Arylsulfonamides and uses related thereto

1. A compound having the formula:

or pharmaceutically acceptable salts or stereoisomers thereof, wherein:

R 1 is a member selected from the group consisting of —OH, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl;

R 2 and R 3 are members independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl and (C 3 -C 8 )cycloalkyl;

N cyc is a nitrogen heterocycle having a formula selected from the group consisting of formula (a), formula (c) and formula (d):

wherein:

R 2a , R 2a′ and R 5a are each H;

R 3a and R 4a are each members independently selected from the group consisting of H, halogen, —CN, —NO 2 , unsubstituted (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 14 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —C(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —OR″, —OC(O)R′, —NR′C(O)OR″, —S(O)R″, —SO 2 R″, —SO 2 N(R′) 2 , —N(R′) 2 , and —NR′C(O)R′; and optionally two adjacent R 3a , R 4a and R 5a members are combined to form a benzene or pyridine ring, fused to the remainder of N cyc ; and within formula (a), at least one of R 2a , R 2a′ , R 3a , R 4a and R 5a is other than H;

any fused benzene or pyridine ring portion of N cyc is optionally substituted with from one to four members selected from the group consisting of H, halogen, —CN, —NO 2 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 14 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′) 2 , —S(O)R″, —SO 2 R″, —SO 2 N(R′) 2 , —N(R′) 2 and —NR′C(O)R′;

each occurrence of R′ is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 14 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group;

each occurrence of R″ is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 14 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl.

2. A compound of claim 1 , wherein one of R 3a and R 4a is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )haloalkyl, (C 2 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 14 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl.

3. A compound of claim 1 , wherein R 4a and R 5a are combined to form a fused benzene ring.

4. A compound of claim 1 , wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of —OH, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 2 -C 4 )hydroxyalkyl and (C 3 -C 5 )cycloalkyl.

5. A compound of claim 4 , wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of —OH, (C 1 -C 4 )alkyl and (C 1 -C 4 )haloalkyl.

6. A compound of claim 5 , wherein R 1 is —OH, R 2 is —CH 3 and R 3 is CF 3 .

7. A compound of claim 5 , wherein each of R 1 , R 2 and R 3 is —CH 3 .

8. A compound of claim 5 , wherein R 1 is —OH, and R 2 and R 3 are each CF 3 .

9. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising the compound of claim 1 , and an additional therapeutic agent selected from the group consisting of insulin, insulin mimetics, insulin secretogues, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinone compounds, prandial glucose regulators, glucagon receptor antagonists, β3 adrenergic receptor agonists, leptin or derivatives thereof, neuropeptide Y antagonists, mazindol, cholesterol lowering agents, bile acid sequestrants, vitamin B 3 , vitamin B 6 , vitamin B 12 , fibric acid derivatives, probucol, nitroglycerin, inhibitors of cholesterol absorption, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors, squalene synthetase inhibitors, thrombolytic agents, heparin derivatives, hirudin derivatives, warfarin derivatives, β-blockers, β adrenergic agonists, angiotensin II antagonists, ACE inhibitors and vasodilators, PPAR agonists, DP antagonists, petrolatum, lanolin, keratolytic agents, vitamin D 3 derivatives, anthralin, etretinate, isotretinoin, cholinergic agonists, cholinesterase inhibitors, carbonic anhydrase inhibitors, non-selective adrenergic agonists, α 2 -selective adrenergic agonists, prostaglandin analogs, osmotic diuretics, corticosteroids, corticosteroid analogs, immunosuppressants, non-steroidal antiinflammatory agents (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, inhibitors of phosphodiesterase type IV (PDE-IV), opioid analgesics, hepatoprotective agents, and 5-aminosalicylic acid.

11. A compound selected from the group consisting of:

5-chloro-1-(4-tert-butylphenylsulfonyl)-2,3-dihydroindole,

3-(R)-1-(4-tert-butylphenylsulfonyl)-3-imidazol-1-yl)-pyrrolidine,

3-(R)-1-(4-tert-butylphenylsulfonyl)-3-methoxypyrrolidine, and

3-(R)-3-(piperidin-1-yl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-phenylsulfonyl)-pyrrolidine.