Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

1. A method for the prophylaxis and/or treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

2. The method of claim 1 , wherein the nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is selected from the group consisting of Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and a combination thereof.

3. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 10 mg to about 160 mg.

4. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

5. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

6. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 10 mg.

7. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 20 mg.

8. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 40 mg.

9. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 80 mg.

10. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin is about 160 mg.

11. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered once a day, twice a day, three times a day, or four times a day.

12. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof.

13. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration.

14. The method of claim 1 , wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the subject's bedtime, or twice daily.

15. The method of claim 1 , wherein the subject is a human.

16. The method of claim 15 , wherein the human is an adult with a diagnosis of a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

17. The method of claim 15 , wherein the human has a concurrent diagnosis of visual hallucinations, and a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

18. The method of claim 15 , wherein the human has a diagnosis of probable Dementia with Lewy Bodies.

19. The method of claim 18 , wherein the diagnosis of probable Dementia with Lewy bodies is defined by the presence of dementia and at least one of:

at least two Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and

one Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and at least one Suggestive Criteria selected from REM Sleep Behavior Disorder, Severe Neuroleptic Sensitivity, Low Dopamine Transporter Uptake on DaT SPECT Imaging Scan; and any combination thereof.

20. The method of claim 15 , wherein the human has a diagnosis of Dementia with Lewy Bodies.

21. The method of claim 15 , wherein the human has a Mini Mental State Examination score of greater than, or equal to, about 18.

22. The method of claim 15 , wherein the human is an adult with a diagnosis of visual hallucinations associated with Dementia with Lewy Bodies.

23. The method of claim 15 , wherein the human is an adult aged 50-85 inclusive.

24. The method of claim 15 , wherein the human has experienced persistent visual hallucinations.

25. The method of claim 24 , wherein the presence of persistent hallucinations is defined by a score of four or greater on the hallucinations component of the Neuropsychiatric Inventory (NPI Item B) at screening.

26. The method of claim 15 , wherein the human has experienced visual hallucinations on at least five days in a week.

27. The method of claim 1 , wherein the subject is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof.

28. The method of claim 27 , wherein the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist and any combination thereof.

29. The method of claim 27 , wherein the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

30. The method of claim 29 , wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

31. The method of claim 29 , wherein the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

32. The method of claim 29 , wherein the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

33. The method of claim 27 , wherein the NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

34. The method of claim 33 , wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

35. The method of claim 27 , wherein the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

36. The method of claim 1 , wherein administration of the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in treatment, and/or prophylaxis of visual hallucinations.

37. The method of claim 1 , wherein treating or prophylaxis results in a decrease in the frequency, severity, or a combination thereof of visual hallucinations.

38. The method of claim 1 , wherein the subject has a score of three or greater on SAPS-H prior to administration of the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

39. The method of claim 1 , wherein treatment results in an improvement in the hallucinations component of the Scale for Assessment of Positive Symptoms (SAPS-H) after 22 days of treatment.

40. The method of claim 1 , wherein treatment results in an improvement in the hallucinations component of the Scale for Assessment of Positive Symptoms (SAPS-H) after 43 days of treatment.

41. The method of claim 1 , wherein treatment results in an improvement in the delusions component of the Scale for Assessment of Positive Symptoms (SAPS-D) after 22 days of treatment.

42. The method of claim 1 , wherein treatment results in an improvement in the delusions component of the Scale for Assessment of Positive Symptoms (SAPS-D) after 43 days of treatment.

43. The method of claim 1 , wherein treatment results in an improvement in investigator assessments of global function as measured by the change in the CGI-I and CGI-S scores after 22 days of treatment.

44. The method of claim 1 , wherein treatment results in an improvement in investigator assessments of global function as measured by the change in the CGI-I and CGI-S scores after 43 days of treatment.

45. The method of claim 1 , wherein treatment results in an improvement in caregiver burden as measured by the Zarit Caregiver Burden Score after 22 days of treatment.

46. The method of claim 1 , wherein treatment results in an improvement in caregiver burden as measured by the Zarit Caregiver Burden Score after 43 days of treatment.

47. The method of claim 1 , wherein treatment results in an improvement in subjective sleep quality as measured by change in the SCOPA-night and SCOPA day wake scores after 22 days of treatment.

48. The method of claim 1 , wherein treatment results in an improvement in subjective sleep quality as measured by change in the SCOPA-night and SCOPA day wake scores after 43 days of treatment.

49. The method of claim 1 , wherein treating or prophylaxis results in an improvement in the subject's Mini-Mental State Examination score, cognition, attention, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) rating, neuropsychiatric inventory (NPI), North-East Visual Hallucinations Interview (NEVHI), Cognitive Drug Research (CDR) computerized assessment system, Scale for the Assessment of Positive Symptoms (SAPS), Parkinson's Disease-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) scale, or any combination thereof.

50. The method of claim 1 , wherein treating or prophylaxis results in fluctuations in cognition, attention or a combination thereof.