ARYLSULFONYLPYROLECARBOXAMIDE DERIVATIVES AS Kv3 POTASSIUM CHANNEL ACTIVATORS

• US 20200131156A1
• Filed: 10/29/2019
• Published: 04/30/2020
• Est. Priority Date: 10/30/2018
• Status: Abandoned Application

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: SAMS, Anette Graven, RASMUSSEN, Lars Kyhn, YU, Wanwan, FLEMING, Paul Robert
• Application Number:
  US16/667,563
• Publication Number:
  US 20200131156A1
• Time in Patent Office: Days
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• 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
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention provides novel compounds which activate the Kv3 potassium channels. The compounds have the structure

Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and use of the compounds to treat disorders responsive to the activation of Kv3 potassium channels.

Claims

1. A compound of Formula I

2. The compound according to claim 1, wherein R₁ is selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, and methoxy.

3. The compound according to claim 1, wherein R₂ and R₆ are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methoxy, and methyl.

4. The compound according to claim 1, wherein R₃ is selected from the group consisting of hydrogen and methyl.

5. The compound according to claim 1, wherein R₄ and R₅ are independently selected from the group consisting of hydrogen, methyl, and fluorine.

6. The compound according to claim 1, wherein R₇ is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy, and methylamino.

7. The compound according to claim 1, wherein HetAr is selected from the group consisting of pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyridyl, oxadiazolyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, thiadiazolyl, and imidazopyrimidinyl.

8. The compound according to claim 1, wherein Y is oxygen.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of

N-[(5-methylpyrimidin-2-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(2-methylpyrimidin-5-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(6-methylpyridazin-3-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

1-(2-fluorophenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(3-fluorophenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-fluorophenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-methoxyphenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

4-methyl-N-[(5-methylpyrazin-2-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

1-(p-tolylsulfonyl)-N-(2-pyridylmethyl)pyrrole-3-carboxamide,

N-[(3-methoxy-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(3-fluoro-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(4-fluoro-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-fluoro-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

1-(p-tolylsulfonyl)-N-(3-pyridylmethyl)pyrrole-3-carboxamide,

N-[(6-methyl-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(4-methyl-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(3-methyl-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methoxy-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(4-methoxy-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-(imidazo[1,2-a]pyrimidin-6-ylmethyl)-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methylpyrazin-2-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(6-methyl-3-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methyl-2-pyridyl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methylpyrazin-2-yl)methyl]-1-(o-tolylsulfonyl)pyrrole-3-carboxamide,

1-(p-tolylsulfonyl)-N-(pyrazin-2-ylmethyl)pyrrole-3-carboxamide,

N-[(5-methylpyrazin-2-yl)methyl]-1-(m-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methylisoxazol-3-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methyl oxazol-2-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(4-methylthiazol-2-yl)methyl]-1-(p-tolyl sulfonyl)pyrrole-3-carboxamide,

N-[(3-methylisoxazol-5-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(1-methylpyrazol-3-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(1-methylpyrazol-4-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(2-methyloxazol-5-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(5-methylthiazol-2-yl)methyl]-1-(p-tolyl sulfonyl)pyrrole-3-carboxamide,

N-[(1-methylimidazol-4-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(1-methyltriazol-4-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1-(p-tolylsulfonyl)pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(2-methyl-1,3-oxazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(benzenesulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3-thiazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3-oxazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3-thiazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,2-oxazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,2-oxazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3-oxazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,2-thiazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3,4-thiadiazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,2,4-oxadiazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(pyrimidin-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-fluorobenzene-1-sulfonyl)-N-[(pyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(3-methylbenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(3-methylbenzene-1-sulfonyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(3-methylbenzene-1-sulfonyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-fluorobenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-fluorobenzene-1-sulfonyl)-N-[(pyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-fluorobenzene-1-sulfonyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(pyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(5-methylpyridin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methoxybenzene-1-sulfonyl)-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(5-methylpyridin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-methylbenzene-1-sulfonyl)-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-chlorobenzene-1-sulfonyl)-N-[(pyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(benzenesulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(benzenesulfonyl)-N-[(5-methylpyridin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(benzenesulfonyl)-N-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-fluorobenzene-1-sulfonyl)-N-[(6-methylpyridin-3-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(1,3-oxazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

5-fluoro-1-(4-methylbenzene-1-sulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

2-fluoro-1-(4-methylbenzene-1-sulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

N-[(5-chloropyrazin-2-yl)methyl]-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrole-3-carboxamide,

1-(4-fluoro-2-methylbenzene-1-sulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

N-[(5-methylpyrazin-2-yl)methyl]-1-[4-(trifluoromethyl)benzene-1-sulfonyl]-1H-pyrrole-3-carboxamide,

1-(3-chloro-4-fluorobenzene-1-sulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-[4-(difluoromethyl)benzene-1-sulfonyl]-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carbothioamide,

1-(2-fluoro-4-methyl-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methylpyrrole-3-carboxamide,

1-(2-fluoro-4-methoxy-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(3-fluoro-4-methoxy-phenyl)sulfonyl-N-(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-methoxy-2-methyl-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-fluoro-2,6-dimethyl-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-fluoro-3,5-dimethyl-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(4-fluoro-3-methyl-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(2,3-dihydrobenzofuran-5-ylsulfonyl)-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

N-[(5-methylpyrazin-2-yl)methyl]-1-(2,4,6-trimethylphenyl)sulfonyl-pyrrole-3-carboxamide,

1-(2-chloro-4-methoxy-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(2-bromo-4-methoxy-phenyl)sulfonyl-N-[(5-methylpyrazin-2-yl)methyl]pyrrole-3-carboxamide,

1-(2-fluoro-4-m ethylbenzene-1-sulfonyl)-N-{[5-(methylamino)pyrazin-2-yl]methyl}-1H-pyrrole-3-carboxamide,

1-[4-(difluoromethoxy)benzene-1-sulfonyl]-N-{[5-methylamino)pyran-2-yl]methyl}-1H-pyrrole-3-carboxamide,

1-(2-fluoro-4-methylbenzene-1-sulfonyl)-N-[(2-methylpyrimidin-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(2-methyl-2H-1,2,3-triazol-4-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-fluoro-4-methylbenzene-1-sulfonyl)-N-[(2-methoxypyrimidin-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(benzenesulfonyl)-N-[(3,5-dimethylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-[4-(difluoromethoxy)benzene-1-sulfonyl]-N-[(2-methoxypyrimidin-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-benzenesulfonyl)-N-[(3-chloro-5-methylpyrazin-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(2-methyl-1,3-thiazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(4-methylbenzene-1-sulfonyl)-N-[(3-methyl-1H-pyrazol-5-yl)methyl]-1H-pyrrole-3-carboxamide,

1-(2-chloro-4-methoxybenzene-1-sulfonyl)-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrrole-3-carboxamide, and

1-(2-chloro-4-methoxybenzene-1-sulfonyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1H-pyrrole-3-carboxamide.

10. A pharmaceutical composition comprising the compound according to claim 1 and one or more pharmaceutically acceptable excipients.

13. A method for the treatment of a neurological or psychiatric disorder comprising the administration of a therapeutically effective amount of the compound according to claim 1, or the pharmaceutical composition of claim 10, to a patient in need thereof.

15. The method of claim 13, wherein the neurological or psychiatric disorder is selected from the group consisting of epilepsy, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive impairment associated with schizophrenia (CIAS), autism spectrum disorder, bipolar disorder, attention deficit hyperactivity disorder (ADHD), anxiety-related disorders, depression, cognitive dysfunction, Alzheimer'"'"'s disease, fragile X syndrome, chronic pain, hearing loss, sleep and circadian disorders, sleep disruption and movement disorders, Huntington'"'"'s disease, L-dopa-induced dyskinesia, obsessive-compulsive disorders, and Tourette'"'"'s syndrome.

18. The method of claim 15, wherein the schizophrenia is of the paranoid, disorganized, catatonic, undifferentiated, or residual type.

19. The method of claim 15, wherein the schizoaffective disorder is of the delusional or depressive type.

20. The compound of claim 1, wherein

R₁ is hydrogen, methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, or methoxy;

R₂ and R₆ are independently hydrogen, fluorine, chlorine, bromine, methoxy, or methyl;

R₃ is hydrogen or methyl;

R₄ and R₅ are independently hydrogen, methyl or fluorine;

R₇ is hydrogen, chlorine, fluorine, methyl, methoxy or methylamino;

HetAr is pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyridyl, oxadiazolyl, isoxazolyl, oxazolyl, thiazolyl, imadozolyl, triazolyl, thiadiazolyl, or imidazopyrimidinyl; and

Y is oxygen.

11. (canceled)

12. (canceled)

14. (canceled)

16. (canceled)

17. (canceled)