Hydroxypyrrolidine-substituted arylsulfonamide compounds with selective activity in voltage-gated sodium channels
Disclosed are compounds of Formula A, or a salt thereof: Wherein “A 1 ”, R 1 , R 2 , R 3 , R 6 , and R 7 are as defined herein, which compounds have properties for blocking Nav 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A or their salts, and methods of treating cough, itch and neuropathic pain disorders using the same.
1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula A:
wherein:
B 1 is —(CR 4 R 5 ) m —,
wherein:
“m” is 1 or 2;
R 4 and R 5 are independently for each occurrence: (i) —H; (ii) a cyclic-, branched-, or linear-alkenyl moiety of up to 6 carbon atoms; (iii) a cyclic-, branched- or linear-alkyl moiety of up to 6 carbon atoms, which alkyl moiety is optionally substituted by one or more substituents which are independently:
(a) an aryl moiety of up to 10 carbon atoms which aromatic moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) cyclic-, branched-, or linear-alkyl moiety of up to 4 carbon atoms which is optionally substituted with —N(R 1a ) 2 , wherein “R 1a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms; (2) branched-, or linear-alkoxy moiety of up to 4 carbon atoms; (3) halogen; (4) —CN; or (v) —N(R 2a ) 2 , wherein “R 2a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms;
(b) a heteroaryl moiety, with up to 5 carbon atoms and at least one ring atom which is N, O, or S, which heteroaryl moiety is optionally substituted with up to 3 substituents which are, independently: (1) cyclic-, branched-, or linear-alkyl moiety of up to 4 carbon atoms which is optionally substituted with —N(R 3a ) 2 , wherein “R 3a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms; (2) branched-, or linear-alkoxy moiety of up to 4 carbon atoms; (3) halogen; (4) —CN; or (v) —N(R 4a ) 2 , wherein “R 4a ” is independently for each occurrence: H; or linear-, branched, or cyclic-alkyl of up to 4 carbon atoms
(c) halogen;
(d) —CN; or
(e) —N(R 5a ) 2 , wherein “R 5a ” is independently for each occurrence: (1) H; (2) linear-, branched, or cyclic-alkyl of up to 4 carbon atoms;
A 1 is —(CR 10 R 11 ) n —, wherein:
“n” is 1, 2, or 3;
in at least one occurrence one of R 10 or R 11 is selected to be —OH; and
the remaining occurrences of R 10 and R 11 are independently for each occurrence:
(a) hydrogen;
(b) halogen;
(c) —OH;
(d) —N(R 1e ) 2 , wherein “R 1e ” is, independently for each occurrence, (i) —H; or (ii) lower alkyl;
(e) a branched-, cyclic- or linear-alkyl moiety of up to 6 carbon atoms which is optionally substituted with one or more substituents which are, independently for each occurrence:
(i) halogen;
(ii) —N(R 2e ) 2 , wherein “R 2e ” is, independently for each occurrence: (1) —H; or (2) lower alkyl;
(iii)-OH;
(iv) an aryl moiety which is optionally substituted with one or more, independently, cyclic-, branched-, or linear-alkoxy moiety of up to 4 carbon atoms; or
(v) a heteroaryl moiety with up to 5 carbon atoms and at least one heteroatom, and which heteroaryl moiety may be optionally substituted with one or more cyclic-, branched-, or linear-alkoxy moiety with up to 6 carbon atoms;
(f) an aryl moiety which is optionally substituted with one or more substituents which are independently:
(i) a cyclic-, branched-, or linear-alkyoxy moiety of up to 4 carbon atoms; or
(ii) —OH; or
(g a heteroaryl moiety, with up to 5 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (i) —CN; (ii) —OH; (iii) halogen, that is —F or —Br; (iv) cyclic-, branched-, or linear-alkyl of up to 6 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or —N(R 13e ) 2 , wherein “R 13e ” is, independently for each occurrence: —H or lower alkyl; or (iv) cyclic-, branched-, or linear-alkoxy of up to 6 carbon atoms,
with the proviso that if “R 10 ” and “R 11 ” are selected to provide more than one occurrence of —OH, then the selection is made to preclude both germinal —OH and —OH depending from two adjacent carbon atoms;
R 6 is:
(c) a branched-, cyclic- or linear-alkyl of up to 6 carbon atoms which is substituted with one or more substituents which are, independently for each occurrence:
(ii) N(R 2b ) 2 , wherein “R 2b ” is, independently for each occurrence, —H or lower alkyl;
(v) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 3b ) 2 , wherein “R 3b ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 4b ) 2 , wherein “R 4b ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms; or (9) a heterocycle moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(vi) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 5b ) 2 , wherein “R 5b ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms;
(d) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 1c ) 2 , wherein “R 1c ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 2c ) 2 , wherein “R 2c ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms; or (9) a heterocycle moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(e) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 3c ) 2 , wherein “R 3c ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(f) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S,
R 7 is:
(a) —H;
(b) A cyclic-, branched-, or linear-alkyl moiety of up to 7 carbon atoms which is optionally substituted with one or more moieties which are, independently:
(i) halogen;
(ii) N(R 1d ) 2 , wherein “R 1d ” is, independently for each occurrence, —H or lower alkyl;
(iii) lower alkyl;
(iv) lower alkoxy;
(v) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 2d ) 2 , wherein “R 2d ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 3d ) 2 , wherein “R 3d ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) a heterocycle moiety, as defined herein, with comprising up to 5 carbon atoms and one or more heteroatoms which are N, O, or S; or
(vi) a heteroaryl moiety, with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 4d ) 2 , wherein “R 4d ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(vii) —OH, with the proviso that “—OH” is not selected as a substituent on a carbon atom bonded adjacent to the nitrogen atom;
(c) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 5d ) 2 , wherein “R 5d ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 6d ) 2 , wherein “R 6d ” is, independently for each occurrence, —H or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms; or (9) a heterocycle moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(d) a heteroaryl moiety, with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (a) —CN; (b) —OH; (c) halogen; (d) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 7d ) 2 , wherein “R 7d ” is, independently for each occurrence, —H or lower alkyl; or (e) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(e) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
R 1 and R 2 are independently for each occurrence: (a) hydrogen; (b) halogen; (c) —CN; or (d) C 1-6 -alkyl, wherein one or more of the carbon atoms is partially or fully substituted with halogen or C 1-4 -alkyl; and
R 3 is
(i) a moiety of Formula S1 or S2:
wherein one or two of X 1 to X 3 is —N═ and the others are [═CR 6 —], wherein “R 6 ” is:
(a) —H;
(b) an alkyl moiety which is —C 1-6 -linear alkyl or —C 4-6 -branched alkyl, which alkyl moiety is optionally substituted with one or more moieties which are independently for each occurrence: (a) halogen; or (b) —C 3-6 -cycloalkyl, which is optionally substituted;
(c) C 1-6 -linear alky-C(O)—O—, C 3-6 -branched alkyl-C(O)—O— or C 3-6 -cycloalkyl-C(O)—O—;
(d) —C 3-6 -cycloalkyl optionally substituted with —F or C 1-6 -linear alkyl; or
(e) halogen; or
(ii) a moiety of Formula S3:
wherein:
“X 4 ” and “X 5 ” are independently [═N—] or [═CR 7 —]; and
“R 7 ” is independently for each occurrence —H or —F, wherein no more than two “R” present in the moiety of S3 are selected to be “—F”.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein “B 1 ” is —CH 2 —.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein “A 1 ” is selected to be —[CR 10a R 11a ] p − , thereby providing a substituent of Formula B 2 -a:
wherein:
“p” is 1 or 2;
one of “R 14a ” or “R 14b ” is selected to be —OH and the other occurrences of “R 14a ” and “R 14b ” are independently for each occurrence:
(a) —H;
(b) an aryl moiety which is optionally substituted on one or more ring carbon atoms with —OH or lower alkoxy;
(c) cyclic-, branched- or linear-alkyl moiety of up to 6 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are, independently: (i) halogen; (ii) —OH; (iii) an aryl moiety which is optionally substituted with one or more substituents which are: (1) lower-alkoxy; (2) —N(R 1j ) 2 , wherein “R 1j ” is, independently for each occurrence —H or lower alkyl; or (3) —OH; (iv) a heteroaryl moiety with up to 5 ring carbon atoms and at least one nitrogen heteroatom, which moiety is optionally substituted on one or more ring carbon atoms with a substituent which is, independently, —OH or lower alkoxy; or (v) heterocycloalkyl with up to 6 carbon atoms and one or more heteroatoms selected from O, S, or N; or
(d) —N(R 1j ) 2 , wherein “R 1j ” is, independently for each occurrence: —H or lower alkyl; and “R 6 ” is:
(b) a branched-, cyclic- or linear-alkyl of up to 6 carbon atoms which is substituted with one or more substituents which are, independently for each occurrence:
(ii) N(R 1k ) 2 , wherein “R 1k ” is, independently for each occurrence, —H or lower alkyl;
(iv) an aryl moiety with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 2k ) 2 , wherein “R 2k ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 3k ) 2 , wherein “R 3k ” is, independently for each occurrence, —H or lower alkyl;
(v) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 4k ) 2 , wherein “R 4k ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 5k ) 2 , wherein “R 5k ” is, independently for each occurrence, —H or lower alkyl; or
(vi) a heterocycloalkyl moiety with one or more heteroatoms which are N, O, or S;
(c) an aryl moiety, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (i) —CN; (ii) —OH; (iii) halogen; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 6k ) 2 , wherein “R 6k ” is, independently for each occurrence, —H or lower alkyl; (v) —N(R 7k ) 2 , wherein “R 7k ” is, independently for each occurrence, —H or lower alkyl; (vi) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms;
(d) a heteroaryl moiety, wherein said heteroaryl moiety has up to 5 ring carbon atoms and at least one heteroatom which is N, S, or O, and wherein said heteroaryl moiety is optionally substituted on one or more ring carbon atoms with a substituent which is independently for each occurrence: (i) —CN; (ii) —OH; (iii) halogen; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are independently: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 8k ) 2 , wherein “R 8k ” is, independently for each occurrence, —H or lower alkyl; or (v) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(e) a heterocycloalkyl moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S; and
“R 7 ” is:
(a) —H;
(b) a cyclic-, branched-, or linear-alkyl moiety of up to 7 carbon atoms which is optionally substituted with one or more moieties which are, independently:
(i) halogen, and when selected to be halogen is —F or —Cl;
(ii) N(R 1L ) 2 , wherein “R 1L ” is, independently for each occurrence: (1) —H; or (2) lower alkyl;
(iii) lower alkyl;
(iv) lower alkoxy;
(v) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen, which is —F or —Br; (4) —N(R 3L ) 2 , wherein “R 3L ” is, independently for each occurrence: (I) —H; or (II) lower alkyl; (5) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: (I) —OH; (II) —CN; (III) halogen; or (IV) —N(R 2L ) 2 , wherein “R 2L ” is, independently for each occurrence: —H; or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(vi) a heteroaryl moiety, with up to 4 carbon atoms and at least one heteroatom, said heteroaryl moiety is a 5-member heterocycle with at least one heteroatom which is N, S, or O, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (1) —CN; (2) —OH; (3) halogen, which is: (I) —F; or (II) —Br; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: (I) —OH; (II) —CN; (III) halogen; or (IV) N(R 4d ) 2 , wherein “R 4d ” is, independently for each occurrence: —H; or lower alkyl; or (5) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(vii)-OH, with the proviso that “—OH” is not selected as a substituent on a carbon atom bonded adjacent to the nitrogen atom;
(c) an aryl moiety, with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (i) —CN; (ii) —OH; (iii) halogen, which is —F or —Br; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are independently: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 5d ) 2 , wherein “R 5d ” is, independently for each occurrence: (I) —H; or (II) lower alkyl; (5) —N(R 6d ) 2 , wherein “R 6d ” is, independently for each occurrence: —H; or lower alkyl; (6) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; (7) alkyl-thiol-moiety of up to 4 carbon atoms, and when selected to be a thiol moiety is H 3 C—S—; (8) alkyl-sulfonyl moiety of up to 4 carbon atoms, and when selected to be a sulfonyl moiety is H 3 C—S(O) 2 —; or (9) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S;
(d) a heteroaryl moiety, with up to 4 carbon atoms and at least one heteroatom, said heteroaryl moiety is a 5-member heterocycle with at least one heteroatom which is N, S, or O, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently: (i) —CN; (ii) —OH; (iii) halogen, which is —F or —Br; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 7d ) 2 , wherein “R 7d ” is, independently for each occurrence: (I) —H; or (II) lower alkyl; or (5) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(e) a heterocycle moiety, with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein, one occurrence of R 14a ″ or “R 14b ” is —OH, and the other occurrences of “R 14a ” and “R 14b ” are independently for each occurrence: (a) —H; or (b) cyclic-, branched-, or linear-alkyl of up to 6 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are, independently: (i) —OH; (ii) halogen; or (iii) —N(R 1ba ) 2 , wherein “R 1ba ” is, independently: (1) —H; or (2) lower-alkyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein “A 1 ” is selected to be —[HC(OH)—CR 10a R 11a ]—, and “R 7 ” is “—H”, thereby providing a substituent of Formula B 2 -b:
wherein “R 10a ” and “R 11a ” are independently for each occurrence:
(a) —H;
(b) an aryl moiety which is optionally substituted on one or more ring carbon atoms with —OH or lower alkoxy;
(c) cyclic-, branched- or linear-alkyl moiety of up to 6 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are, independently: (i) halogen; (ii) —OH; (iii) an aryl moiety which is optionally substituted with one or more substituents which are: (1) lower-alkoxy; (2) —N(R 1j ) 2 , wherein “R 1j ” is, independently for each occurrence —H or lower alkyl; or (3) —OH; (iv) a heteroaryl moiety with up to 5 ring carbon atoms and at least one nitrogen heteroatom, which moiety is optionally substituted on one or more ring carbon atoms with a substituent which is, independently, —OH or lower alkoxy; or (v) heterocycloalkyl with up to 6 carbon atoms and one or more heteroatoms selected from O, S, or N; or
(d) —N(R 1j ) 2 , wherein “R 1j ” is, independently for each occurrence: —H or lower alkyl; and “R 6 ” is:
(b) a branched-, cyclic- or linear-alkyl of up to 6 carbon atoms which is substituted with one or more substituents which are, independently for each occurrence:
(ii) N(R 1k ) 2 , wherein “R 1k ” is, independently for each occurrence, —H or lower alkyl;
(iv) an aryl moiety with up to 6 ring carbon atoms, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 2k ) 2 , wherein “R 2k ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 3k ) 2 , wherein “R 3k ” is, independently for each occurrence, —H or lower alkyl;
(v) a heteroaryl moiety with up to 4 carbon atoms and at least one heteroatom, wherein said heteroaryl moiety is optionally substituted with one or more substituents which are independently for each occurrence: (1) —CN; (2) —OH; (3) halogen; (4) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: —OH; —CN; halogen; or N(R 4k ) 2 , wherein “R 4k ” is, independently for each occurrence, —H or lower alkyl; (5) —N(R 5k ) 2 , wherein “R 5k ” is, independently for each occurrence, —H or lower alkyl; or
(vi) a heterocycloalkyl moiety with one or more heteroatoms which are N, O, or S;
(c) an aryl moiety, wherein the aryl ring of said moiety is optionally substituted with up to 3 substituents which are independently for each occurrence: (i) —CN; (ii) —OH; (iii) halogen; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 6k ) 2 , wherein “R 6k ” is, independently for each occurrence, —H or lower alkyl; (v) —N(R 7k ) 2 , wherein “R 7k ” is, independently for each occurrence, —H or lower alkyl; (vi) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms;
(d) a heteroaryl moiety, wherein said heteroaryl moiety has up to 5 ring carbon atoms and at least one heteroatom which is N, S, or O, and wherein said heteroaryl moiety is optionally substituted on one or more ring carbon atoms with a substituent which is independently for each occurrence: (i) —CN; (ii) —OH; (iii) halogen; (iv) cyclic-, branched-, or linear-alkyl of up to 4 carbon atoms, which alkyl moiety is optionally substituted with one or more substituents which are independently: (1) —OH; (2) —CN; (3) halogen; or (4) —N(R 8k ) 2 , wherein “R 8k ” is, independently for each occurrence, —H or lower alkyl; or (v) cyclic-, branched-, or linear-alkoxy of up to 4 carbon atoms; or
(e) a heterocycloalkyl moiety with up to 5 carbon atoms and one or more heteroatoms which are N, O, or S.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is a moiety of Formula S1a:
wherein: one of X 1a to X 3a is —N═ and the others are —CR 8 ═, where —R 8 is independently for each occurrence: (i) —H; (ii) lower-alkyl; or (iii) a halogen, and when a halogen R 8 is —Cl or —F.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is a moiety of Formula S1b:
8. A compound, or a pharmaceutically acceptable salt thereof, which is:
4-((((2S,4S)-2-benzyl-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-4-((((2S,4S)-2-(cyclobutylmethyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-phenethylpyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
4-((((2S,4S)-2-(4-bromobenzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
4-((((2S,4S)-2-(4-(aminomethyl) benzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-(3-phenylpropyl) pyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
4-((((2S,4S)-2-(3-(aminomethyl) benzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
4-((((2S,4S)-2-(3-bromobenzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-(3-methoxybenzyl) pyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-(3-methylbenzyl) pyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-2-(3-fluorobenzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-4-((((2S,4S)-2-(3-cyanobenzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-4-((((2S,4S)-2-(3,3-dimethylbutyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-(4-(pyridin-2-yl) benzyl) pyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,4S)-4-hydroxy-2-(4-(oxazol-2-yl) benzyl) pyrrolidin-2-yl) methyl) amino)-N-(thiazol-2-yl) benzenesulfonamide;
4-((((2S,4S)-2-(4-(1H-pyrazol-5-yl) benzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-5-chloro-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide; or
5-chloro-4-((((2S,4S)-2-(4-cyanobenzyl)-4-hydroxypyrrolidin-2-yl) methyl) amino)-2-fluoro-N-(thiazol-2-yl) benzenesulfonamide.
9. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9 comprising additionally an effective amount of at least one other pharmaceutically active ingredient which is: (i) an opiate agonist or antagonist; (ii) a calcium channel antagonist; (iii) an NMDA receptor agonist or antagonist; (iv) a COX-2 selective inhibitor; or (v) an NSAID (non-steroidal anti-inflammatory drug), and a pharmaceutically acceptable carrier.
11. A method of treating an inflammatory or neuropathic pain disorder, cough, or acute itch or chronic itch disorder comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 10 .
12. A formulation comprising an amount of the compound of claim 8 , or a pharmaceutically acceptable salt thereof, which is sufficient to provide a therapeutic response in a subject in need of therapy for an inflammatory or neuropathic pain disorder, cough, or acute itch or chronic itch disorder.
13. A method of treating a neuropathic pain disorder comprising administering to a patient in need thereof a therapeutically effective amount of a formulation of claim 12 .
14. The compound, or pharmaceutically acceptable salt thereof according to claim 1 for treating neuropathic pain disorders.
15. The compound, or pharmaceutically acceptable salt thereof according to claim 8 for treating neuropathic pain disorders.