Sulfonyl Substituted 1H-Indoles as Ligands for the 5-Hydroxytryptamine Receptors

Abstract

The present invention is directed to compounds of Formula I:

Description

Claims

1. A compound of Formula I:

2. The compound of claim 1 wherein A is C2-5 alkylene.

3. The compound of claim 1 wherein A is ethan-1,2-diyl or propan-1,3-diyl.

4. The compound of claim 1 wherein R1 is aryl substituted with 1, 2, 3, or 4 independently selected R1a groups.

5. The compound of claim 1 wherein R1 is phenyl substituted with 1, 2, 3, or 4 independently selected R1a groups.

6. The compound of claim 1 wherein R1 is phenyl or 3-fluorophenyl.

7. The compound of claim 1 wherein R1 is phenyl.

8. The compound of claim 1 wherein each R2 is, independently, a bond.

9. The compound of claim 1 wherein R3 is H, C1-6 alkyl, or aryl.

10. The compound of claim 1 wherein R3 is H, methyl, ethyl, or phenyl.

11. The compound of claim 1 wherein R4 is H.

12. The compound of claim 1 wherein: R5 is H, C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl is substituted with 1, 2, 3, or 4 independently selected R5a groups; andR6 is H, C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl is substituted with 1, 2, 3, or 4 independently selected R6a groups.

13. The compound of claim 1 wherein R5 and R6 are each, independently, H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl.

14. The compound of claim 1 wherein R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocycloalkyl ring or 5-, 6-, 7- or 8-membered heteroaryl ring, wherein said heterocycloalkyl ring and said heteroaryl ring are each optionally substituted with 1, 2, 3, or 4 independently selected R8 groups.

15. The compound of claim 1 wherein R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R8 groups.

16. The compound of claim 1 wherein R5 and R6, together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl, or azetidin-1-yl ring.

17. The compound of claim 1 wherein each R7 is H.

18. The compound of claim 1 wherein: A is C2-5 alkylene which is optionally substituted with 1, 2, 3, or 4 independently selected RA groups;R1 is C1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein each is optionally substituted by 1, 2, 3, or 4 R1a;each R2 is, independently, a bond;R3 is H, C1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R3a groups;R4 is H, C1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R4a groups;R5 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;R6 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R6a groups;or R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring or 5-, 6-, 7- or 8-membered heteroaryl ring, wherein said heterocycloalkyl ring and said heteroaryl ring are each optionally substituted with 1, 2, 3, or 4 independently selected R8 groups; andeach R7 is, independently, H, halogen, C1-6 alkyl, cycloalkyl, aryl, or heteroaryl, wherein said C1-6 alkyl, cycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R7a groups.

19. The compound of claim 1 wherein: A is C2-5 alkylene;R1 is aryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R1a groups;each R2 is, independently, a bond;R3 is H, C1-6 alkyl, or aryl, wherein said C1-6 alkyl and aryl are each optionally substituted by 1, 2, 3, or 4 independently selected R3a groups;R4 is H;R5 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;R6 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R6a groups;or R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R8 groups; andeach R7 is, independently, H.

20. The compound of claim 1 wherein: A is ethan-1,2-diyl or propan-1,3-diyl;R1 is phenyl, which is optionally substituted by 1, 2, 3, or 4 independently selected R1a groups;each R2 is, independently, a bond;R3 is H, C1-6alkyl, or phenyl;R4 is H;R5 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;R6 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R6a groups;or R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R8 groups;each R7 is, independently, H;each R1a is, independently, halogen;each R5a is, independently, OR5b or NR5eR5f;each R6a is, independently, OR6b or NR6eR6f;each R8 is, independently, C1-6 alkyl.

21. The compound of claim 1 wherein: A is ethan-1,2-diyl or propan-1,3-diyl;R1 is phenyl, which is optionally substituted by 1, 2, 3, or 4 independently selected R1a groups;each R2 is, independently, a bond;R3 is H, methyl, ethyl, or phenyl;R4 is H;R5 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5a groups;R6 is H, C1-10 alkyl, cycloalkyl, aryl, heterocycloalkylalkyl, or arylalkyl, wherein said C1-10 alkyl, cycloalkyl, heterocycloalkylalkyl, and arylalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R6a groups;or R5 and R6, together with the N atom to which they are attached, form a 3-, 4-, 5-, 6- 7- or 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is optionally substituted with 1, 2, 3, or 4 independently selected R8 groups;each R7 is, independently, H;each R1a is, independently, F;each R5a is, independently, OH or N(CH3)2;each R6a is, independently, OH or N(CH3)2;each R8 is, independently, methyl; andp is 0 or 1.

22. The compound of claim 1 wherein: A is ethan-1,2-diyl or propan-1,3-diyl;R1 is phenyl or 3-fluorophenyl;R3 is H, methyl, ethyl or phenyl;R4 is H;R5 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl, wherein said ethyl is optionally substituted with 1 R5a;R6 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl, wherein said propyl is optionally substituted with 1 R6a;or R5 and R6, together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl, or azetidin-1-yl ring;each R5a is, independently, OH;each R6a is, independently, N(CH3)2; andp is 0.

23. The compound of claim 1 wherein: A is ethan-1,2-diyl or propan-1,3-diyl;R1 is phenyl or 3-fluorophenyl;R3 is H, methyl, ethyl or phenyl;R4 is H;R5 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl.R6 is H, methyl, ethyl, propyl, isopropyl, isobutyl, pentan-3-yl, 1,2,2-trimethylpropyl, 2,2-dimethylpropyl, 2-methyl-1-butyl, 2-hydroxyethyl, dimethylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or (tetrahydrofur-2-yl)methyl.or R5 and R6, together with the N atom to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 2-methylpyrrolidin-1-yl, azepan-1-yl, 4-methylpiperazin-1-yl, or azetidin-1-yl ring; andp is 0.

24. A compound of claim 1 having Formula I-A:

25. The compound of claim 1 having Formula I-B:

26. The compound of claim 1 having Formula I-C:

27. The compound of claim 1 having Formula I-D:

28. The compound of claim 1 which is:

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or pharmaceutically acceptable salt thereof.

30. A method of treating disorders that are related to or affected by norepinephrine reuptake inhibition, the 5-HT6 receptor, or the 5-HT2A receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.

31. A method of treating a learning disorder, cognitive disorder, memory disorder, personality disorder, behaviorial disorder, movement disorder, neurodegenerative disorder, drug withdrawal, sleep disorder, eating disorder, acute drug toxicity, cardiovascular disorder, sexual dysfunction, gastronintestinal disorder, genitourinary disorder, pain disorder, nerve disorder, or vasomotor symptom disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.

32. A method of treating Alzheimer's disease, attention deficit disorder, schizophrenia, Parkinson's disease, tardive dyskinesia, ataxia, bradykinesia, paroxysmal dyskinesias, restless leg syndrome, tremor, essential tremor, epilepsy, stroke, or head trauma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.

33. A method of treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, atrial fibrillation, platelet aggregation, risk of blood clot formation, irritable bowel syndrome, chronic constipation, gastroesophageal reflux disease, dyspepsia, stress urinary incontinence, or urge urinary incontinence comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.

34. A method of treating depression, obsessive compulsive disorder, suicidality, anxiety disorder, bipolar disorder, panic disorder, nicotine withdrawal, alcohol withdrawal, cocaine withdrawal, heroin withdrawal, amphetamine withdrawal, narcotic drug withdrawal insomnia, sleep apnea, narcolepsy, seasonal affective disorder, restless leg syndrome, shift work sleep disorder, delayed sleep phase syndrome, anorexia nervosa, bulimia nervosa, night eating syndrome, compulsive overeating, chronic fatigue syndrome, fibromyalgia, pain neuropathy, antinociceptive pain, chronic pain syndrome, diabetic neuropathy, hot flushes or night sweats, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof.