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CN-122003233-A - Sodium channel blocking compounds, derivatives thereof, and methods of use thereof

CN122003233ACN 122003233 ACN122003233 ACN 122003233ACN-122003233-A

Abstract

The present invention provides compounds useful for treating conditions associated with aberrant activity of voltage-gated sodium channels Na V 1.8.8, and methods of treating conditions such as pain, itching, and cough in a subject with these compounds.

Inventors

  • M.D. Kaufman
  • Y.Zeng
  • T. HOLT
  • J. M. balkovic
  • A Xiaoke.baji

Assignees

  • 拉堤果生物医疗股份有限公司

Dates

Publication Date
20260508
Application Date
20240731
Priority Date
20230801

Claims (20)

  1. 1. A compound of formula (I): (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, Wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S and N, wherein a is unsubstituted or substituted with one or more substituents selected from the group consisting of: H is formed; halogenating; a substituted or unsubstituted C 1 -C 6 alkyl group; C 1 -C 6 branched alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkoxy, C 3 -C 6 haloalkoxy, nitro, cyano, -CH 2 -(C 3 -C 8 ) -cycloalkyl, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CH 2 -aryl, -CF 2 -aryl, -CH (-CH 3 ) -aryl, -C (=O) - (C 1 -C 6 ) -alkyl, -C (=O) -cycloalkyl, -C (=O) -NH-alkyl, -C (=O) NH 2 , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR 'R' ', NHSO 2 R 1 , -NHC (=O) -alkyl, -NH (C=O) -NR' R '', C 1 -C 6 fluoroalkyl wherein the alkenyl chain may be fully or partially fluorinated, bromo, -fluoro, -cyclopropyl, -3-membered cycloalkyl, one membered cycloalkyl, or more 6 membered cycloalkyl, one membered cycloalkyl, or more, 6 membered cycloalkyl, one membered cycloalkyl, or more, and one-membered cycloalkyl, optionally 14 membered cycloalkyl, which may be substituted by one or more than one member, may be optionally substituted by any one of the three members selected from the three of the three substituents heteroatoms of S and N; b is selected from the group consisting of a monocyclic, bicyclic or spiro cycloalkyl ring and a monocyclic, bicyclic or spiro cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O and S, and wherein one or more carbons of the cycloalkyl ring or the cycloheteroalkyl ring may be optionally substituted with one or more halogens or one or more haloalkyl groups; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl and bridged cycloalkyl, wherein said aryl, said heteroaryl, said heterocyclyl and said bridged cycloalkyl comprise one or more substitutions (other than the R 2 group) selected from the group consisting of H, halo, alkyl, cyano, haloalkyl and nitro; R 1 is selected from H and C 1 -C 3 alkyl; R 2 is H, -C (=o) NH 2 , -C (=o) NHR ', -C (=o) NR' R ', -C (=o) OH, alkylamino and-S (=o) R' or formula (II): Wherein: X 1 is O and X 2 is NH or NR'; x 1 is O and X 2 is NR 3 , or X 1 and X 2 are independently selected from NH and NR'; Wherein, the R 3 is independently selected from -(C=O)-(CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 O) n R a 、-(C=O)-(CH 2 ) n -(NHCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n - (NHCH 2 CH 2 O) n R a 、-(CH 2 ) n R a 、-(CH 2 )n(CR b R c )R a 、-(C=O)-(NHCH 2 CH 2 NH) n R a 、-(C=O)-(CHR b )R a 、-(CH 2 ) n (CR b R c )(CH 2 )nR a or- (c=o) - (CR b R c )R a ; R a is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R 4 is selected from C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more R d ; Wherein R d is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino, and n = 0、1、2、3、4、5、6。
  2. 2. A compound of formula (I): (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, Wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S and N, wherein a is unsubstituted or substituted with one or more substituents selected from the group consisting of: H, halo, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 branched alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkoxy, C 3 -C 6 haloalkoxy, nitro, cyano, -CH 2 -(C 3 -C 8 ) -cycloalkyl, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CH 2 -aryl, -CF 2 -aryl, -CH (-CH 3 ) -aryl, -C (=O) - (C 1 -C 6 ) -alkyl, -C (=O) -cycloalkyl, -C (=O) -NH-alkyl, -C (=O) -NH 2 , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, -amino, -NR 'R' '-NHSO 2 R 1 , -NHC (=O) -alkyl, -NH (C=O) NR' R '', wherein the C 1 -C 6 fluoroalkyl may be fully or partially fluorinated, wherein the 3-membered cycloalkyl may be substituted with one or more 3-membered heterocyclic groups, one or more of which may be substituted by 3-membered methyl, 8 membered heterocyclic groups, one or more of which may be substituted, methyl, 3-membered heterocyclic groups may be substituted, one or more of which may be substituted, and one or more of which may be substituted, optionally substituted, one or more may be substituted, and optionally substituted, may be substituted by one or more may be substituted heteroatoms of S and N; B is selected from the group consisting of: A monocyclic, bicyclic or spiro cycloheteroalkyl ring, wherein said cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O and S, wherein one or more N atoms of said cycloheteroalkyl is optionally substituted with a haloalkyl, wherein said haloalkyl chain may be fully or partially halogenated, and A monocyclic, bicyclic or spiro cycloalkyl ring; wherein one or more carbons of the cycloalkyl or the cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl and bridged cycloalkyl, wherein said aryl, said heteroaryl, said heterocyclyl and said bridged cycloalkyl comprise one or more substitutions (other than the R 2 group) selected from the group consisting of H, halo, alkyl, cyano, haloalkyl and nitro; R 1 is selected from H and C 1 -C 3 alkyl; R 2 is H, -C (=o) NH 2 , -C (=o) NHR ', -C (=o) NR' R ', -C (=o) OH, alkylamino and-S (=o) R' or formula (II): Wherein: X 1 is O and X 2 is NH or NR'; x 1 is O and X 2 is NR 3 , or X 1 and X 2 are independently selected from NH and NR'; Wherein, the R 3 is independently selected from -(C=O)-(CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 O) n R a 、-(C=O)-(CH 2 ) n -(NHCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n - (NHCH 2 CH 2 O) n R a 、-(CH 2 ) n R a 、-(CH 2 )n(CR b R c )R a 、-(C=O)-(NHCH 2 CH 2 NH) n R a 、-(C=O)-(CHR b )R a 、-(CH 2 ) n (CR b R c )(CH 2 )nR a or- (c=o) - (CR b R c )R a ; R a is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R 4 is selected from C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more R d ; Wherein R d is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino, and n = 0、1、2、3、4、5、6。
  3. 3. A compound of formula (I): (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, Wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S and N, wherein a is unsubstituted or substituted with one or more substituents selected from the group consisting of: H, halo, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 branched alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkoxy, C 3 -C 6 haloalkoxy, nitro, cyano, -CH 2 -(C 3 -C 8 ) -cycloalkyl, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CH 2 -aryl, -CF 2 -aryl, -CH (-CH 3 ) -aryl, -C (=O) - (C 1 -C 6 ) -alkyl, -C (=O) -cycloalkyl, -C (=O) -NH-alkyl, -C (=O) -NH 2 , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, -amino, -NR 'R' '-NHSO 2 R 1 , -NHC (=O) -alkyl, -NH (C=O) NR' R '', wherein the C 1 -C 6 fluoroalkyl may be fully or partially fluorinated, wherein the 3-membered cycloalkyl may be substituted with one or more 3-membered heterocyclic groups, one or more of which may be substituted by 3-membered methyl, 8 membered heterocyclic groups, one or more of which may be substituted, methyl, 3-membered heterocyclic groups may be substituted, one or more of which may be substituted, and one or more of which may be substituted, optionally substituted, one or more may be substituted, and optionally substituted, may be substituted by one or more may be substituted heteroatoms of S and N; B is selected from the group consisting of: A monocyclic, bicyclic or spiro cycloheteroalkyl ring, wherein said cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O and S, wherein one or more N atoms of said cycloheteroalkyl is optionally substituted with a haloalkyl, wherein said haloalkyl chain may be fully or partially halogenated, and A monocyclic, bicyclic or spiro cycloalkyl ring; Wherein one or more carbons of the cycloalkyl or the cycloheteroalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and haloalkyl, wherein the haloalkyl chain may be fully or partially halogenated; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl and bridged cycloalkyl, wherein said aryl, said heteroaryl, said heterocyclyl and said bridged cycloalkyl comprise one or more substitutions (other than the R 2 group) selected from the group consisting of H, halo, alkyl, cyano, haloalkyl and nitro; R 1 is selected from H and C 1 -C 3 alkyl; R 2 is H, -C (=o) NH 2 , -C (=o) NHR ', -C (=o) NR' R ', -C (=o) OH, alkylamino and-S (=o) R' or formula (II): Wherein: X 1 is O and X 2 is NH or NR'; x 1 is O and X 2 is NR 3 , or X 1 and X 2 are independently selected from NH and NR'; Wherein, the R 3 is independently selected from -(C=O)-(CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n -(OCH 2 CH 2 O) n R a 、-(C=O)-(CH 2 ) n -(NHCH 2 CH 2 ) n R a 、-(C=O)-(CH 2 ) n - (NHCH 2 CH 2 O) n R a 、-(CH 2 ) n R a 、-(CH 2 )n(CR b R c )R a 、-(C=O)-(NHCH 2 CH 2 NH) n R a 、-(C=O)-(CHR b )R a 、-(CH 2 ) n (CR b R c )(CH 2 )nR a or- (c=o) - (CR b R c )R a ; R a is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R b is selected from F, C 1 -C 6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1 -C 6 -alkyl or F; R c R b together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R 4 is selected from C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more R d ; Wherein R d is H, C 1 -C 6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CF 2 -aryl, -NH 2 , -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2 , -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino, and n = 0、1、2、3、4、5、6。
  4. 4. A compound according to any one of claims 1 to 3, wherein R 2 is selected from H or formula (II): (II), Wherein: m and p are 0 or 1, and X 1 is O and X 2 is NH or NR' X 1 is O and X 2 is NR 3 R 3 is defined in claim 1.
  5. 5. A compound according to any one of claims 1 to 3, wherein R 2 is: Wherein: m and p are 0 or 1, and X 1 is O and X 2 is NH or NR' X 1 is O and X 2 is NR 3 R 3 is defined in claim 1.
  6. 6. The compound of any one of claims 1 to 3, wherein A is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5-or 6-membered heteroaryl having one or more heteroatoms, wherein the heteroaryl contains a nitrogen atom in the ring, such nitrogen atom being capable of being in the form of an N-oxide, wherein A is optionally pyridinyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and pyridazinyl N-oxide.
  7. 7. A compound according to any one of claims 1 to 3, wherein A contains a nitrogen atom in the heteroaryl ring, such nitrogen atom being capable of being in the form of an N-oxide selected from the group consisting of pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and pyridazinyl N-oxide, and wherein A may be substituted with one or more substituents.
  8. 8. A compound according to any one of claims 1 to 3, wherein a is optionally substituted aryl.
  9. 9. A compound according to any one of claims 1 to 3, wherein a is optionally substituted heteroaryl having one heteroatom.
  10. 10. A compound according to any one of claims 1 to 3, wherein a is an optionally substituted heteroaryl having two heteroatoms.
  11. 11. A compound according to any one of claims 1 to 3, wherein the heteroaryl a is substituted with at least trifluoromethyl.
  12. 12. A compound according to any one of claims 1 to 3, wherein the heteroaryl ring a is substituted with at least cyclopropylmethyl.
  13. 13. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein each of Q 1 、Q 2 、Q 3 and Q 4 is independently N, N-O or CR 5 ; wherein R 5 is H; a hydroxyl group; halogen; -CD 3 , substituted or unsubstituted C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, wherein the alkyl chain may be fully or partially deuterated, branched alkyl, allyl, alkenyl, alkynyl, halo-C 1 -C 4 alkyl, wherein the haloalkyl chain may be fully or partially halogenated, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH 2 -cycloalkyl, -CF 2 CH 3 ;-CF 2 CF 3 ;CH 2 CF 2 ;-CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CH 2 -aryl, -CF 2 -heteroaryl, -CF 2 -heterocyclyl, -CH (-CH 3 ) -aryl, C (=o) -alkyl, -C (=o) -cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH 2 , -C (=o) NHR ', C (=o) NR' R, hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR 'R', NHR 'R', one membered cycloalkyl, or more than one membered cycloalkyl, wherein the three membered cycloalkyl groups may be independently selected from the group consisting of heterocyclic groups including C (=o) 3-cycloalkyl, C (=o) NH 2 , C (=o) NHR 'R', hydroxy, -COOH (and 3, C (=o) n Heteroatoms of S and N.
  14. 14. A compound according to any one of claims 1 to 3 wherein a is an optionally substituted 5-or more-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from N, O or S.
  15. 15. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein: Q 2 and Q 4 are N, N-O; Q 2 is N, N-O, Q 4 is CR 5 ; Q 2 is CR 5 ;Q 4 is N, N-O; R 6 is H, halogen, -CD 3 、C 1 -C 6 alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, NH 2 、NHR'、NR'R''、NHC(=O)R'、NHSO 2 R, -C (=o) R ', -C (=o) NHR', -C (=o) NR 'R', aryl, heteroaryl, -CF 2 CH 3 、-CF 2 CF 3 ; R 7 is H, hydroxy, halogen, -CD 3 、C 1 -C 6 alkyl, branched alkyl, allyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH 2 -cycloalkyl, -CF 2 CH 3 、-CF 2 CF 3 、CH 2 CF 2 、-CF 2 -cycloalkyl, -CH (CH 3 ) -cycloalkyl, -CH 2 -aryl, -CF 2 -heteroaryl, -CF 2 heterocyclyl, -CH (-CH 3 ) -aryl, C (=o) -alkyl, -C (=o) cycloalkyl, -C (=o) -NH-alkyl, -C (=o) NH 2 , -C (=o) NHR ', -C (=o) NR ' R ", hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR ' R ', -NHSO 2 R ', -NHC (=o) -alkyl, -NH (c=o) NR ' R ', trifluoromethyl, cyclopropylmethyl, methylsulfonyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl groups comprise at least one heteroatom selected independently from O, S; Wherein no more than two of Q 1 、Q 2 、Q 3 and Q 4 are present, or N-O.
  16. 16. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein: Q 3 and Q 4 are N, wherein Q 3 is N, N-O, Q 4 is CR 5 , or wherein Q 3 is CR 5 ,Q 4 is N, N-O; r 5 is defined in claim 9, and R 6 and R 7 are defined in claim 15 above.
  17. 17. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein Q 1 and Q 4 are N, N-O, Q 1 is N, N-O, Q 4 is CR 5 ;Q 1 is CR 5 ,Q 4 is N, N-O, or Q 1 and Q 4 are CR 5 , and wherein R 6 and R 7 are as defined in claim 15 above.
  18. 18. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein: Q 1 and Q 2 are N, and R 6 and R 7 are defined in claim 15 above.
  19. 19. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein: Q 1 is CR 5 and Q 2 is N; R 6 and R 7 are defined in claim 15 above.
  20. 20. A compound according to any one of claims 1 to 3, wherein a is represented by the formula: Wherein Q 1 is N and Q 2 is CR 5 , and R 6 and R 7 are defined in claim 15 above.

Description

Sodium channel blocking compounds, derivatives thereof, and methods of use thereof Technical Field The present application relates generally to sodium channel blocking compounds, derivatives thereof, and the use of such compounds as pharmacological agents. Background Millions of people suffer from conditions associated with pain, itching and/or coughing. Pain may be a symptom or cause of conditions such as neuropathy, hyperalgesia, and opiate use disorders. In many cases, drugs used to treat such conditions do not provide relief or produce intolerable side effects. Thus, current treatments are inadequate to treat many patients with various conditions. Disclosure of Invention The present invention provides compounds useful for treating conditions such as pain, itching, and cough associated with aberrant activity of voltage-gated sodium channels Na V 1.8.8. In one aspect, the invention provides a compound of formula (I): (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, Wherein: A is an aryl or heteroaryl ring containing one or more heteroatoms independently selected from O, S and N, wherein a is unsubstituted or substituted with one or more substituents selected from the group consisting of: H is formed; halogenating; substituted or unsubstituted C 1-C6 alkyl, C 1-C6 branched alkyl, C 1-C6 alkenyl, C 1-C6 alkynyl, C 1-C6 haloalkyl wherein the haloalkyl chain may be fully or partially halogenated, C 1-C6 alkoxy, C 1-C6 cycloalkoxy, C 3-C6 haloalkoxy, nitro, cyano, -CH 2-(C3-C8) -cycloalkyl, -CF 2 -cycloalkyl, -CH (CH 3) -cycloalkyl, -CH 2 -aryl, -CF 2 -aryl, -CH (-CH 3) -aryl, C (=O) - (C 1-C6) -alkyl, -C (=O) -cycloalkyl, -C (=O) -NH-alkyl, -C (=O) NH 2, hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, -NR ' R ' ', NHSO 2R1, -NHC (=O) -alkyl, -NH (C=O) NR ' R ' C 1-C6 fluoroalkyl wherein the alkyl may be partially fluorinated, wherein the heterocyclyl may be substituted with one or more than one membered heterocyclic ring, 3-membered cycloalkyl, one membered heterocyclic ring may be substituted with one or more than one membered heterocyclic ring, or more than one membered heterocyclic ring may be substituted with one or more than one membered heterocyclic ring, and one membered heterocyclic ring may be substituted with one or more than one membered heterocyclic ring, wherein the heterocyclic ring may be substituted or more aryl groups may be substituted with one or more aryl groups, wherein the heterocyclic ring may be substituted or the heterocyclic ring may be substituted with one or more aryl ring heteroatoms of S and N; B is selected from the group consisting of a monocyclic, bicyclic or spiro cycloalkyl ring and a monocyclic, bicyclic or spiro cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms independently selected from N, O and S, and wherein one or more carbons of the cycloalkyl ring or the cycloheteroalkyl ring may be optionally substituted with one or more halogens or one or more haloalkyl groups; C is selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl and bridged cycloalkyl, wherein said aryl, said heteroaryl, said heterocyclyl and said bridged cycloalkyl comprise one or more substitutions (other than the R 2 group) selected from the group consisting of H, halo, alkyl, cyano, haloalkyl and nitro; R 1 is selected from H and C 1-C3 alkyl; R 2 is H, -C (=o) NH 2, -C (=o) NHR ', -C (=o) NR' R ', -C (=o) OH, alkylamino and-S (=o) R' or formula (II): Wherein: X 1 is O and X 2 is NH or NR'; x 1 is O and X 2 is NR 3, or X 1 and X 2 are independently selected from NH and NR'; Wherein, the R 3 is independently selected from -(C=O)-(CH2)nRa、-(C=O)-(CH2)n-(OCH2CH2)nRa、-(C=O)-(CH2)n-(OCH2CH2O)nRa、-(C=O)-(CH2)n-(NHCH2CH2)nRa、-(C=O)-(CH2)n- (NHCH2CH2O)nRa、-(CH2)nRa、-(CH2)n(CRbRc)Ra、-(C=O)-(NHCH2CH2NH)nRa、-(C=O)-(CHRb)Ra、-(CH2)n(CRbRc)(CH2)nRa or- (c=o) - (CR bRc)Ra; R a is H, C 1-C6 -alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, -CF 2 -cycloalkyl, -CH (CH 3) -cycloalkyl, -CF 2 -aryl, -NH 2, -NR ' R ' ', aminocycloalkyl, 4-to 7-membered heterocyclyl, -OH, -COONH 2, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, or amino; R b is selected from F, C 1-C6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1-C6 -alkyl or F; R cRb together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having one or more heteroatoms; R b is selected from F, C 1-C6 -alkyl, haloalkyl, branched alkyl, aryl, heteroaryl, 3-7 membered carbocyclyl, 4-7 membered heterocyclyl having one or more heteroatoms; R c is C 1-C6 -alkyl or F; R cRb together with the carbon atom to which it is attached form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring having