SUMMARY

The present invention relates to certain diaryl and arylheteroaryl urea derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2Aserotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations. In some embodiments the hallucinations may be associated with a neurodegenerative disease. In some embodiments, the hallucinations may be associated with Lewy Body dementia. In some embodiments, the hallucinations are visual hallucinations.

One aspect of the present invention encompasses certain diaryl and arylheteroaryl urea derivatives as shown in Formula I:


or a pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein:
i) R1is aryl or heteroaryl each optionally substituted with R9, R10, R11, R12, R13, R14, and R15each selected independently from the group consisting of C1-6acyl, C1-6acyloxy, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylureyl, amino, C1-6alkylamino, C2-8dialkylamino, C1-6alkylimino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, C2-8dialkylsulfonamide, halogen, C1-6haloalkoxy, C1-6haloalkyl, C1-6haloalkylsulfinyl, C1-6haloalkylsulfonyl, C1-6haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent R9, R10, R11, R12, R13, R14, and R15together with the atoms to which they are attached form a C5-7cycloalkyl group or heterocyclic group each optionally substituted with F, Cl, or Br; and wherein said C2-6alkenyl, C1-6alkyl, C2-6alkynyl, C1-6alkylamino, C1-6alkylimino, C2-8dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C1-6acyl, C1-6acyloxy, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylureyl, amino, C1-6alkylamino, C2-8dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, halogen, C1-6haloalkoxy, C1-6haloalkyl, C1-6haloalkylsulfinyl, C1-6haloalkylsulfonyl, C1-6haloalkylthio, hydroxyl, thiol and nitro;
ii) R2is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-7cycloalkyl;
iii) R3is selected from the group consisting of H, C2-6alkenyl, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C2-6alkenyl, C1-6alkyl, C2-6alkynyl, C1-6alkylsulfonamide, C3-7cycloalkyl, heteroaryl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C1-5acyl, C1-5acyloxy, C2-6alkenyl, C1-4alkoxy, C1-8alkyl, C1-6alkylamino, C2-8dialkylamino, C1-4alkylcarboxamide, C2-6alkynyl, C1-4alkylsulfonamide, C1-4alkylsulfinyl, C1-4alkylsulfonyl, C1-4alkylthio, C1-4alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6cycloalkyl, C2-6dialkylcarboxamide, halogen, C1-4haloalkoxy, C1-4haloalkyl, C1-4haloalkylsulfinyl, C1-4haloalkylsulfonyl, C1-4haloalkylthio, hydroxyl, nitro and sulfonamide;
iv) R4is selected from the group consisting of H, C1-6acyl, C1-6acyloxy, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylureyl, amino, C1-6alkylamino, C2-8dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, C2-8dialkylsulfonamide, halogen, C1-6haloalkoxy, C1-6haloalkyl, C1-6haloalkylsulfinyl, C1-6haloalkylsulfonyl, C1-6haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;
v) R5is selected from the group consisting of C1-6acyl, C1-6acyloxy, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylureyl, amino, C1-6alkylamino, C2-8dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, C2-8dialkylsulfonamide, halogen, C1-6haloalkoxy, C1-6haloalkyl, C1-6haloalkylsulfinyl, C1-6haloalkylsulfonyl, C1-6haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, wherein said C1-6alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C1-5acyl, C1-5acyloxy, C2-6alkenyl, C1-4alkoxy, C1-8alkyl, amino, C1-6alkylamino, C2-8dialkylamino, C1-4alkylcarboxamide, C2-6alkynyl, C1-4alkylsulfonamide, C1-4alkylsulfinyl, C1-4alkylsulfonyl, C1-4alkylthio, C1-4alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6cycloalkyl, C2-6dialkylcarboxamide, halogen, C1-4haloalkoxy, C1-4haloalkyl, C1-4haloalkylsulfinyl, C1-4haloalkylsulfonyl, C1-4haloalkylthio, hydroxyl, nitro and phenyl; and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C1-6-alkoxy;
vi) R6a, R6b, and R6care each independently selected from the group consisting of H, C1-6acyl, C1-6acyloxy, C2-6alkenyl, C1-6alkoxy, C1-6alkyl, C1-6alkylcarboxamide, C2-6alkynyl, C1-6alkylsulfonamide, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkylthio, C1-6alkylureyl, amino, C1-6alkylamino, C2-8dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7cycloalkyl, C2-8dialkylcarboxamide, C2-8dialkylsulfonamide, halogen, C1-6haloalkoxy, C1-6haloalkyl, C1-6haloalkylsulfinyl, C1-6haloalkylsulfonyl, C1-6haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;
vii) R7and R8are independently H or C1-8alkyl;
viii) X is O or S; and
ix) Q is C1-3alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C1-3alkyl, C1-4alkoxy, carboxy, cyano, C1-3haloalkyl, halogen and oxo; or Q is a bond.

One aspect of the present invention encompasses pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention encompasses methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations, associated with a neurodegenerative disease in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a 5-HT2Ainverse agonist. One aspect of the present invention encompasses methods for the prophylaxis and/or treatment of hallucinations associated with Lewy Body dementia in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a 5-HT2Ainverse agonist. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations.

One aspect of the present invention encompasses methods for the prophylaxis and/or treatment of visual hallucinations associated with a neurodegenerative disease in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a 5-HT2Ainverse agonist. One aspect of the present invention encompasses methods for the prophylaxis and/or treatment of visual hallucinations associated with Lewy Body dementia in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a 5-HT2Ainverse agonist.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a 5-HT2Ainverse agonist. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations.

Some embodiments are directed to methods 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 a 5-HT2Ainverse agonist.

In some embodiments, the 5-HT2Ainverse agonist is selected from nelotanserin, pimavanserin, pruvanserin, eplivanserin, volinanserin, glemanserin, ketanserin, ritanserin, clozapine, or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the 5-HT2Ainverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the therapeutically effective amount of nelotanserin is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 10 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 20 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 40 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 80 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 160 mg. In some embodiments, the therapeutically effective amount of the 5-HT2Ainverse agonist is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the 5-HT2Ainverse agonist is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the 5-HT2Ainverse agonist is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration. In some embodiments, the therapeutically effective amount of the 5-HT2Ainverse agonist 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.

In some embodiments, the subject is a human. In some embodiments, 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. In some embodiments, the human has a concurrent diagnosis of 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. In some embodiments, 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. In some embodiments, the human has a diagnosis of probable Dementia with Lewy Bodies. In some embodiments, the diagnosis of probable DLB 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. In some embodiments, the human has a diagnosis of Dementia with Lewy Bodies. In some embodiments, the human has a Mini Mental State Examination score of greater than, or equal to, about 18. In some embodiments, the human is an adult with a diagnosis of visual hallucinations associated with Dementia with Lewy Bodies. In some embodiments, the human is an adult aged 50-85 inclusive. In some embodiments, the human has experienced persistent visual hallucinations. In some embodiments, 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. In some embodiments, the human has experienced visual hallucinations on at least five days in a week.

In some embodiments, 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. In some embodiments, the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof. In some embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

In some embodiments, administration of a therapeutically effective amount of a 5-HT2Ainverse agonist results in treatment, and/or prophylaxis of neuropsychiatric symptoms such as, but not limited to hallucinations. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, administration of a therapeutically effective amount of a 5-HT2Ainverse agonist results in treatment, and/or prophylaxis of visual hallucinations. In some embodiments, treating or prophylaxis results in a decrease in the frequency, severity, or a combination thereof of visual hallucinations. In some embodiments, the subject has a score of three or greater on SAPS-H prior to administration of a therapeutically effective amount of a 5-HT2Ainverse agonist. In some embodiments, treatment results in an improvement in the hallucinations component of the Scale for Assessment of Positive Symptoms (SAPS-H) after 22 days of treatment. In some embodiments, treatment results in an improvement in the hallucinations component of the Scale for Assessment of Positive Symptoms (SAPS-H) after 43 days of treatment. In some embodiments, treatment results in an improvement in the delusions component of the Scale for Assessment of Positive Symptoms (SAPS-D) after 22 days of treatment. In some embodiments, treatment results in an improvement in the delusions component of the Scale for Assessment of Positive Symptoms (SAPS-D) after 43 days of treatment. In some embodiments, 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. In some embodiments, 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. In some embodiments, treatment results in an improvement in caregiver burden as measured by the Zarit Caregiver Burden Score after 22 days of treatment. In some embodiments, treatment results in an improvement in caregiver burden as measured by the Zarit Caregiver Burden Score after 43 days of treatment. In some embodiments, 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. In some embodiments, 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. In some embodiments, treating or prophylaxis results in a decrease in the severity, frequency, or a combination thereof, of visual hallucinations. In some embodiments, treating or prophylaxis results in an improvement in the subject's Mini-Mental State Examination score.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations associated with Lewy Body Dementia, in a subject in need thereof comprising administering to said subject a daily dose of about 40 mg of nelotanserin. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the subject has a concurrent diagnosis of 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of visual hallucinations associated with Lewy Body Dementia, in a subject in need thereof comprising administering to said subject a daily dose of about 40 mg of nelotanserin. In some embodiments, the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the subject 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 40 mg of nelotanserin. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject has a concurrent diagnosis of 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 40 mg of nelotanserin. In some embodiments, the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 80 mg of nelotanserin. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the daily dose of about 80 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject has a concurrent diagnosis of 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 80 mg of nelotanserin. In some embodiments, the daily dose of about 80 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject 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, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 160 mg of nelotanserin. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the daily dose of about 160 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject has a concurrent diagnosis of 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a daily oral dose of about 160 mg of nelotanserin. In some embodiments, the daily dose of about 160 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day. In some embodiments, the subject 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of neuropsychiatric symptoms such as, but not limited to hallucinations in a subject in need thereof comprising administering to said subject a dose of about 40 mg of nelotanserin for a first time period followed by administering to said subject a dose of about 80 mg of nelotanserin for a second time period. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the subject is a human 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of visual hallucinations in a subject in need thereof comprising administering to said subject a dose of about 40 mg of nelotanserin for a first time period followed by administering to said subject a dose of about 80 mg of nelotanserin for a second time period. In some embodiments, the subject is a human 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.

Some embodiments are directed to methods for the prophylaxis and/or treatment of dementia with Lewy Bodies in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a 5-HT2Ainverse agonist. In some embodiments, the 5-HT2Ainverse agonist is selected from nelotanserin, pimavanserin, pruvanserin, eplivanserin, volinanserin, glemanserin, ketanserin, ritanserin, clozapine, or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the 5-HT2Ainverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, 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. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from 10 mg to about 160 mg. In some embodiments, 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. In some embodiments, the therapeutically effective amount of nelotanserin is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 10 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 20 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 40 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 80 mg. In some embodiments, the therapeutically effective amount of nelotanserin is about 160 mg. In some embodiments, the therapeutically effective amount of the 5-HT2Ainverse agonist is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the 5-HT2Ainverse agonist is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the 5-HT2Ainverse agonist is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration. In some embodiments, the therapeutically effective amount of the 5-HT2Ainverse agonist 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.

In some embodiments, the subject is a human. In some embodiments, 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. In some embodiments, the human has a concurrent diagnosis of neuropsychiatric symptoms such as, but not limited to 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. In some embodiments, hallucinations are visual hallucinations. In some embodiments, the human has a concurrent diagnosis of 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. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, 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. In some embodiments, the human has a diagnosis of probable Dementia with Lewy Bodies. In some embodiments, 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. In some embodiments, the human has a diagnosis of Dementia with Lewy Bodies. In some embodiments, the human has a Mini Mental State Examination score of greater than, or equal to, about 18. In some embodiments, the human is an adult with a diagnosis of visual hallucinations associated with Dementia with Lewy Bodies. In some embodiments, the human is an adult aged 50-85 inclusive. In some embodiments, the human has experienced persistent visual hallucinations. In some embodiments, 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. In some embodiments, the human has experienced hallucinations on at least five days in a week. In some embodiments, the human has experienced visual hallucinations on at least five days in a week.

In some embodiments, 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, an NMDA receptor antagonist, and a combination thereof. In some embodiments, the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof. In some embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

In some embodiments, administration of a therapeutically effective amount of a 5-HT2Ainverse agonist results in treatment, and/or prophylaxis of Lewy Body Dementia or the symptoms thereof in a subject experiencing neuropsychiatric symptoms such as, but not limited to hallucinations. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof. In some embodiments, hallucinations are visual hallucinations. In some embodiments, administration of a therapeutically effective amount of a 5-HT2Ainverse agonist results in treatment, and/or prophylaxis of Lewy Body Dementia or the symptoms thereof in a subject experiencing visual hallucinations. In some embodiments, 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. In some embodiments, treating or prophylaxis results in fluctuations in cognition, attention or a combination thereof.

These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.

