SODIUM CHANNEL INHIBITORS

• US 20090023740A1
• Filed: 07/14/2008
• Published: 01/22/2009
• Est. Priority Date: 07/13/2007
• Status: Active Grant

• Current Assignee: Icagen, Inc.
• Original Assignee: Icagen, Inc.
• Inventors: Seconi, Darrick Conway, West, Christopher William, Zhou, Shulan, Wang, Xiaodong, Johnson, Matthew Scott, Fulp, Alan Bradley, Marron, Brian Edward, Markworth, Christopher John
• Granted Patent: US 8,124,610 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-gated sodium channels. More particularly, the invention provides substituted sulfonamides, compositions comprising these compounds, as well as methods of using these compounds or compositions in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrence of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a voltage-gated sodium channel.

Claims

1. A compound having Formula (II):

or a pharmaceutically acceptable salt or solvate thereof;

Z is selected from the group consisting of 5-membered heteroaryl having from 1 to 4 heteroatoms as ring members selected from N, O or S and 6-membered heteroaryl having from 1 to 3 nitrogen heteroatoms as ring members;

Y is selected from the group consisting of 5-membered heteroaryl having from 1 to 4 heteroatoms as ring members selected from N, O or S, 6-membered heteroaryl having from 1 to 3 nitrogen heteroatoms as ring members, and aryl optionally fused with a 5-membered heteroaryl having 1 to 2 heteroatoms as ring members selected from O, N or S;

or Y and X¹ are taken together to form a 5-membered fused heteroaryl ring having from 0-2 additional nitrogen atoms as ring members and R¹ is a lone pair, wherein the fused heteroaryl ring is optionally substituted with a R^b group;

wherein the heteroaryl and aryl of Y and Z substituents are each optionally substituted with from 1 to 3 R^a substituents, at each occurrence, each R^a is independently selected from the group consisting of C_1-8alkyl-NH—

, (C_1-8alkyl)₂N—

, aryl, R^b, C_1-8haloalkyl, aryl-C_3-8cycloalkyl, C_3-8cycloalkyl, heterocycloalkyl, arylsulfonyl, arylsulfinyl and R^f, wherein R^b is C_1-8alkyl optionally substituted with from 1-3 members independently selected from the group consisting of aryl, aryl-C(O)—

, aryloxy, (R^c)(R^d)N—

, C_3-5cycloalkyl, hetero-C_4-5cycloalkyl, arylthio and heteroaryl;

wherein R^c is —

H or C_1-6alkyl and R^d is C_3-7cycloalkyl or C_1-8alkyl optionally substituted with from 1-2 aryl groups, or optionally R^c and R^d together with the nitrogen atom to which they are attached form a 5 or 6-membered ring having 0-2 additional heteroatoms as ring members selected from N, O or S;

wherein the aryl portion of each R^a substituent is further optionally substituted with from 1-3 substituents independently selected from the group consisting of C_1-4haloalkyl, C_1-4haloalkoxy and R^f, and the heterocycloalkyl of the R^b group is further optionally substituted with a hetero-C_4-5cycloalkyl-C_1-6alkyl;

or any two adjacent R^a substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, wherein 1-2 ring carbon atoms of the carbocyclic ring are optionally replaced by a carbonyl and the carbocyclic ring is optionally substituted with 1-2 members independently selected from an halogen, aryl or C_1-8alkyl;

wherein R^f is halogen, —

OH, —

OR^g, —

OC(O)O—

R^g, —

OC(O)R^g, —

OC(O)NHR^g, —

OC(O)N(R^g)₂, —

SH, —

SR^g, —

S(O)R^g, —

S(O)₂R^g, —

SO₂NH₂, —

S(O)₂NHR^g, —

S(O)₂N(R^g)₂, —

NHS(O)₂R^g, —

NR^gS(O)₂R^g, —

C(O)NH₂, —

C(O)NHR^g, —

C(O)N(R^g)₂, —

C(O)R^g, —

C(O)H, —

C(═

S)R^g, —

NHC(O)R^g, —

NR^gC(O)R^g, —

NHC(O)NH₂, —

NR^gC(O)NH₂, —

NR^gC(O)NHR^g, —

NHC(O)NHR^g, —

NR^gC(O)N(R^g)₂, —

NHC(O)N(R^g)₂, —

CO₂H, —

CO₂R^g, —

NHCO₂R^g, —

NR^gCO₂R^g, —

CN, —

NO₂, —

NH₂, —

NR^gS(O)NH₂, —

NR^gS(O)₂NHR^g, —

NHC(═

NR^g)NH₂, —

N═

C(NH₂)NH₂, —

C(═

NR^g)NH₂, —

NH—

OH, —

NR^g—

OH, —

NR^g—

OR^g, —

N═

C═

O and —

N═

C═

S;

wherein each R^g is independently a C_1-8alkyl;

X¹, X², X³ and X⁴ are each independently —

N═

, or C(R²)═

, wherein R² is selected from the group consisting of —

H, halogen, —

OH, C_1-8alkyl, —

CN, C_1-6haloalkyl and C_1-6haloalkoxy;

or any two adjacent R² substituents together with the atoms to which they are attached form a fused benzene ring, optionally substituted with a C_1-6alkyl, with the proviso that not more than three of X¹, X², X³ and X⁴ are —

N═

;

L is a bond or

i) L, the aromatic carbon atom to which L is attached, and X¹ taken together form a fused 5- or 6-membered carbocyclic ring, wherein 1-2 ring carbon atoms of the fused carbocyclic ring are optionally replaced with —

C(O)—

or —

S(O)₂—

group;

or

ii) L, the two atoms to which L is attached, and X¹ taken together form a 5- or 6-membered fused heterocyclic ring having from 0-2 additional heteroatoms selected from N, O or S, wherein 1-2 ring carbon atoms of the fused heterocyclic ring are optionally replaced with —

C(O)—

or —

S(O)₂—

group;

R¹ is —

H, a lone pair or C_1-8alkyl;

with the proviso that the compound is other than 4-(4-methylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

4-(4-(4-chlorophenyl)phthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

N-(thiazol-2-yl)-4-(4-p-tolylphthalazin-1-ylamino)benzenesulfonamide; and

4-(4-phenylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide; and

at each occurrence, “

alkyl”

by itself or as part of another substituent, is an unsubstituted, fully saturated, straight or branched chain hydrocarbon radical;

at each occurrence, “

cycloalkyl”

by itself or as part of another substituent is an unsubstituted, fully saturated, cyclic hydrocarbon radical; and

at each occurrence, “

aryl”

by itself or as part of another substituent is a monovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical.

2. The compound of claim 1, wherein

Z is selected from the group consisting of:

i) 5-membered heteroaryl having from 1-3 heteroatoms as ring members selected from N, O or S, wherein the heteroaryl is optionally substituted with from 1 to 2 substituents selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl; and

ii) 6-membered heteroaryl having from 1-2 nitrogen atoms as ring members, wherein the heteroaryl is optionally substituted with 1-3 C_1-8alkyl; and

X¹, X², X³ and X⁴ are each independently —

N═

, or C(R²)═

, wherein R² is selected from the group consisting of —

H, halogen, C_1-8alkyl, —

OH, —

CN, C_1-6haloalkyl and C_1-6haloalkoxy;

or any two adjacent R² substituents together with the atoms to which they are attached form a fused benzene ring, optionally substituted with a C_1-6alkyl, with the proviso that not more than three of X¹, X², X³ and X⁴ are —

N═

;

L is a bond or

i) L, the aromatic carbon atom to which L is attached, and X¹ taken together form a fused 5- or 6-membered carbocyclic ring, wherein 1-2 ring carbon atoms of the fused carbocyclic ring are optionally replaced with —

C(O)—

or —

S(O)₂—

group;

or

ii) L, the two atoms to which L is attached, and X¹ taken together form a 5- or 6-membered fused heterocyclic ring having from 0-2 additional heteroatoms selected from N, O or S, wherein 1-2 ring carbon atoms of the fused heterocyclic ring are optionally replaced with —

C(O)—

or —

S(O)₂—

group;

Y is selected from the group consisting of;

i) 5-membered heteroaryl having from 1-4 heteroatoms as ring members selected from N, O or S, wherein the heteroaryl is optionally substituted with 1-3 R^a members, at each occurrence, each R^a is independently selected from the group consisting of C_1-8alkyl-NH—

, (C_1-8alkyl)₂N—

, aryl, R^b, C_1-8haloalkyl, aryl-C_3-8cycloalkyl, C_3-5cycloalkyl, heterocycloalkyl, arylsulfonyl, arylsulfinyl and R^f, wherein R^b is C_1-8alkyl optionally substituted with from 1-3 members independently selected from the group consisting of aryl, aryl-C(O)—

, aryloxy, (R^c)(R^d)N—

, C_3-5cycloalkyl, hetero-C_4-5cycloalkyl, arylthio and heteroaryl;

wherein R^c is —

H or C_1-6alkyl and R^d is C_3-7cycloalkyl or C_1-8alkyl optionally substituted with from 1-2 aryl groups;

wherein the aryl portion of each R^a substituent is further optionally substituted with from 1-3 substituents independently selected from the group consisting of C_1-4haloalkyl, C_1-4haloalkoxy and R^f, and the heterocycloalkyl of the R^b group is further optionally substituted with a hetero-C_4-5cycloalkyl-C_1-6alkyl;

or any two adjacent R^a substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, wherein 1-2 ring carbon atoms of the carbocyclic ring are optionally replaced by a carbonyl and the carbocyclic ring is optionally substituted with 1-2 members independently selected from an halogen, aryl or C_1-8alkyl;

wherein R^f is halogen, —

OH, —

OR^g, —

OC(O)O—

R^g, —

OC(O)R^g, —

OC(O)NHR^g, —

OC(O)N(R^g)₂, —

SH, —

SR^g, —

S(O)R^g, —

S(O)₂R^g, —

SO₂NH₂, —

S(O)₂NHR^g, —

S(O)₂N(R^g)₂, —

NHS(O)₂R^g, —

NR^gS(O)₂R^g, —

C(O)NH₂, —

C(O)NHR^g, —

C(O)N(R^g)₂, —

C(O)R^g, —

C(O)H, —

C(═

S)R^g, —

NHC(O)R^g, —

NR^gC(O)R^g, —

NHC(O)NH₂, —

NR^gC(O)NH₂, —

NR^gC(O)NHR^g, —

NHC(O)NHR^g, —

NR^gC(O)N(R^g)₂, —

NHC(O)N(R^g)₂, —

CO₂H, —

CO₂R^g, —

NHCO₂R^g, —

NR^gCO₂R^g, —

CN, —

NO₂, —

NH₂, —

NR^gS(O)NH₂, —

NR^gS(O)₂NHR^g, —

NH₂C(═

NR^g)NH₂, —

N═

C(NH₂)NH₂, —

C(═

NR^g)NH₂, —

NH—

OH, —

NR^g—

OH, —

NR^g—

OR^g, —

N═

C═

O and —

N═

C═

S;

wherein each R^g is independently a C_1-8alkyl.

ii) 6-member heteroaryl having from 1-3 nitrogen atoms as ring members, wherein the heteroaryl is optionally substituted with 1-3 R^e substituents independently selected from the group consisting of —

OH, aryl, aryl-C_1-6alkyl, aryl-C_1-6alkoxy, C_3-6cycloalkyl-C_1-6alkoxy and C_1-8alkoxy, wherein the aliphatic portion of the R^e group is further optionally substituted with an aryl and the aromatic portion of the R^e group is further optionally substituted with from 1-2 members independently selected from C_1-6haloalkyl, halogen or C_1-6alkyl;

or any two adjacent R^e substituents together with the atoms to which they are attached form a 6-membered fused benzene ring, optionally substituted with a halogen or C_1-6 alkyl; and

iii) aryl optionally substituted with an aryl or C_1-6alkyl; and

R¹ is —

H, a lone pair or C_1-6alkyl;

3. The compound of claim 2, wherein L is a bond and Y is selected from the group consisting of:

i) 5-membered heteroaryl having from 1-4 heteroatoms as ring members selected from N, O or S, wherein the heteroaryl is optionally substituted with 1-3 R^a members, at each occurrence, each R^a is independently selected from the group consisting of —

NH₂, C_1-8alkyl-NH—

, (C_1-8alkyl)₂N—

, aryl, R^b, C_1-8haloalkyl, aryl-C_3-8cycloalkyl, C_3-5cycloalkyl, heterocycloalkyl, arylsulfonyl, arylsulfinyl, NH₂C(O)—

, (C_1-8alkyl)(H)NC(O)—

, (C_1-8alkyl)₂NC(O)—

, C_1-8alkylcarbonyl and C_1-8alkoxycarbonyl, wherein R^b is C_1-8alkyl optionally substituted with from 1-2 members independently selected from the group consisting of aryl, aryl-(CO)—

, aryloxy, (R^c)(R^d)N—

, C_3-5cycloalkyl, hetero-C_4-5cycloalkyl, arylthio and heteroaryl;

wherein R^c is —

H or C_1-6alkyl and R^d is C_3-7cycloalkyl or C_1-8alkyl optionally substituted with from 1-2 aryl groups;

wherein the aryl portion of each R^a substituent is further optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkoxy, —

CN, C_1-4alkylsulfonyl, OH and —

NO₂; and

the heterocycloalkyl of the R^b group is further optionally substituted with a hetero-C_4-5cycloalkyl-C_1-6alkyl;

or any two adjacent R^a substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, wherein one of the ring carbon atom of the carbocyclic ring is optionally replaced by a carbonyl and the carbocyclic ring is optionally substituted with 1-2 members independently selected from an halogen, aryl or C_1-8alkyl;

ii) 6-member heteroaryl having from 1-3 nitrogen atoms as ring members, wherein the heteroaryl is optionally substituted with 1-3 R^e substituents independently selected from the group consisting of —

OH, aryl, aryl-C_1-6alkyl, aryl-C_1-6alkoxy, C_3-6cycloalkyl-C_1-6alkoxy and C_1-8alkoxy, wherein the aliphatic portion of the R^e group is further optionally substituted with an aryl and the aromatic portion of the R^e group is further optionally substituted with from 1-2 members independently selected from C_1-6haloalkyl, halogen or C_1-6alkyl;

or any two adjacent R^e substituents together with the atoms to which they are attached form a 6-membered fused benzene ring, optionally substituted with a halogen or C_1-6 alkyl; and

iii) aryl optionally substituted with an aryl or C_1-6alkyl;

4. The compound of claim 1, wherein R¹ is —

H.

5. The compound of any of claims 1, wherein Z is a 5-membered heteroaryl having from 1-3 heteroatoms as ring members selected from N, O or S, wherein the heteroaryl is optionally substituted with a member selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl.

6. The compound of claim 5, wherein Z is selected from the group consisting of thiazolyl, isothiazolyl, isoxazoly, oxazolyl, 1,3,4-thiadiazoly, 1,2,3-thiadiazoly, 1,2,4-thiadiazoly, 1,3,4-oxadiazoly, 1,2,3-oxadiazoly, 1,2,4-oxadiazoly, 1,2,5-thiadiazolyl, pyrazolyl, 1,2,5-oxadiazolyl, 1,2,3,5-thiatriazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazolyl and imidazoly, each of which is optionally substituted with a member selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl.

7. The compound of claim 6, wherein Z is selected from the group consisting of thiazol-2-yl, 4-thiazolyl, 5-thiazolyl, isoxazol-3-yl, 2-oxazolyl, 1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-oxadiazol-2yl, 1,2,5-thiadiazol-4-yl, pyrazolyl, 1,2,5-oxadiazol-4-yl, 1,2,3,5-thiatriazol-4-yl, 1,2,3,4-thiatriazol-5-yl, 1,2,3,5-oxatriazol-4-yl, 1,2,3,4-oxatriazol-5-yl and 2-imidazolyl, each of which is optionally substituted with a member selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl.

8. The compound of claim 7, wherein Z is substituted with a member selected from the group consisting of 3-chloropropyl, phenylaminomethyl, —

CH₃, CH₂CH₃, —

Cl, —

CF₃, —

CF₂H, CH₃OCH₂—

, cyclopropyl, isopropyl and —

CN.

9. The compound of any of claims 1, wherein Z is 6-membered heteroaryl having from 1-2 nitrogen atoms as ring members, wherein the heteroaryl is optionally substituted with 1-3 C_1-8alkyl.

10. The compound of claim 9, wherein Z is selected from the group consisting of pyridyl, pyridazinyl, primidinyl or pyrizinyl, each of which is optionally substituted with from 1-3 C_1-6alkyl.

11. The compound of claim 10, wherein Z is selected from the group consisting of 2-pyridyl, 3-pyridazinyl, 4-primidinyl and 2-pyrizinyl, each of which is optionally substituted with from 1-3 C_1-6alkyl.

12. The compound of any of claims 1, wherein Y is 5-membered heteroaryl having from 1-3 heteroatoms as ring members selected from N, O or S, wherein the heteroaryl is optionally substituted with 1-3 R^a members, at each occurrence, each R^a is independently selected from the group consisting of —

NH₂, C_1-8alkyl-NH—

, (C_1-8alkyl)₂N—

, aryl, R^b, C_1-8haloalkyl, aryl-C_3-8cycloalkyl, C_3-5cycloalkyl, heterocycloalkyl, arylsulfonyl, arylsulfinyl, NH₂C(O)—

, (C_1-8alkyl)(H)NC(O)—

, (C_1-8alkyl)₂NC(O)—

, C_1-8alkylcarbonyl and C_1-8alkoxycarbonyl, wherein R^b is C_1-8alkyl optionally substituted with from 1-2 members independently selected from the group consisting of aryl, aryloxy, (R^c)(R^d)N—

, C_3-5cycloalkyl, hetero-C_4-5cycloalkyl, arylthio and heteroaryl;

wherein R^c is —

H or C_1-6alkyl and R^d is C_3-7cycloalkyl or C_1-8alkyl optionally substituted with from 1-2 aryl groups;

wherein the aryl portion of each R^a substituent is further optionally substituted with from 1-3 substituents independently selected from the group consisting of halogen, C_1-4haloalkyl, C_1-4haloalkoxy, C_1-4alkoxy, —

CN, C_1-4alkylsulfonyl, OH and —

NO₂; and

the heterocycloalkyl of the R^b group is further optionally substituted with a hetero-C_4-5cycloalkyl-C_1-6alkyl;

or any two adjacent R^a substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, wherein one of the ring carbon atom is optionally replaced by a carbonyl and the carbocyclic ring is optionally substituted with 1-2 members independently selected from an halogen, aryl or C_1-8alkyl.

13. The compound of claim 12, wherein Y is selected from the group consisting of thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazol-4-yl, 1,2,5-oxadiazol-4-yl, 1,2,3,5-thiatriazol-4-yl, 1,2,3,4-thiatriazol-5-yl, 1,2,3,5-oxatriazol-4-yl, 1,2,3,4-oxatriazol-5-yl, benzimidazolyl, benzoxazolyl, benzthiazolyl, tetrahydrobenzothiazolyl and dihydrobenzothiazolone, each of which is optionally substituted with 1-3 R^a members.

14. The compound of claim 13, wherein Y is selected from the group consisting of thiazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-3-yl, 1,2,4-triazol-1yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzthiazol-2-yl, tetrahydrobenzothiazol-2-yl and dihydrobenzothiazol-2-yl-7-one, each of which is optionally substituted with 1-3 R^a members.

15. The compound of claim 14, wherein R^a is selected from the group consisting of -Ph, Ph₂CH—

, PhOCH₂—

, Ph₂CHCH₂—

, Ph-O(CH₂)₃—

, cyclopentylethyl, 4-chlorophenoxymethyl, 2-phenylcyclopropyl, Ph₂CHCH₂NHCH₂—

, PhOCH₂CH₂NHCH₂—

, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, Ph₂NHCH₂—

, Ph₂CHCH₂CH₂NHCH₂—

, 4-t-butyl-phenoxymethyl, PhO(CH₃)CH—

, 1-(4-chlorophenyl)cyclopentyl, 4-chlorophenyl-CH₂NHCH₂—

, 3,4-dimethoxyphenyl-(CH₂)₂NHCH₂—

, Ph(CH₂)₂N(CH₃)CH₂—

, (CH₃CH₂)₂NCH₂—

, Ph(CH₂)₄NHCH₂—

, Ph₂CHN(CH₃)CH₂—

, 4-CF₃-Ph-CH₂NHCH₂—

, 4-NO₂-Ph-CH₂NHCH₂—

, 4-dimethylaminophenyl-CH₂NHCH₂—

, 4-pyridyl-CH₂CH₂N(CH₃)CH₂—

, 3,5-dimethoxyphenyl-CH₂NH—

CH₂—

, —

CH₃, CH₃OC(O)—

, 2,4-difluorobenzyl, 4-fluoro-Ph-SCH₂—

, —

CF₃, 4-trifluoromethylphenyl, 4-fluorophenylsulfinylmethyl, 4-chlorophenylsulfinylmethyl, 2-fluoro-4-trifluoromethylphenyl, 4-chlorobenzyl, 4-chlorophenoxypropyl, 2,4-dichlorophenoxymethyl, 2-methyl-4-chlorophenoxymethyl, 4-chlorophenoxy-C(CH₃)₂—

, t-butoxyphenoxymethyl, 4-chlorophenyl, t-butyl, 4-methoxybenzyl, 4-methylsulfonylbenzyl, 4-cyanobenzyl, 4-chlorophenylsulfonyl, acetyl, —

NH₂, 3-chloro-4-fluoro-phenyl, 4-trifluoromethylbenzyl, neopentyl, 4-methoxybenzyl, 2-methoxybenzyl, 1-(4-chlorophenyl)cyclopropyl, CF₃CH₂—

, —

CN, —

NO₂, 4-pyridylmethyl, cyclohexylmethyl, cyclopropyl, isopropyl, 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-methylbenzyl, 2-fluoro-4-chlorobenzyl, cylopentyl, 2-fluorophenyl, cyclopropyl-(CH₃)CH—

, 3-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-fluoro-phenyl, 2-trifluoromethyl-4-fluorophenyl, 2-methoxyphenyl, 2,6-dichlorophenyl, 2,6-difluororophenyl, 2,6-dimethylphenyl, 2,4-difluorobenzyl, 3-trifluoromethylphenyl, 1-methypiperidinyl, 2-chloro-4-fluorobenzyl, 2-chlorobenzyl, 3-fluoro-4-chlorobenzyl, benzyl, (CH₃CH₂)₂NC(O)—

CH₂—

, 4-fluorobenzyl, 3-chlorobenzyl, 2-methoxy-4-chlorophenyl, 2-methoxyphenyl, 4-methoxybenzyl, 3-trifluoromethyl-4-chlorobenzyl, 2-methoxy-4-chlorophenyl, 3-methoxyphenyl, 4-methoxybenzyl, 3-trifluormethyl-4-chlorobenzyl, 2-methoxy-5-trifluoromethoxybenzyl and NH₂C(O)—

.

16. The compound of any of claims 1, wherein Y is a 6-member heteroaryl having from 1-3 nitrogen atoms as ring members, wherein the heteroaryl is optionally substituted with 1-3 R^e substituents independently selected from the group consisting of —

OH, aryl, aryl-C_1-6alkyl, aryl-C_1-6alkoxy, C_3-6cycloalkyl-C_1-8alkoxy and C_1-8alkoxy, wherein the aliphatic portion of the R^e group is further optionally substituted with an aryl and the aromatic portion of the R^e group is further optionally substituted with from 1-2 members independently selected from C_1-6haloalkyl, halogen or C_1-6alkyl;

or any two adjacent R^e substituents together with the atoms to which they are attached form a 6-membered fused benzene ring, optionally substituted with a halogen or C_1-6alkyl.

17. The compound of claim 16, wherein Y is selected from the group consisting of primidinyl, pyridazinyl, prazinyl, triazinyl and phthalazinyl, each of which is optionally substituted with from 1-3 R^e substituents.

18. The compound of claim 17, wherein Y is selected from the group consisting of 2-primidinyl, 4-pyrimidinyl, pyridazinyl, 3-prazinyl, 1,2,4-triazin-3-yl and 1-phthalazinyl, each of which is optionally substituted with from 1-3 R^e substituents.

19. The compound of claim 18, wherein R^e is selected from the group consisting of 4-chlorophenyl, 4-methylphenyl, Ph-, benzyloxy, Ph₂CHCH₂O—

, 4-trifluoromethylbenzyloxy, cyclohexylmethyloxy, methoxy, Ph₂CH—

, —

OH, and 3,5-difluorobenzyl.

20. The compound of any of claims 1, wherein Y is an aryl, optionally substituted with an aryl or C_1-6alkyl.

21. The compound of claim 20, wherein Y is an aryl, optionally substituted with phenyl or —

CH₃.

22. The compound of claim 21, wherein Y is phenyl.

23. The compound of any of claims 1, wherein X¹, X², X³ and X⁴ are ═

CH—

.

24. The compound of any of claims 1, wherein X¹ is —

N═

, and X², X³ and X⁴ are ═

CH—

.

25. The compound of any of claims 1, wherein X² is —

N═

, and X¹, X³ and X⁴ are ═

CH—

.

26. The compound of any of claims 1, wherein X¹ is ═

CF—

, ═

CCl—

, ═

C(OCF₃)—

, ═

C(CH₃)—

or —

C(CH)═ and

X², X³ and X⁴ are ═

CH—

.

27. The compound of any of claims 1, wherein X² is ═

CF—

, ═

CCl—

, ═

C(OCF₃)—

, ═

C(CH₃)—

, —

C(CN)═

, —

C(CF₃)═

or —

C(CH)═ and

X¹, X³ and X⁴ are ═

CH—

or ═

C(CH₃)—

.

28. The compound of any of claims 1, wherein X² and X³ are ═

CH—

.

29. The compound of any of claims 1, wherein X³ and X⁴ are ═

CH—

.

30. The compound of any of claims 1, wherein X², X³ and X⁴ are ═

CH—

.

31. The compound of any of claims 1, wherein X¹, X² and X³ are ═

CH—

.

32. The compound of any of claims 1, wherein R² is selected from the group consisting of —

H, halogen, C_1-8alkyl, —

CN, C_1-6haloalkyl and C_1-6haloalkyoxy;

or any two adjacent R² substituents together with the atoms to which they are attached form a fused benzene ring, optionally substituted with a C_1-6alkyl.

33. The compound of claim 32, wherein R² is selected from the group consisting of —

H, —

Cl, —

F, —

CF₃, —

OCF₃, —

CH₃ and —

CN.

34. The compound of claim 32, wherein two adjacent R² substituents together with the atoms to which they are attached form a fused benzene ring, optionally substituted with a halogen or C_1-6alkyl.

35. The compound of any of claims 1, having Formula (IIa):

wherein Z is 2-thiazoly, 4-thiazolyl, 5-thiazolyl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-4-yl, 1,2,4-thiazol-3-yl or 1,2,4-thiazol-5-yl, each of which is optionally substituted with from 1-2 R³ substituents selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl; and

R⁴ is selected from the group consisting of —

H, —

OH, C_0-6alkylaryl, aryl-C_1-6alkyl, aryl-C_1-6alkoxy, C_3-6cycloalkyl-C_1-6alkoxy and C_1-6alkoxy, wherein the aryl group is optionally substituted with from 1-3 R^f substituents.

36. The compound of claim of claims 1, having Formula (IIb):

wherein Y is 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, pyridyl or 1,2,4-triazin-3-yl, each of which is optionally substituted with a member selected from the group consisting of —

H, C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl; and

Z is 2-thiazolyl or 3-isoxazolyl, each of which is optionally substituted with a member selected from the group consisting of —

H, —

OH, aryl, aryl-C_1-6alkyl, aryl-C_1-6alkoxy, C_3-6cycloalkyl-C_1-6alkoxy and C_1-6alkoxy.

37. The compound of any of claims 1, having Formula (IIc):

wherein Z is 2-thiazoly, 4-thiazolyl, 5-thiazolyl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-4-yl, 1,2,4-thiazol-3-yl or 1,2,4-thiazol-5-yl, each of which is optionally substituted with from 1-2 R⁵ substituents selected from the group consisting of —

H, C_1-8haloalkyl, —

CN, halogen, —

OH, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl;

R⁶ is —

H, aryl or C_1-6alkyl; and

X¹ and X² are each independently —

CH═

, —

C(CF₃)═

, ═

C(OH)—

or —

C(halo)=.

38. The compound of any of claims 1, wherein Z is selected from the group consisting of 2-thiazolyl and 3-isoxazolyl, each of which is optionally substituted with a member selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl; and

Y is selected from the group consisting of 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, imidazoly and 1,2,4-triazol-3-yl, each of which is optionally substituted with from 1-3 R^a groups, wherein any two adjacent R^a substituents together with the atoms to which they are attached optionally form a 5- or 6-membered carbocyclic ring, wherein one of the ring carbon atom is optionally replaced by a carbonyl and the carbocyclic ring is optionally substituted with 1-2 members independently selected from an halogen, aryl or C_1-8alkyl.

39. The compound of claim 38, wherein Z is 2-thiazolyl, optionally substituted with a member selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl.

40. The compound of claim 38, wherein the carbocyclic ring is a benzene ring, a cyclopentane ring or cyclohexane ring.

41. The compound of any of claims 1, having Formula (IId)

wherein Z is 2-thiazoly, 4-thiazolyl, 5-thiazolyl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-4-yl, 1,2,4-thiazol-3-yl or 1,2,4-thiazol-5-yl, each of which is optionally substituted with from 1-2 R⁷ substituents selected from the group consisting of C_1-8haloalkyl, —

CN, halogen, —

OH, C_3-7cycloalkyl, aryl, C_1-8alkyl, aryl-NH—

C_1-6alkyl and C_1-8alkoxy-C_1-4alkyl; and

m is an integer of from 0-3.

42. The compound of any of claims 1, having Formula (IIe):

wherein

Z is selected from the group consisting of pyridyl, pyridazinyl, primidinyl or pyrizinyl, each of which is optionally substituted with from 1-3 C_1-6alkyl;

X¹ or X² is —

CH═ and

the other is —

CF═

; and

the subscript p is an integer of 0-3.

43. The compound of any of claims 1, having Formula (IIf):

wherein Z is selected from the group consisting of, 1,2,3,-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-triazolyl and 1,3,4-oxadiazolyl; and

subscript q is an integer from 0-3.

44. The compound of claim 1, having Formula (IIg):

wherein X⁵ and X⁶ are each independently —

S(O)₂—

, —

C(O)—

or —

CHR²—

.

45. The compound of claim 1, having Formula (IIh):

wherein X⁵ and X⁶ are each independently —

S(O)₂—

, —

C(O)—

or —

CHR²—

.

46. The compound of claim 1, having Formula (IIi):

wherein X⁷, X⁸ and X⁹ are each independently CHR²—

, —

S(O)₂—

or —

C(O)—

.

47. The compound of claim 1, having Formula (IIj):

wherein X⁷, X⁸ and X⁹ are each independently CHR²—

, —

S(O)₂—

or —

C(O)—

.

48. The compound of any of claims 44, wherein X², X³ and X⁴ are each independently —

CR²═

.

49. The compound of claim 1, wherein the compound has inhibitory activity against a voltage-gated sodium channel.

50. A pharmaceutical formulation comprising:

a compound of any of claims 1 or and a pharmaceutically acceptable excipient.

52. A method of modulating activity of a sodium channel in a subject, said method comprising:

administering to said subject in need thereof an effective amount of a compound of any of claims 1 to modulate the activity of a sodium channel.

54. A method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn'"'"'s disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachy-arrhythmias, said method comprising:

administering to said subject in need thereof an effective amount of a compound of any of claims 1 to ameliorate or alleviate said condition.

56. The method according to claim 54, wherein said condition is pain, and said pain is a member selected from acute pain, chronic pain, visceral pain, inflammatory pain and neuropathic pain.

51. A pharmaceutical formulation comprising:

a compound selected from the group consisting of 4-(4-methylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

4-(4-(4-chlorophenyl)phthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

N-(thiazol-2-yl)-4-(4-p-tolylphthalazin-1-ylamino)benzenesulfonamide;

or 4-(4-phenylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide and a pharmaceutically acceptable excipient.

53. A method of modulating activity of a sodium channel in a subject, said method comprising:

administering to said subject in need thereof an effective amount of 4-(4-methylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

4-(4-(4-chlorophenyl)phthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

N-(thiazol-2-yl)-4-(4-p-tolylphthalazin-1-ylamino)benzenesulfonamide;

or 4-(4-phenylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide to modulate the activity of a sodium channel.

55. A method of ameliorating or alleviating a condition in a subject, wherein said condition is a member selected from pain, irritable bowel syndrome, Crohn'"'"'s disease, epilepsy, seizures, multiple sclerosis, bipolar depression and tachy-arrhythmias, said method comprising:

administering to said subject in need thereof an effective amount of 4-(4-methylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

4-(4-(4-chlorophenyl)phthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide;

N-(thiazol-2-yl)-4-(4-p-tolylphthalazin-1-ylamino)benzenesulfonamide;

or 4-(4-phenylphthalazin-1-ylamino)-N-(thiazol-2-yl)benzenesulfonamide to ameliorate or alleviate said condition.