Aryl amides useful as inhibitors of voltage-gated sodium channels

1. A compound of formula III-A, III-B or III-C:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or

wherein ring A is optionally substituted with up to y occurrences of R 5 ;

R 1 is C 1-6 aliphatic, wherein up to two carbon atoms other than the atom attached to the nitrogen or oxygen atom is optionally replaced with O, S, NR N , or C(O);

each R 2 is independently hydrogen, or C 1-6 aliphatic, wherein up to two carbon atoms other than the atom attached to the nitrogen or oxygen atom is optionally replaced with O, S, NR N , or C(O);

y is 0-4;

each occurrence of R N is independently selected from hydrogen or a C 1-6 aliphatic group;

R 3 is hydrogen, halogen, CN, CF 3 , NO 2 , or an optionally substituted group selected from C 1-6 aliphatic, C 1-6 cycloaliphatic, C 6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —C(O)R′, —COOR′, —NRCOR′, —CON(R′) 2 , —S(O) 2 R′, or —S(O) 2 N(R′) 2 ;

each occurrence of R 5 is independently selected from hydrogen, halogen, CN, NO 2 , or an optionally substituted group selected from C 1-4 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NRCOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 ;

each occurrence of R is independently selected from hydrogen or a C 1-6 aliphatic group;

each occurrence of R′ is independently selected from hydrogen or a C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; and

provided that the following compounds are excluded:

2-(4-methoxy-phenoxy)-5-nitro-N-(3-sulfamoyl-phenyl)-benzamide;

Benzamide, N-[3-(methylsulfonyl)phenyl]-2-phenoxy-;

Benzamide, N-[3-[(dimethylamino)sulfonyl]-4-methylphenyl]-2-phenoxy-;

Benzamide, N-[5-[(diethylamino)sulfonyl]-2-methoxyphenyl]-2-phenoxy-

Benzamide, N-[3-[(dimethylamino)sulfonyl]phenyl]-2-phenoxy-;

Benzamide, N-[5-[(dimethylamino)sulfonyl]-2-methoxyphenyl]-2-phenoxy-;

Benzamide, N-[3-(aminosulfonyl)phenyl]-2-(4-methoxyphenoxy)-5-nitro-;

Benzamide, N-[2-chloro-5-(methylsulfonyl)phenyl]-2-phenoxy-; and

Benzamide, N-[5-[(1-ethylpropyl)sulfonyl]-2-methoxyphenyl]-2-phenoxy-.

2. The compound according to claim 1 , wherein ring A is optionally substituted phenyl.

3. The compound according to claim 1 , wherein ring A is

4. The compound according to claim 1 , wherein R 3 is methyl, ethyl, propyl, isopropyl, t-butyl, or sec-butyl.

5. The compound according to claim 1 , wherein y is 1-3, and each R 5 is independently selected from Cl, Br, F, CF 3 , methyl, ethyl, CN, —COOH, —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CONH 2 , —COOCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or an optionally substituted group selected from C 1-4 -alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

6. The compound according to Formula III-B of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

7. The compound according to Formula III-C of claim 1 , wherein both R 2 are hydrogen.

8. The compound according to Formula III-A of claim 1 , wherein R 1 is C 1 -C 6 alkyl and R 2 is hydrogen or C 1 -C 6 alkyl.

9. A compound selected from:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

or

19.

10. A method of modulating a sodium channel comprising the step of contacting said channel with a compound of formula III-A, III-B or III-C:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or

wherein ring A is optionally substituted with up to y occurrences of R 5 ;

R 1 is C 1-6 aliphatic, wherein up to two carbon atoms other than the atom attached to the nitrogen or oxygen atom is optionally replaced with O, S, NR N , or C(O);

each R 2 is independently hydrogen, or C 1-6 aliphatic, wherein up to two carbon atoms other than the atom attached to the nitrogen or oxygen atom is optionally replaced with O, S, NR N , or C(O);

y is 0-4;

each occurrence of R N is independently selected from hydrogen or a C 1-6 aliphatic group;

R 3 is hydrogen, halogen, CN, CF 3 , NO 2 , or an optionally substituted group selected from C 1-6 aliphatic, C 1-6 cycloaliphatic, C 6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —C(O)R′, —COOR′, —NRCOR′, —CON(R′) 2 , —S(O) 2 R′, or —S(O) 2 N(R′) 2 ;

each occurrence of R 5 is independently selected from hydrogen, halogen, CN, NO 2 , or an optionally substituted group selected from C 1-4 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NRCOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 ;

each occurrence of R is independently selected from hydrogen or a C 1-6 aliphatic group;

each occurrence of R′ is independently selected from hydrogen or a C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms.

11. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

12. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable composition comprising a compound to said subject in need thereof.