl)oxy)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(6-chloro-3-((6-fluoro-2- methylpyridin-3-yl)oxy)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (150 mg, 0.27 mmol
  • Step 2 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)nicotinamide
  • the chloride intermediate was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl) (oxo)- ⁇ 6 -sulfaneylidene)carbamate (82 mg, 0.31 mmol) and DIEA (80 mg, 0.62 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 (R)-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert- butyl (R)-((3-(3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (100 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • Reagents & conditions a) SOCl 2 , NH 3 /H 2 O, THF; b) Xantphos-Pd-G2, Cs 2 CO 3 , 1,4- dioxane, 100 °C; c) PhI(OAc) 2 , NH 2 CO 2 NH 4 , MeOH, 70 °C; d) Chiral SFC separation Step 1: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6- phenylpyridazine-4-carboxylic acid (500 mg, 1.515 mmol) in SOCl 2 (5 mL) was heated at 80 °C for 1 hour.
  • reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 4 (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide and (R)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5- (trifluoromethyl)nicotinamide : 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(2-(S- )pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (80 mg) was purified by Chiral-Prep-HPLC (Chiralpak-IC, 4.6*250 mm, eluting with 20% CO 2 -MeOH containing 0.1% NH 3 )
  • reaction solution was stirred at room temperature for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 3-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide : A solution of tert-butyl (tert-butoxycarbonyl)((3-(3- ((6-fluoro-2-methylpyridin-3-yl)oxy)-5-methyl-6-(trifluoromethyl)pyridazine-4- carboxamido)phenyl)sulfonyl)carbamate (80 mg, 0.12 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • the reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 3 (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(4-fluoro-3-(S- methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide and (R)-2-((6-fluoro-2- methylpyridin-3-yl)oxy)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5- (trifluoromethyl)nicotinamide : 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(4-fluoro-3-(S- methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide was purified by Chi
  • reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was diluted with THF and added dropwise to a stirred solution of NH 3 -H 2 O (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 2 2-(4-cyano-2-methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4- methylnicotinamide: A mixture 5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinamide (280 mg, 0.77mmol) and (4-(difluoromethyl)phenyl)boronic acid (200 mg, 1.16 mmol) in 1,4- dioxane/H 2 O (10/1, 20 mL), K 3 PO 4 (492 mg, 2.32 mmol) and [1,1’- Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (57 mg, 0.08 mmol) was heated at 100 °C in a microwave reactor for 1 hours under an atmosphere of N 2 .
  • Step 3 2-(4-cyano-2-methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4-methyl-N-(2- (methylsulfinyl)pyridin-4-yl)nicotinamide: A solution of 2-(4-cyano-2-methoxyphenoxy)-5-(4- (difluoromethyl)phenyl)-4-methylnicotinamide (300 mg, 0.73 mmol) in dioxane (8 mL) was added 4-bromo-2-(methylsulfinyl)pyridine (461 mg, 2.19 mmol), cesium carbonate (620 mg, 1.90 mmol) and Xantphos-Pd-G2 (130 mg, 0.15 mmol) at room temperature.
  • reaction mixture was heated at 70 °C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 5 (S)-2-(4-cyano-2-methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4-methyl-N-(2- (S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide and (R)-2-(4-cyano-2-methoxyphenoxy)-5- (4-(difluoromethyl)phenyl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide : 2-(4-cyano-2-methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4-methyl-N-(2-(S- methylsulfonimidoyl)pyridin-4-yl)nicotinamide was purified by Chiral-Prep-HPLC (Chiralpak- IC, 4.6*250 mm, eluting with 20% CO 2 -MeOH containing
  • the mixture was stirred at room temperature for 0.5 hour. Then the solution was concentrated under vacuum to provide the chloride intermediate.
  • the chloride intermediate was dissolved in DCM (2 mL) and was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (314 mg, 1.16 mmol) and TEA (352 mg, 3.48 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with water (40 mL) and extracted with DCM (30 mL x 2).
  • Step 2 tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-5-(4-cyanophenyl)-4- methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (100 mg, 0.1628 mmol) and (4-cyanophenyl)boronic acid (120 mg, 0.8143 mmol) in 1,4-dioxane/H 2 O (4/1, 10 mL), potassium carbonate (68 mg, 0.4884 mmol) and [1,1’-Bis(diphenylphosphino)fer
  • the reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combine organic phases were washed with brine, dried over Na 2 SO 4 , concentrated under vacuum.
  • Step 3 (R)-2-(4-cyano-2-methoxyphenoxy)-5-(4-cyanophenyl)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide : A solution of tert-butyl (R)-((3-(2-(4-cyano-2- methoxyphenoxy)-5-(4-cyanophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (72 mg, 0.113 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-5-(p-tolyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4- cyano-2-methoxyphenoxy)-4-methyl-5-(p-tolyl)nicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (60 mg, 0.096 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • Step 2 (R)-6'-(4-cyano-2-methoxyphenoxy)-4',5-dimethyl-N-(3-(S- methylsulfonimidoyl)phenyl)-[2,3'-bipyridine]-5'-carboxamide: A solution of tert-butyl (R)-((3- (6'-(4-cyano-2-methoxyphenoxy)-4',5-dimethyl-[2,3'-bipyridine]-5'- carboxamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate(60 mg, 0.096 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • Step 2 (R)-2-(4-cyano-2-methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4-methyl-N- (3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4-cyano-2- methoxyphenoxy)-5-(4-(difluoromethyl)phenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (80 mg, 0.121 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • Example 24C (R)-5-bromo-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide Reagents & conditions: TFA, DCM, rt A solution of tert-butyl (R)-((3-(5-bromo-2-(4-cyano-2-methoxyphenoxy)-4- methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (60 mg, 0.096 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature.
  • Step 2 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid
  • Step 3 tert-butyl ((3-(5-chloro-2-(4-cyano-2-methoxyphenoxy)-4- methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: A solution of 5-chloro- 2-(4-cyano-2-methoxyphenoxy)-4-methylnicotinic acid (80 mg, 0.25 mmol) in DCM (3 mL) and DMF (one drop) was added oxalyl chloride (62 mg, 0.50 mmol). The solution was stirred at room temperature for 10 min.
  • Step 4 5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-2-(4-cyano-2- methoxyphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (60 mg, 0.105 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated.
  • Step 2 (R)-5-chloro-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4-cyano- 2-methoxyphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (85 mg, 0.15 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours.
  • the reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated under vacuum.
  • Step 2 (R)-2-(4-cyano-2-methoxyphenoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methyl- N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4-cyano- 2-methoxyphenoxy)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl) (oxo)- ⁇ 6 -sulfaneylidene)carbamate (80 mg, 0.127 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 2 N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-cyano-2- methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamide: A solution of 2-(4-cyano-2- methoxyphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamide (200 mg, 0.57 mmol), 3-bromo- N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (1.2 g, 2.28 mmol), Cs 2 CO 3 (926 mg, 2.85 mmol) and Xantphos-Pd-G2 (202 mg, 0.22 mmol) in dioxane (20 mL) was heated at 110 °C for 8 hours
  • Step 3 2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)nicotinamide: A solution of N-(3-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-5- (trifluoromethyl)nicotinamide (115 mg, 0.14 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature.
  • Example 29C 4-(4-cyano-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 3-methanesulfonylaniline, T3P, DIEA, DCM To a solution of 4-(4-cyano-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-3- carboxylic acid (120 mg, 0.37 mmol), 3-methanesulfonylaniline (64 mg, 0.37 mmol) and T3P (472 mg , 50% in EtOAc) in DCM (5 mL) was added DIEA (287 mg , 2.23 mmol).
  • Example 30C 4-(3,4-difluoro-2-methoxyphenoxy)-N-(3-(methylsulfinyl) phenyl)-6-(trifluoromethyl) pyridazine-3-carboxamide Reagents & conditions: a) 3-(methylsulfinyl)aniline , HATU, DIEA, DMF To a solution of 4-(3,4-difluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-3-carboxylic acid (100 mg, 0.29 mmol), 3-(methylsulfinyl)aniline (53 mg, 0.34 mmol) and HATU (217 mg , 0.57 mmol) in DMF (2 mL) was added DIEA (110 mg , 0.86 mmol).
  • Example 31C 4-(3,4-difluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide Reagents & conditions: PhI(OAc) 2 NH 4 OAc, MeOH, 70°C
  • PhI(OAc) 2 NH 4 OAc, MeOH, 70°C
  • a solution of 4-(3,4-difluoro-2-methoxyphenoxy)-N-(3-(methylsulfinyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide 120 mg, 0.25 mmol
  • NH 4 OAc 95 mg, 1.23 mmol
  • PhI(OAc) 2 396 mg, 1.23 mmol
  • Reagents & conditions a) methylboronic acid, Cu(OAc) 2 , pyridine, 1,4-dioxane
  • a mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide See: WO2022/192487; 100 mg, 0.21 mmol), Cu(OAc) 2 (63 mg, 0.32 mmol.), pyridine (33 mg, 0.42 mmol) in 1, 4-dioxane (8 mL) was stirred for 5 min at room temperature under open air condition.
  • Step 1 4-(4-cyano-2-methoxyphenoxy)-N-(3-(methylsulfinyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4-cyano-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylic acid (130 mg, 0.38 mmol) and 3-methanesulfinylaniline (59 mg, 0.38 mmol) in DCM (5 mL) was added T3P (583 mg , 50% in DMF) and DIEA (297 mg , 2.30 mmol).
  • Step 2 4-(4-cyano-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide : A solution of 4-(4-cyano-2-methoxyphenoxy)-N-(3- (methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (90 mg, 0.19 mmol), NH 4 OAc (44 mg, 0.57 mmol) and PhI(OAc) 2 (183 mg, 0.57 mmol) in MeOH (5 mL) was heated at 70 °C for 2 hours.
  • Step 3 ethyl 2-amino-5-chloro-4-methyl-6-(trifluoromethyl)nicotinate: To a solution of ethyl 2-amino-4-methyl-6-(trifluoromethyl)nicotinate (3.2 g, 0.013 mol) in MeCN (30 mL) and was added NCS (3.5 g, 0.026 mol) at room temperarure. Then the mixture was heated at 50 °C for 3 hours under an atmosphere of N 2 . LCMS showed the rection was completed. The mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried with Na 2 SO 4 , and concentrated under vacuum.
  • Step 5 ethyl 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-6- (trifluoromethyl)nicotinate: A solution of ethyl 2-bromo-5-chloro-4-methyl-6- (trifluoromethyl)nicotinate (700 mg, 0.99 mmol), 6-fluoro-2-methylpyridin-3-ol (514 mg, 4.04 mmol), (1R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (115 mg, 0.81 mmol), K 2 CO 3 (558 mg, 4.04 mmol), pyridine (320 mg, 4.04 mmol), Cu power (26 mg, 0.40 mmol) and CuI (77 mg, 0.40 mmol) in 1,4-dioxane (20 mL) was heated at 100 °C for 16 hours under N 2 .
  • Step 6 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-6- (trifluoromethyl)nicotinic acid: To a solution of ethyl 5-chloro-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-methyl-6-(trifluoromethyl)nicotinate (300 mg, 0.76 mmol) in THF/H 2 O (1/1, 10 mL) was added LiOH (183 mg, 7.64 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated to remove most THF.
  • Step 7 tert-butyl (R)-((3-(5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate : To a solution of 5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-6-(trifluoromethyl)nicotinic acid (220 mg, 0.60 mmol) in DCM (5 mL) was added oxalyl chloride (766 mg , 6.03 mmol) and DMF (20 ⁇ L).
  • Step 8 (R)-5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide : A solution of tert-butyl (R)-((3- (5-chloro-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-6- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (120 mg, 0.19 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature.
  • Reagents & conditions a) LDA, THF, ethyl carbonochloridate, -78 °C; b) 6-fluoro-2- methylpyridin-3-ol, Cs 2 CO 3 , MeCN; c) methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, DMF; d) NaOH, THF/H 2 O; e) (i) (COCl) 2 , DMF, DCM; (ii) tert-butyl (R)-((3- aminophenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate, Et 3 N, THF; f) TFA, DCM Step 1: ethyl 2-bromo-3,5-difluoroisonicotinate: To a solution of 2-bromo-3,5- difluoropyridine 1 (1.2 g, 10.31 mmol) in T
  • Step 2 ethyl 2-bromo-5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)isonicotinate: To a solution of ethyl 2-bromo-3,5-difluoroisonicotinate (1.0 g, 3.76 mmol) and 6-fluoro-2- methylpyridin-3-ol (478 mg, 3.76 mmol) in MeCN (20 mL) was added Cs 2 CO 3 (1.84 g, 5.64 mmol), the reaction mixture was stirred at room temperature for 12 hours.
  • Step 3 ethyl 5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinate : To a solution of ethyl 2-bromo-5-fluoro-3-((6-fluoro-2- methylpyridin-3-yl)oxy)isonicotinate (400 mg, 1.07 mmol) and CuI (408 mg, 2.14 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.03 g, 5.36 mmol) dropwise at room temperature under an atmosphere of N 2 .
  • Step 4 5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-(trifluoromethyl)isonicotinic acid : To a solution of ethyl 5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinate (250 mg, 0.69 mmol) in THF/H 2 O (1/1, 5 mL) was added NaOH (138 mg, 3.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours.
  • Step 5 tert-butyl (R)-((3-(5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: To a solution of 5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2-(trifluoromethyl)isonicotinic acid (100 mg, 0.30 mmol) in DCM (3 mL) was added oxalyl chloride (380 mg , 2.30 mmol) and DMF (20 ⁇ L).
  • Step 6 (R)-5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide: A solution of tert-butyl (R)-((3- (5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature.
  • Step 2 ethyl 2-cyclopropyl-5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)isonicotinate: To a solution of ethyl 2-cyclopropyl-3,5-difluoroisonicotinate (300 mg, 1.13 mmol) and 6-fluoro- 2-methylpyridin-3-ol (143 mg, 1.13 mmol) in MeCN (10 mL) was added Cs 2 CO 3 (404 mg, 1.24 mmol), the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (30 mL x 3).
  • Step 4 tert-butyl (R)-((3-(2-cyclopropyl-5-fluoro-3-((6-fluoro-2-methylpyridin-3- yl)oxy)isonicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate: To a solution of 2- cyclopropyl-5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)isonicotinic acid (100 mg, 0.33 mmol) in DCM (3 mL) was added oxalyl chloride (414 mg , 3.27 mmol) and DMF (20 ⁇ L).
  • Step 5 (R)-2-cyclopropyl-5-fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S- methylsulfonimidoyl)phenyl)isonicotinamide : A solution of tert-butyl (R)-((3-(2-cyclopropyl-5- fluoro-3-((6-fluoro-2-methylpyridin-3-yl)oxy)isonicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate (65 mg, 0.12 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature.
  • Example 38C 4-(4-cyano-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3- carboxamide Reagents & conditions: a) 3-methanesulfonylaniline T3P(50% in EtOAc) DCM DIEA To a solution of 4-(4-cyano-2-methoxyphenoxy)-6-(trifluoromethyl) pyridazine-3- carboxylic acid (50 mg, 0.15 mmol), 3-methanesulfonylaniline (25 mg, 0.15 mmol) and T3P (224 mg, 50% in EtOAc) in DCM (5 mL) was added DIEA (114 mg, 0.88 mmol).
  • Example 39C 4-(4-cyano-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide Reagents & conditions: a) 3-methanesulfinylaniline, T 3 P(50% in EtOAc), DIEA, DCM; b) PhI(OAc) 2 , NH 4 OAc, MeOH, 70 °C Step 1: 4-(4-cyano-2-methylphenoxy)-N-(3-(methylsulfinyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4-cyano-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-3-carboxylic acid (240 mg, 0.74 mmol), 3-methanesulfinylaniline (115 mg, 0.74 mmol) and
  • Step 2 4-(4-cyano-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-3-carboxami: A solution of 4-(4-cyano-2-methylphenoxy)-N-(3- (methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (160 mg, 0.35 mmol), NH 4 OAc (80 mg, 1.04 mmol) and PhI(OAc) 2 (336 mg , 1.23 mmol) in MeOH (5 mL) was heated at 70 °C for 2 hours.
  • Example 40C ((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)-16-sulfanediylidene)diamine
  • Reagents & conditions a) Cs 2 CO 3 , Xantohos-Pd-G2, 1,4-dioxane, 100 °C; b) DCM, TFA Step 1: A mixture of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinamide (300 mg, 0.91 mmol), di-tert-butyl ((3-bromophenyl)(methyl)-16- sulfanediylidene)dicarbamate (470 mg, 1.09 mmol), Cs 2 CO 3 (890 mg, 2.73 mmol) and Xantphos- Pd-G
  • Step 2 To a solution of di-tert-butyl ((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)-16-sulfanediylidene)dicarbamate (200 mg, 0.29 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated.
  • the residue was purified by prep-HPLC (Gemini 5 um C 18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H 2 O containing 0.05% NH 3 ) to provide ((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido) phenyl)(methyl)-16-sulfanediylidene)diamine (54.3 mg, 38.30% yield) as a white solid.
  • Reagents & conditions a) Cs 2 CO 3 , Xantohos-Pd-G2, 1,4-dioxane, 100 °C; b) DCM, TFA Step1: tert-butyl ((3-((tert-butoxycarbonyl)amino)-3-ethylpentyl)(3-(2-((6-fluoro-2- methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(oxo)-16- sulfaneylidene)carbamate: A mixture of tert-butyl ((3-bromophenyl)(3-((tert- butoxycarbonyl)amino)-3-ethylpentyl)(oxo)-16-sulfaneylidene)carbamate (389.6 mg, 0.73 mmol), 2-((6-fluoro-2-methyl
  • Reagents & conditions a) (i) SOCl 2 ; (ii) DIEA, THF; b) TFA, DCM Step1.
  • Reagents & conditions a) N-(tert-butoxycarbonyl)glycine, HATU, DIEA, DMF; b) TFA, DCM, rt; c) BH 3 -THF, THF, 0°C Step 1: tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-oxoethyl) carbamate: A mixture of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S- methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (100 mg, 0.21 m
  • Step 2 (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide : A solution of tert-butyl (R)-(2-(((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido) phenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)amino)-2-oxoethyl)carbamate (100 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature.
  • reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 3 A solution of (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(N-glycyl-S- methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (250 mg, 0.46 mmol) in THF (15 mL) was added BH 3 -THF (1.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the mixture was quenched with water and the aqueous solution was extracted with DCM (20 mL x 3).
  • Step 2 A solution of tert-butyl (R)-((3-(5-((6-fluoro-2-methylpyridin-3-yl)oxy)-3-methyl- 2-(trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (90 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3).
  • Example 45C (R)-3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-2- (trifluoromethyl)isonicotinamide
  • Reagents & conditions a) (i) SOCl 2 , 80 ⁇ C; (ii)TEA, THF; b) TFA, DCM Step 1: A solution of 3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)-2- (trifluoromethyl)isonicotinic acid (160 mg, 0.46 mmol) in SOCl 2 (2 mL) was heated to 80 °C for 0.5 h.
  • Step 2 A solution of tert-butyl (R)-((3-(3-chloro-5-((6-fluoro-2-methylpyridin-3-yl)oxy)- 2-(trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (150 mg, 0.25 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was quenched with saturated aqueous NaHCO 3 (10 mL) and extracted with DCM (10 mL x 3).
  • Example 46C and Example 47C (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N,4-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)- 5-(trifluoromethyl)nicotinamide & (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N,4-dimethyl-N- (3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide
  • Reagents & conditions a) HATU, DIEA, DMF; b) NH 2 COONH 4 , PhI(OAc) 2 , EtOH, 50 ⁇ C; c) SFC Step 1: A solution of N-methyl-3-(methylthio)aniline (204 mg, 1.33 mmol) in DMF (10 mL) was added 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (400 mg, 1.21 mmol), HATU (599 mg, 1.58 mmol) and DIEA (501 mg, 3.88 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours.
  • Step 2 To a solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-N,4-dimethyl-N-(3- (methylthio)phenyl)-5-(trifluoromethyl)nicotinamide (540 mg, 1.16 mmol) in EtOH (10 mL) was added PhI(OAc) 2 (747 mg, 2.32 mmol) and ammonium carbamate (134 mg, 1.74 mmol) at room temperature. The reaction mixture was heated at 50 °C for 1 hour.
  • Reagents & conditions a) (i) SOCl 2 , 80 ⁇ C; (ii)TEA, NH 3 •H 2 O, THF; b) Cs 2 CO 3 , MeCN, 50 ⁇ C; c) K 3 PO 4 , Pd(PPh3)4, dioxane/H 2 O, 100 ⁇ C; d) KOsO 4 • H 2 O, NaIO 4 , THF/H 2 O, rt; e) Cs 2 CO 3 , Xantphos-Pd-G2; dioxane, 0 ⁇ C; f) DAST, DCM; g) TFA, DCM Step 1: A solution of 5-bromo-2-chloro-4-methylnicotinic acid (1.5 g, 6.05 mmol) in SOCl 2 (15 mL) was heated to 80 °C and stirred for 0.5 hour.
  • Step 2 A solution of 5-bromo-2-chloro-4-methylnicotinamide (1.2 g, 4.86 mmol), 6- fluoro-2-methylpyridin-3-ol (746 mg, 5.87 mmol) and Cs 2 CO 3 (4.68 g, 14.27 mmol) in MeCN (20 mL) was heated to 80 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered through celite.
  • Step 3 A mixture of 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methylnicotinamide (1.1 g, 3.24 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (997 mg, 6.48 mmol), K 3 PO 4 (1.37 g, 6.48 mmol) and Pd(PPh3)4 (187 mg, 0.16 mmol) in 1,4- dioxane/H 2 O (10/3, 13 mL) was heated to 90 °C and stirred for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature and filtered through celite.
  • Step 4 A solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5- vinylnicotinamide (750 mg, 2.61 mmol) and K 2 OSO 4 ⁇ 2H 2 O (190 mg, 0.5 mmol) in THF/H 2 O (3/1, 12 mL) was added NaIO 4 (2.22 g, 10.33 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with EtOAc (30 mL) and washed with water (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum.
  • Step 5 A mixture of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-5-formyl-4- methylnicotinamide (400 mg, 1.38 mmol), tert-butyl ((4-bromopyridin-2-yl)(methyl)(oxo)-16- sulfaneylidene)carbamate (930 mg, 2.78 mmol), Cs 2 CO 3 (1.35 g, 4.12 mmol) and Xantphos-Pd- G2 (123 mg, 0.14 mmol) in 1,4-dioxane (10 mL) was stirred at 0 °C for 6 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite.
  • Step 7 A solution of tert-butyl ((4-(5-(difluoromethyl)-2-((6-fluoro-2-methylpyridin-3- yl)oxy)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (180 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated.
  • the residue was purified by prep-HPLC (Gemini 5 um C 18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H 2 O containing 0.05% NH 3 ) to provide 5-(difluoromethyl)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide (64.2 mg, 43.1% yield) as a white solid.
  • Example 130C Compound profiling human NaV1.8/ ⁇ 3 cell line – SyncroPatch384PE Assay
  • Compounds were tested on recombinant human Nav1.8/b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device.
  • Cells were cultured at 37°C/5% CO 2 in Ham’s F-12 supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 mg/mL streptomycin sulfate and selection antibiotics (0.01 mg/ml Blasticidin, 0.4 mg/ml Zeocin and 0.25 mg/ml Hygromycin).
  • HBSS Hank’s Balanced Salt Solution
  • the cells were washed in HBSS to remove the Accutase and re- suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl 2 , 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH.
  • Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2, 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.
  • Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid.
  • Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds.
  • Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO + pluronic acid) controls.
  • the Table below shows the potency of compounds against human NaV1.8, where “A” represents an IC50 less than or equal to 5 nM, “B” represents an IC50 greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50 greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50 greater than 100 nM to less than or equal to 200 nM, “ E” represents an IC50 greater than 200 nM.
  • Example 131C Compound profiling human NaV1.8/ ⁇ 1 cell line – Sophion QPatch II Assay
  • Compounds were tested on recombinant human NaV1.8/ ⁇ 1 stably transfected HEK293 (Eurofins, CYL3025, St. Charles, MO) cells using the QPatch II system (Sophion Bioscience A/S, Ballerup – Denmark), an automated patch clamp device.
  • Cells were cultured at 37°C/5% CO 2 in DMEM/ F-12 supplemented with 10% fetal bovine serum, 1x Non-Essential Amino Acids, and selection antibiotics (0.625 ⁇ g/mL Puromycin, 400 ⁇ g/mL Geneticin, and 100 ⁇ g/mL Hygromycin).
  • Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl 2 , 2; EGTA, 5; HEPES, 10; pH adjusted to 7.2 with CsOH.
  • Extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl 2 , 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH.
  • 500 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents. Compounds were tested in an interleaved manner across two cohorts of wells to develop an aggregate 8-point concentration response curve.
  • Final concentrations include 0.1% DMSO and 0.03% pluronic Acid. In general, the concentration range spans a range from 0.01 – 300 nM.
  • Compounds were diluted 1:10 with extracellular solution within their respective cohort. DMSO (0.1% by volume) served as a vehicle control to ascertain assay performance.
  • Whole cell patch clamp recordings were conducted according to Sophion standard procedure for QPatch II®. Cells were held at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied to elicit inward Na + currents. Inter-sweep interval was 15 sec.
  • the Table below shows the potency of compounds against human NaV1.8, where “A” represents an IC50 less than or equal to 5 nM, “B” represents an IC50 greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50 greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50 greater than 100 nM to less than or equal to 200 nM, “ E” represents an IC50 greater than 200 nM.
  • the invention provides a compound of Formula (I): and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: A is a substituted or unsubstituted heteroaryl ring comprising at least one heteroatom selected from a group consisting of O, S, or N; wherein the one or more substitutions on A are selected from H, -OH, halo, C 1 -C 8 -alkyl, C 1 -C 8 fully or partially fluorinated fluoroalkyl, C 2 -C 8 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -C(R ’ )(R ” )-cycloalkyl, C(R ’ )(R ” )-aryl, -NR’R’’, substituted or unsubstituted 3-8 membere
  • R 5 is H, halogen, -CD 3 , alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -CF 3 , - OCF 3 , or cycloalkoxy
  • R 4 is H, -OH, halo, -CD 3 , C 1 -C 6 -alkyl, branched alkyl, haloalkyl where the alkyl chain is fully or partially halogenated, alkoxy, arylalkoxy, cycloalkoxy, haloalkoxy, cyano, -CH 2 - cycloalkyl, -CH(CH 3 )-cycloalkyl, trifluoromethyl, cyclopropylmethyl, 3-6 membered cycloalkyl or 3-6 member
  • ring A is substituted or unsubstituted 5-6 membered heteroaryl with one or more heteroatom.
  • the 5-6 membered ring heteroaryl includes N as the one or more heteroatom.
  • the heteroatom N may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of: pyridyl N-oxide, pyrazinyl N-oxide, pyridazinyl N-oxide, and pyrimidinyl N- oxide.
  • A is a 6-membered heteroaryl comprising at least one heteroatom, wherein the heteroatom is N.
  • A is a 6-membered heteroaryl comprising 2 N atoms.

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Abstract

L'invention concerne des composés qui sont utiles pour le traitement d'états associés à une activité aberrante du canal sodique dépendant de la tension Navl.8, et des procédés de traitement d'un sujet avec ces composés visant des états tels que la douleur, le prurit et la toux.
PCT/US2023/032280 2022-09-09 2023-09-08 Composés bloquant les canaux sodiques, leurs dérivés et leurs procédés d'utilisation WO2024054622A2 (fr)

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