Bicycloamine-substituted-N-benzenesulfonamide compounds with selective activity in voltage-gated sodium channels
View Patent ↗Disclosed are compounds of Formula A-a, or a salt thereof: Where “B 1 ” and “R 1 ” through “R 5 ” are as defined herein, which compounds have properties for blocking Na v 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A-a or their salts, and methods of treating neuropathic pain disorders using the same.
1. A compound of Formula A-a, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R 2 are independently: (a) hydrogen; (b) halogen; (c) —CN; or (d) an alkyl moiety which is —C 1-10 -linear-alkyl, —C 3-10 -branched-alkyl, or —C 3-10 -cycloalkyl, which alkyl moiety is optionally substituted with one or more halogen atoms;
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 —], where R 6 is:
A. —H;
B. an alkyl moiety which is —C 1-6 -linear alkyl or —C 3-6 -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 alkyl-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 S4:
wherein X 4 and X 5 are independently [═N-] or [═CR 7 —], wherein R 7 is independently for each occurrence —H or —F, and wherein no more than two R 7 are selected to be —F;
R 4 and R 5 are independently for each occurrence: (a) hydrogen; or (b) a cyclic-, branched-, or linear-alkyl moiety comprising up to 6 carbon atoms, which alkyl moiety is optionally substituted with one or more moieties which are, independently: (i) —F; (ii) perfluoro-C 1-4 -linear-alkyl; (iii) C 3-6 -cycloalkyl; (iv) —N(R S4a ) 2 , wherein R S4a is independently for each occurrence, —H or lower-alkyl; or (v) an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy or —C 3-6 -cycloalkoxy; and
B 1 is a moiety of the formula:
wherein, A 1 and A 2 are, independently, (—CR 8 R 9 —) n ,
wherein:
n is independently for each occurrence 2, 3, 4 or 5; and
R 8 and R 9 are independently for each occurrence:
(a) hydrogen;
(b) halogen;
(c) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which alkyl moiety is optionally substituted with one or more moieties which are, independently:
(i) halogen;
(ii) —OH;
(iii) an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy, or —C 3-6 -cyclic-alkoxy;
(iv) —N(R A4a ) 2 , wherein R A4a is independently for each occurrence, —H or an alkyl moiety which is C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or C 3-6 -cycloalkyl;
(v) -heterocycloalkyl, where said heterocycloalkyl comprises from 2 to 6 carbon atoms and one or two nitrogen atoms in the ring;
(vi) —C 6-10 -aryl which is optionally substituted on any ring carbon atom thereof with one or more moieties which are independently: halogen; an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy, or —C 3-6 -cyclic-alkoxy; or an alkyl moiety which is —C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl; or
(vii) —C 6-10 -heteroaryl, as defined herein, which is optionally substituted on any ring carbon atom thereof with one or more moieties which are independently: halogen; an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy, or —C 3-6 -cyclic-alkoxy; or an alkyl moiety which is —C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or C 3-6 -cycloalkyl;
(d) an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy, or —C 3-6 -cyclic-alkoxy;
(e) —N(R A5a ) 2 , wherein R A5a is independently for each occurrence: —H; or an alkyl moiety which is —C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or C 3-6 -cycloalkyl;
(f) —C 2-6 -heterocycloalkyl, wherein said heterocycloalkyl comprises from 2 to 6 carbon atoms and one or two nitrogen atoms in the ring;
(g) aryl, optionally substituted with one or more moieties which are, independently: (i) halogen; (ii) an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy or —C 3-6 -cyclic-alkoxy; or (iii) an alkyl moiety which is —C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or C 3-6 -cycloalkyl;
(h) heteroaryl, optionally substituted with one more moieties which are, independently: (i) halogen; (ii) an alkoxy moiety which is —C 1-6 -linear-alkoxy, —C 3-6 -branched-alkoxy or —C 3-6 -cyclic-alkoxy; or (iii) an alkyl moiety which is —C 1-6 -linear-alkyl, C 3-6 -branched-alkyl, or C 3-6 -cycloalkyl; or
R 8 and R 9 on one carbon together form:
(a) a dioxalane moiety;
(b) an arylspirocycloalkyl moiety having a C 3-6 -cycloalkyl portion that, together with the substrate carbon to which it is bonded forms a spirocycloalkyl structure wherein two carbons of the spirocycloalkyl ring portion is fused to an aryl moiety;
(c) a heteroarylspirocycloalkyl moiety having a C 3-6 -cycloalkyl portion that, together with the substrate carbon to which it is bonded forms a spirocycloalkyl structure wherein two carbon atoms of the cycloalkyl ring portion of the moiety are fused to a heteroaryl moiety; or
(d) —C 3-6 -spirocycloalkyl moiety.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 and R 5 are independently: —H; or a cyclic-, branched- or linear-alkyl moiety of up to 6 carbon atoms; and
R 1 and R 2 are independently: —H; —F; —Cl; —Br; —CN; a cyclic-, branched, or linear-alkyl moiety comprising up to 6 carbon atoms; or —CF 3 .
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is: —H; —F; —Cl; —Br; —CN; or —CH 3 ;
R 2 is: —H; —F; —Cl; —Br; —CN; CH 3 ; —CH 2 CH 3 ; or —CF 3 ; and
R 4 and R 5 are independently: (i) —H; or (ii) —CH 3 .
4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein, in the structure of Formula A-a, the moiety of Formula B 1 has the structure of Formula B 1a :
wherein:
A 3 is —(CR 10 R 11 ) p , wherein:
p is 1 or 2; and
R 10 and R 11 are independently for each occurrence:
(a) hydrogen;
(b) halogen;
(c) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which moiety is optionally substituted with one or more substituents which are independently: (i) halogen; (ii) aryl, which is optionally substituted with lower alkoxy; or (iii) —OH; or
(d) aryl, optionally substituted with an alkoxy moiety which is C 1-4 -linear-alkoxy or C 3-4 -branched-alkoxy; or
R 10 and R 11 together form: (i) a dioxalane moiety or (ii) a C 3-6 -spirocycloalkyl moiety;
A 4 is —(CR 12 R 13 ), wherein R 12 and R 13 are independently: (a) hydrogen; (b) a cyclic-, branched-, or liner-alkyl moiety comprising up to 6 carbon atoms, which moiety is optionally substituted with one or more substituents which are, independently: (i) halogen; or (ii) —OH; or (c) aryl, which is optionally substituted with one or more substituents which are, independently: (i) lower-alkyl; or (ii) lower-alkoxy; and
A 5 is —(CR 14 R 15 ) m , wherein: m is 1 or 2, and R 14 and R 15 are independently for each occurrence: (a) hydrogen; or (b)) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which alkyl moiety is optionally substituted with one or more substituents which are, independently: (i) —OH or halogen.
5. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A 3 , A 4 and A 5 are each [—CH 2 —]; and
in the structure of Formula A-a:
R 1 is independently: —H; —F; —Cl; —Br; —CN; or CH 3 ;
R 2 is independently: —H; —F; —Cl; —Br; —CN; —CF 3 , —CH 3 ; or —CH 2 CH 3 .
6. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A is [—CR 10a2 R 11a2 —], wherein:
[—R 10a2 ] and [—R 11a2 ] are independently for each occurrence:
(a) hydrogen;
(b) halogen;
(c) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which alkyl moiety is optionally substituted with one or more: (i) halogen; (ii) an aryl moiety optionally substituted with C 1-4 -linear-alkoxy or C 3-4 -branched-alkoxy; or (iii) —OH; or
(d) an aryl moiety optionally substituted with C 1-4 -linear-alkoxy or C 3-4 -branched-alkoxy; or
R 10a2 and R 11a2 together form:
(a) a dioxalane moiety; or
(b) a C 3-6 -spirocycloalkyl moiety;
A 4 and A 5 are each [—CH 2 —]; and
in the moiety of Formula A-a:
R 1 is independently: —H; or —F; and
R 2 is independently: (i) —H; (ii) —Cl; (iii) —CN; or (iv) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which alkyl moiety is optionally substituted with one or more —F.
7. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A 4 is [—CR 12a3 R 13a3 —], wherein:
R 12a3 and R 13a3 are independently for each occurrence:
(a) hydrogen; or
(b) an alkyl moiety which is —C 1-6 -linear-alkyl, —C 3-6 -branched-alkyl, or —C 3-6 -cycloalkyl, which alkyl moiety is optionally substituted with one or more: (i) halogen; (ii) —OH;
A 3 and A 5 are each [—CH 2 —].
8. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A 3 is independently [—CH 2 -] or [—CH 2 —CH 2 —];
A 4 is [—CH 2 —];
A 5 is [—CH 2 —CH 2 —];
R 1 is independently: —H; —F; —Cl; —Br; —CN; or —CH 3 ; and
R 2 is, independently: —H; —F; —Cl; —Br; —CN; CH 3 ; —CH 2 CH 3 ; or —CF 3 .
9. A compound of any claim 2 , or a pharmaceutically acceptable salt thereof, wherein the moiety [—R 3 ] in the structure of Formula A-a is a moiety of Formula R 3a :
wherein: —R 16a and —R 17a are independently:
(a) —H;
(b) A branched- or linear-alkyl moiety comprising up to 6 carbon atoms which is optionally substituted with one or more halogen moieties;
(c) —CF 3 ;
(d) an ester moiety which is C 1-6 -linear-alkyl-C(O)—O—, C 3-6 -branched-alkyl-C(O)—O—, or C 3-6 -cyclo-alkyl-C(O)—O—;
(e) —C 3-5 -cycloalkyl which is optionally substituted with: (i) —F; or (ii) branched- or linear-alkyl moiety comprising up to 6 carbon atoms;
(f) —CN;
(g) a heteroaryl moiety;
(h) an aryl moiety; or
(i) halogen.
10. A compound of claim 9 , or a pharmaceutically acceptable salt thereof wherein:
(a) —R 16a is —H, —Cl, —CH 3 , —F, —Br or —C(O)—CH 2 —CH 3 ; and
(b) —R 17a is —H, —Cl, or CH 3 .
11. A compound of claim or a pharmaceutically acceptable salt thereof, wherein [—R 3 ] is a moiety of Formula R 3b :
wherein: —R 16b is:
(i) —H;
(ii) —CF 3
(iii) a lower-alkyl comprising up to 6 carbon atoms and is optionally substituted with one or more substituents which are independently:
(a) halogen;
(b) —C 3-5 -cycloalkyl optionally substituted with, independently for each occurrence: (1) —F; or (2) lower alkyl; or
(c) a heteroaryl substituent; or
(iv) heteroaryl.
12. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein [—R 3 ] is a moiety of Formula R 3c :
wherein: —R 16c is:
(i) —H;
(ii) —CF 3 ;
(iii) a cyclic- or branched-, or linear-alkyl moiety comprising up to 6 carbon atoms which is optionally substituted with one or more substitutents which are independently for each occurrence:
(a) halogen;
(b) an ester of the formula: (1) C 1-6 -linear-; (2) C 3-6 -branched-; or (3) C 3-6 -cyclic-alkyl-C(O)—O—; or
(c) —C 3-5 -cycloalkyl optionally substituted with, independently for each occurrence: (1) —F; or (2) lower alkyl.
13. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein [—R 3 ] is a moiety of Formula R 3e :
wherein:
one of X e1 or X e2 is [═CR e4 —], and the other is independently [═N-] or [═CR e4 —], wherein R e4 is, independently for each occurrence: (a) —H; (b) halogen; or (c) C 1-6 -linear alkyl or —C 3-6 -branched alkyl; and
X e3 is [═CR e5 —], wherein, one of R e5 is a bond to the substrate and the other two are, independently for each occurrence: (i) —H; (ii) lower alkyl.
14. A compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein [—R 3 ] is a moiety of Formula R 3ea :
wherein:
one of X e1 and X e2 is [—CR e4 ═], and the other is independently [—N═] or [—CR e4 ═], wherein R e4 independently for each occurrence: (a) —H; (b) halogen; or (c) lower alkyl.
15. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:
5-chloro-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
2,5-difluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
3-cyano-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(5-methyl-1,3-thiazol-2-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-cyano-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide;
N-(5-chloro-1,3-thiazol-2-yl)-5-cyano-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
N-(5-bromothiazol-2-yl)-5-chloro-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
3-chloro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-5-methyl-N-(thiazol-2-yl)benzenesulfonamide;
ethyl 2-(5-chloro-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)phenylsulfonamido)thiazole-5-carboxylate;
5-bromo-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
2-chloro-5-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide;
4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoro-4-methylthiazol-2-yl)-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
3-cyano-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-cyano-N-(6-fluoropyridin-2-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
2,5-difluoro-N-(6-fluoropyridin-2-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(pyrimidin-4-yl)-4-[(tetrahydro-1H-pyrrolizin-7a (5H)-ylmethyl)amino]benzenesulfonamide;
N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(pyridazin-3-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]benzenesulfonamide;
3-cyano-4-{[(2-methyltetrahydro-1H-pyrrolizin-7a(5 Hyl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-cyano-4-{[(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-cyano-4-{[((2S,7aR)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-cyano-4-{[((2R,7aS)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-{[(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)-benzenesulfonamide;
5-chloro-2-fluoro-4-{[((2S,7a R)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)-benzenesulfonamide;
5-chloro-2-fluoro-4-{[((2R,7aS)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)-benzenesulfonamide;
5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-(((2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzene-sulfonamide;
5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-((((2S,7a R)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzene-sulfonamide;
5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-((((2R,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzene-sulfonamide;
3-chloro-4-(((2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
3-chloro-4-((((2S,7a R)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
3-chloro-4-((((2R,7aS)-2-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
3-cyano-4-{[1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(S)-3-cyano-4-{[1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(R)-3-cyano-4-{[1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-{[1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-2-fluoro-4-{[(1R)-1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-2-fluoro-4-{[(1S)-1-(tetrahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
3-cyano-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(S)-3-cyano-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(R)-3-cyano-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide
5-chloro-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide;
5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluorobenzenesulfonamide;
(R)-5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluorobenzenesulfonamide;
(S)-5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-4-{[(2,2-difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl]amino}-2-fluorobenzenesulfonamide;
5-chloro-2-fluoro-4-[(tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)amino]-N-(1,3-thiazol-4-yl)benzenesulfonamide;
5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-N-(5-chlorothiazol-2-yl)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluorobenzenesulfonamide;
(R)-5-chloro-N-(5-chlorothiazol-2-yl)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluorobenzenesulfonamide;
(S)-5-chloro-N-(5-chlorothiazol-2-yl)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluorobenzenesulfonamide;
5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
(S)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
(R)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide
5-chloro-2-fluoro-4-(((2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,7aR)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,7a R)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
4-(((2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
4-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
4-((((2S,7aR)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
3-chloro-4-(((2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide;
3-chloro-4-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide
3-chloro-4-((((2S,7aR)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(5-fluorothiazol-2-yl)benzenesulfonamide
5-chloro-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)benzenesulfonamide;
(S)-5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)benzenesulfonamide;
(R)-5-chloro-N-(5-chlorothiazol-2-yl)-2-fluoro-4-(((hexahydrospiro[[1,3]dioxolane-2,2′-pyrrolizin]-7a′-yl)methyl)amino)benzenesulfonamide;
5-chloro-2-fluoro-4-(((3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3S,7aS)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3R,7a R)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
4-(((3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
4-((((3S,7aS)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
4-((((3R,7aR)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)-3-(trifluoromethyl)benzenesulfonamide;
3-chloro-N-(5-fluorothiazol-2-yl)-4-(((3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
3-chloro-N-(5-fluorothiazol-2-yl)-4-((((3S,7aS)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
3-chloro-N-(5-fluorothiazol-2-yl)-4-((((3R,7a R)-3-methylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
2-bromo-5-chloro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-cyano-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-2-methyl-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)-methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-2-fluoro-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)-methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-2-fluoro-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)-methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
N-(5-fluorothiazol-2-yl)-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)methyl)amino)-3-(trifluoromethyl)benzenesulfonamide; (racemic)
(S)-N-(5-fluorothiazol-2-yl)-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)methyl)amino)-3-(trifluoromethyl)benzenesulfonamide;
(R)-N-(5-fluorothiazol-2-yl)-4-(((hexahydrospiro[cyclopropane-1,2′-pyrrolizin]-7a′-yl)methyl)amino)-3-(trifluoromethyl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((3-(fluoromethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3R,7aR)-3-(fluoromethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3S,7aS)-3-(fluoromethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((−3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((3R,7a R)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((−2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2R,7aS)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,7a R)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-(((−2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((((2R,7aS)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
5-chloro-2-fluoro-N-(5-fluorothiazol-2-yl)-4-((((2S,7a R)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
5-chloro-2-fluoro-4-(((−2-(4-methoxyphenyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2S,7aS)-2-(4-methoxyphenyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-((((2R,7a R)-2-(4-methoxyphenyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((octahydroindolizin-8a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(R)-5-chloro-2-fluoro-4-(((octahydroindolizin-8a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
(S)-5-chloro-2-fluoro-4-(((octahydroindolizin-8a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-chloro-2-fluoro-4-(((octahydro-1H-quinolizin-9a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-ethyl-2-fluoro-4-(((2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-ethyl-2-fluoro-4-((((2R,7aS)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-ethyl-2-fluoro-4-((((2S,7a R)-2-(4-methoxybenzyl)hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-ethyl-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide;
5-ethyl-2-fluoro-N-(5-fluorothiazol-2-yl)-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)benzenesulfonamide;
4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide;
(S)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide; or
(R)-4-(((2,2-dimethylhexahydro-1H-pyrrolizin-7a-yl)methyl)amino)-5-ethyl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide.
17. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
18. A dosage form comprising an amount of the composition of claim 17 that provides an amount of said compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is sufficient to provide a therapeutic response when administered to a patient in need of therapy for a neuropathic pain disorder.
19. A method of treating a neuropathic pain disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 17 .