WO2019220139A1

WO2019220139A1 - Ketamine derivatives to treat neurological or psychological disorders

Info

Publication number: WO2019220139A1
Application number: PCT/GB2019/051373
Authority: WO
Inventors: Peter RANDS; Marie LAYZELL; Richard MYERSON; Trevor ROBBINS; Benjamin Phillips; Tiffanie BENWAY; Zelah JOEL; Ellen James
Original assignee: Small Pharma Ltd
Priority date: 2018-05-18
Filing date: 2019-05-17
Publication date: 2019-11-21
Also published as: GB201808150D0; WO2019220138A1

Abstract

The present invention describes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human; wherein n is 0, 1, 2, 3, 4 or 5, R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C₁-C₄ alkyl, each R³ is independently selected from OH, 0-(C₁-C₄ alkyl), F, Cl, Br, I, and -CF₃, X is selected from CR⁷ and CHR⁷, R⁷ is selected from H, OH, C₁-C₄ alkyl, O-(C₁-C₄ alkyl), benzyl, O(C=O)-R⁸, O(C=O)O-R⁸, O(C=O)NR⁸R⁹, OSO₂R⁸, OSO₃R⁸, OPO₃R⁸ wherein R⁸ is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₆-C₁₀ aryl, C₆-C₁₀ heteroaryl, and R⁹ is selected from H and C1-C₄ alkyl, wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷. In particular, compounds of Formula (I) are useful for treating disorders selected from neurocognitive, neurodevelopmental, and neuropsychiatric disorders, and have specific applications in increasing motivation, and for decreasing apathy.

Description

KETAMINE DERIVATIVES TO TREAT NEUROLOGICAL OR PSYCHOLOGICAL DISORDERS

FIELD OF THE INVENTION

The present invention describes a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;

I

wherein n is 0, 1, 2, 3, 4 or 5,

R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and Ci-C₄ alkyl, each R³ is independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, and -CF₃,

X is selected from CR⁷ and CHR⁷,

R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸,

0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C1-C4 alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷.

In particular, compounds of Formula I are useful for treating disorders selected from neurocognitive, neurodevelopmental, and neuropsychiatric disorders, and have specific applications in increasing motivation, and for decreasing apathy.

BACKGROUND TO THE INVENTION

The role of cognitive deficits in neurological and psychological disorders is a developing area of interest, and have particular relevance in disorders of motivational deficit, such as apathy. There is a need in the art to develop more safe and effective methods of controlling or improving cognitive deficit and to develop improved therapies for patients afflicted with apathy.

The ketamine metabolite 2R,6R-hydroxynorketamine, has recently been implicated as a contributor to the antidepressant effects observed in depression patients treated with ketamine (Zanos et al , Nature, (2016), 533, 481-486), providing preclinical support for an

antidepressant effect at dose levels of lOmg/kg. It is known that exposure to 2R,6R- hydroxynorketamine as a metabolite of ketamine contributes to the antidepressant effects of ketamine at sub-anaesthetic doses (Zanos et al, Br. J Pharmacol, (2019), E Pub ahead of print, PMID: 30941749). However high degrees of heterogeneity across ketamine metabolism phenotypes contribute to unpredictable outcomes for ketamine-treated depression patients. There remains a need in the art to develop compounds which are capable of a ketamine-like pharmacological profile without the above-referenced drawbacks. SUMMARY OF THE INVENTION

A first aspect of the present disclosure provides a compound of Formula I, or a

pharmaceutically acceptable salt thereof;

I

wherein n is 0, 1, 2, 3, 4 or 5,

X is selected from CR⁷ and CHR⁷,

R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C1-C4 alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷, with the proviso that R³ is not ortho-F, ortho-Cl, or ortho-Br.

In embodiments of the first aspect of the present invention, in particular when X is CHR⁷, R⁷ is selected from OH, C1-C4 alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸, preferably selected from OH, 0-(Ci-C₄ alkyl), 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, and OPO3R⁸.

In embodiments of the first aspect of the present disclosure, the compound of Formula I does not include a compound of Formula II wherein R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C1-C4 alkyl, n is 0, 1, 2, 3, 4 or 5, each R³ is independently selected from F, Cl, Br, I, and R⁷ is selected from OH and O-C1-C4 alkyl.

A second aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;

I wherein n is 0, 1, 2, 3, 4 or 5,

R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and Ci-C₄ alkyl, each R³ is independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, -CF₃,

X is selected from CR⁷ and CHR⁷,

R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C₁-C₄ alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷.

A third aspect of the present invention provides a compound of Formula I, or a

pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a disorder selected from a neurocognitive disorder and a neurodevelopmental disorder,

I

wherein n is 0, 1, 2, 3, 4 or 5,

R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C1-C4 alkyl, each R³ is independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, -CF₃,

X is selected from CR⁷and CHR⁷,

R⁷ is selected from H, OH, C1-C4 alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSOsR⁸, OPO_SR⁸ wherein R⁸ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C1-C4 alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷, and wherein

a. the neurocognitive disorder is selected from (i) delirium, (ii) pseudodementia, (iii) frontotemporal neurocognitive disorder, (iv) dementia with Lewy Bodies (v) vascular neurocognitive disorder, (vi) multi-infarct dementia, (vii) a tauopathy, (viii) Parkinson's disease, (ix) Huntingdon's disease, (x) transmissible spongiform encephalopathy, (xi) traumatic brain injury, (xii) post-concussion syndrome, (xiii) amnesia, (xiv) substance-induced neurocognitive disorder, (xv) alcohol-induced neurocognitive disorder, and (xvi) stroke disorder, (xvii) hypersomnia, and (xviii) clonic perseveration, (xvii) brain injury disorder, and (xviii) progressive supranuclear palsy, or b. the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I X is either CR⁷, wherein R⁷ is H, or CHR⁷, wherein R⁷ is OH.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I n is 1 and R³ is selected from F, Cl, and OMe.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I R³ is selected from ortho-Cl and meta-OMe.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I R¹ is H and R² is selected from H, Me, or Et.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I R⁴, R⁵, and R⁶ are each H.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I one or both of R⁴ and R⁶ are Me and R⁵ is H, or R⁴ and R⁶ are H and R⁵ is tBu.

In preferred embodiments of the first, second or third aspect of the present invention, the compound of Formula I X is CHR⁷ and wherein R⁷ is on the same stereochemical face of the cyclohexanone ring as -NR'R².

In embodiments of the first, second or third aspect of the present invention the compound of Formula I is not selected from 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, R- 5,6-dehydronorketamine and S-5,6-dehydronorketamine.

A fourth aspect of the present invention provides a compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from one or more of a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.

In preferred embodiments of the fourth aspect of the present invention, the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.

In preferred embodiments of the fourth aspect of the present invention, the

neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

In preferred embodiments of the fourth aspect of the present invention, the psychocognitive disorder is selected from (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.

A fifth aspect of the present invention provides a compound according to the first, second, third or fourth aspect of the present invention for use in treating a disorder of diminished motivation in a patient. In preferred embodiments of the fifth aspect the compound is for use in treating a disorder of diminished motivation in a patient suffering from a comorbid disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering delirium.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Alzheimer’s disease.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering pseudodementia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering frontotemporal neurocognitive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dementia with Lewy Bodies.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering vascular neurocognitive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering multi-infarct dementia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering a tauopathy.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Parkinson's Disease. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Huntingdon's disease.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering transmissible spongiform encephalopathy.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering amyotrophic lateral sclerosis.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering traumatic brain injury.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering post-concussion syndrome.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering amnesia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering substance-induced neurocognitive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering alcohol-induced neurocognitive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering stroke disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering hypersomnia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering progressive clonic perseveration.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering intellectual disability.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering learning disability.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dyslexia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dyscalculia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dyspraxia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering dysgraphia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering autism-spectrum disorder. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering stereotypic movement disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering tic disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering cerebral palsy.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering fragile-X syndrome.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Down Syndrome.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering attention-deficit disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering hypogonadotropic hypogonadal syndrome.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering neurotoxicant poisoning.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering foetal alcohol spectrum disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Minamata disease.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering Rett Syndrome.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering an obsessive compulsive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering a depressive disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering a schizophrenia disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering a schizotypal disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering an anxiety disorder.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating substance abuse.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating a patient suffering an avolition disorder. In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating apathy.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating aboulia.

In a preferred embodiment of the first or second aspect of the invention, the compound of Formula I is for use in treating akinetic mutism.

In preferred embodiments of the first or second aspect of the present invention, the compound is non-neurotoxic. In preferred embodiments of the first or second aspect of the present invention, the compound is non-sedating.

A sixth aspect of the present invention provides a solid oral dosage form comprising the compound of any aspect of the present invention.

In preferred embodiments of the sixth aspect of the present invention, the solid oral dosage form is selected from a tablet and a capsule.

In embodiments of the sixth aspect of the invention the solid oral dosage form comprises a crystalline form of the free base or low molecular weight salt of the compound of Formula I.

In embodiments of the sixth aspect of the invention the solid oral dosage form comprises a diluent blend comprising one or more diluent. In embodiments of the invention the diluent blend comprises microcrystalline cellulose. In embodiments of the invention the diluent blend comprises dicalcium phosphate. In alternative embodiments the solid oral dosage form comprises no diluent.

In embodiments of the sixth aspect of the invention the solid oral dosage form is a capsule comprising a capsule shell comprising a constituent selected from gelatin and hydroxypropyl methylcellulose.

A seventh aspect of the present invention provides compounds or solid oral dosage forms according to any other aspect of the present invention for use in combination with a serotonin modulator. In preferred embodiments of the ninth aspect, the serotonin modulator is a selective serotonin reuptake inhibitor. Preferred serotonin modulators for use in the ninth aspect of the present invention are selected from vortioxetine, etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, trazodone, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, venlafaxine, milnacipran, duloxetine, levomilnacipran, desvenlafaxine, sibutramine, aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline. Particularly preferred serotonin modulators for use in the ninth aspect of the present invention are selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and dapoxetine.

An eighth aspect of the present invention provides compounds or solid oral dosage forms according to any other aspect of the invention for use as an adjunct to behavioural therapy.

A ninth aspect of the present invention provides a kit comprising a package and one or more unit dose(s) of the dosage form of any preceding aspect.

In preferred embodiments of the ninth aspect of the present invention, the composition is comprised in a solid oral dosage form. In preferred embodiments of the ninth aspect of the present invention, the kit comprises 28 unit doses.

In preferred embodiments of the eleventh aspect of the present invention, the kit comprises unit doses packaged in individual blisters in one or more blister packs.

In preferred embodiments of the eleventh aspect, each blister pack comprises a number of unit doses selected from 7, 14, 21, 28 and 56. More preferably each blister pack comprises 14 unit doses.

In preferred embodiments of the ninth aspect, the kit comprises a number of blister packs selected from 1, 2, 3, 4, 5, 6, 7 and 8. More preferably the kit comprises 2 blister packs, wherein each blister pack preferably comprises 14 unit doses.

In preferred embodiments of the ninth aspect, the blister pack is a foil blister pack.

In preferred embodiments of the ninth aspect, the blister pack displays identified s) to indicate the date and/or time at which each unit dose is to be administered.

A tenth aspect of the present invention provides a method of treating a patient suffering from a disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder, wherein said method comprises the steps of

a. identifying a deficit in a cognitive domain of said patient, wherein the cognitive domain is selected from executive function, perceptual function, learning ability, memory, and attention, and b. administering to said patient a composition comprising a compound of

Formula I.

In preferred embodiments of the tenth aspect of the present invention, the composition comprises any composition or dosage form as defined herein.

In particularly preferred embodiments of the tenth aspect of the present invention, the deficit in said cognitive domain is identified using a computer-based cognitive assessment.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: The number of marbles buried by male Swiss mice decreased within 30 minutes following oral administration of 30 and lOOmg/kg 2R,6R-hydroxynorketamine as a hydrochloride salt (2R,6R-HNK HC1). 2R,6R-HNK HC1 dosed at 30mg/kg or lOOmg/kg reduced the number of marbles buried compared to the vehicle treated group and the variation of data within test cohorts was increased, with the high dose of lOOmg/kg producing a 16% decrease in the number of marbles buried. Clobazam (32mg/kg, p.o.) was used as a positive control. Figure 2: Daily administration of 300mg/kg 2R,6R-hydroxynorketamine as an L- pyroglutamate salt (2R,6R-HNK) resulted in a significant increase in motivation as tested using the progressive ratio task. Baseline testing was completed on day 1. Following this, 2R,6R-HNK (300mg/kg), ketamine (lOmg/kg) or saline were administered (IP) daily for 4 consecutive days. Mice were tested 20 minutes after each injection. 2R,6R-HNK resulted in a significant increase in breakpoint compared to ketamine and vehicle groups (A (interaction r<0.0001), B). Analysis of the running rate coefficients revealed a trend toward a main effect of drug in predicted peak responding (C , p= 0.12). 2R,6R-HNK n=l6; ketamine n=l6, vehicle n=l3. Error bars indicate SEM. Two-way ANOVA with Tukey’s post hoc comparison, significance of 2R,6R-HNK from vehicle indicated by asterisks, significance of 2R,6R-HNK from ketamine indicated by hashes; p<0.01 **/##, p<0.001 ***/###, p<0.0001 ****/####.

Figure 3: Daily administration of 300mg/kg 2R,6R-HNK resulted in a significant increase in accuracy as tested using the progressive ratio task. Baseline testing was completed on day 1. Following this, 2R,6R-HNK (300mg/kg), ketamine (lOmg/kg) or saline were administered (IP) daily for 4 consecutive days. Mice were tested 20 minutes after each injection. 2R,6R- HNK resulted in a significant increase in the number of target touches (A, interaction p<0.000l), the ratio of target touches to blank touches (C, interaction p=0.0l) and the % of correct touches (D, interaction p=0.0023) compared to ketamine and vehicle groups. 2R,6R- HNK n=l6; ketamine n=l6, vehicle n=l3. Error bars indicate SEM. Two-way ANOVA with Tukey’s post hoc comparison, significance of 2R,6R-HNK from vehicle indicated by asterisks, significance of 2R,6R-HNK from ketamine indicated by hashes; p<0.05*/#, p<0.01 **/##, p<0.001 ***/###, pO.OOOl ****/####.

Figure 4: The increase in motivation following administration of 300mg/kg 2R,6R-HNK could be replicated. 2R,6R-HNK resulted in a significant increase in breakpoint compared to ketamine and vehicle groups. 2R,6R-HNK n=l6; ketamine n=l6, vehicle n=l3. Error bars indicate SEM. One-way ANOVA with Tukey’s post hoc comparison, significance of 2R,6R- HNK from vehicle indicated by asterisks, significance of 2R,6R-HNK from ketamine indicated by hashes; p<0.05*/#, p<0.01 **/##.

Figure 5: The increase in accuracy following administration of 300mg/kg 2R,6R-HNK could be replicated. 2R,6R-HNK resulted in a significant increase in the number of target touches (A), the ratio of target touches to blank touches (C) and the % of correct touches (D) compared to ketamine and vehicle groups. 2R,6R-HNK n=l6; ketamine n=l6, vehicle n=l3. Error bars indicate SEM. One-way ANOVA with Tukey’s post hoc comparison, , significance of 2R,6R-HNK from vehicle indicated by asterisks, significance of 2R,6R-HNK from ketamine indicated by hashes; p<0.05*/#.

Figure 6: The cognitive effects seen following administration of 2R,6R-HNK are not mediated by the pyroglutamate counterion. Sodium L-pyroglutamate (NaPg) did not increase breakpoint compared to vehicle controls (A, B). 2R,6R-HNK n=l6; NaPg n=l5, vehicle n=l4. Error bars indicate SEM.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification, one or more aspect of the invention may be combined with one or more features described in the specification to define distinct embodiments of the invention. References herein to a singular of a noun encompass the plural of the noun, and vice-versa, unless the context implies otherwise.

The present invention relates to the treatment of neurological and psychiatric disorders, based on the discovery that 2R,6R-hydroxynorketamine and related compounds rapidly improve cognition in various neurocognitive domains. The DSM-5 recognises six neurocognitive domains: complex attention, executive function, learning and memory, language, perceptual- motor function, and social cognition, each of which encompasses multiple subdomains.

Accordingly, an aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof;

I wherein n is 0, 1, 2, 3, 4 or 5,

X is selected from CR⁷ and CHR⁷,

wherein == is a double bond when X is CR⁷, , or a single bond when X is selected from CHR⁷,

with the proviso that R³ is not ortho-F, ortho-Cl, or ortho-Br.

In embodiments of the present invention, in particular when X is CHR⁷, R⁷ is selected from OH, C1-C4 alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸, preferably selected from OH, 0-(Ci-C₄ alkyl), 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, and OPO3R⁸.

In embodiments, the compound of Formula I does not include a compound of Formula II wherein R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C₁-C₄ alkyl, n is 0, 1, 2, 3, 4 or 5, each R³ is independently selected from F, Cl, Br, I, and R⁷ is selected from OH and O-C₁-C₄ alkyl.

An aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;

I wherein n is 0, 1, 2, 3, 4 or 5,

X is selected from CR⁷ and CHR⁷,

wherein == is a double bond when X is CR⁷, , or a single bond when X is CHR⁷.

An aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a disorder selected from a neurocognitive disorder and a neurodevelopmental disorder,

wherein n is 0, 1, 2, 3, 4 or 5,

R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C1-C4 alkyl, each R³ is independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, and -CF₃, X is selected from CR⁷ and CHR⁷, R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸,

0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C₁-C₄ alkyl,

a. the neurocognitive disorder is selected from (i) delirium, (ii) pseudodementia, (iii) frontotemporal neurocognitive disorder, (iv) dementia with Lewy Bodies (v) vascular neurocognitive disorder, (vi) multi-infarct dementia, (vii) a tauopathy, (viii) Parkinson's disease, (ix) Huntingdon's disease, (x)

transmissible spongiform encephalopathy, (xi) traumatic brain injury, (xii) post-concussion syndrome, (xiii) amnesia, (xiv) substance-induced neurocognitive disorder, (xv) alcohol-induced neurocognitive disorder, and (xvi) stroke disorder, (xvii) hypersomnia, and (xviii) clonic perseveration, (xvii) brain injury disorder, and (xviii) progressive supranuclear palsy, or b. the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

In preferred embodiments of the compound of Formula I, X is either CR⁷, wherein R⁷ is H, or CHR⁷, wherein R⁷ is OH.

In preferred embodiments of the compound of Formula I, n is 1 and R³ is selected from F, Cl, and OMe.

In preferred embodiments of the compound of Formula I, R³ is selected from ortho-Cl and meta-OMe.

In preferred embodiments of the compound of Formula I, R¹ is H and R² is selected from H, Me, or Et.

In preferred embodiments of the compound of Formula I, R⁴, R⁵, and R⁶ are each H.

In preferred embodiments of the compound of Formula I, one or both of R⁴ and R⁶ are Me and R⁵ is H, or R⁴ and R⁶ are H and R⁵ is tBu.

In preferred embodiments of the compound of Formula I, X is CHR⁷ and wherein R⁷ is on the same stereochemical face of the cyclohexanone ring as -NR'R²

In embodiments the compound of Formula I is not selected from 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, R-5,6-dehydronorketamine and S-5,6-dehydronorketamine.

As used herein, the term‘pharmaceutically acceptable salt’ is defined as the product of an acid addition reaction in which an amine group of a compound of the invention is protonated by an organic or inorganic acid to form a non-toxic salt, or as the product of a base addition reaction in which an acidic group in a compound of the invention is deprotonated by an organic or inorganic base to form a non-toxic salt. The term pharmaceutically acceptable salt includes solvates thereof. Wherever a compound is referred to by its generic or systematic name, the term is taken to include all pharmaceutically acceptable salts.

As used herein Ή’ means a hydrogen atom. Also encompassed in the definition of hydrogen atom are isotopes of hydrogen, for example deuterium or tritium.

As used herein‘Ci-C₄ alkyl’ means a saturated carbon chain having one to four carbon atoms and which may be linear or branched. Examples of alkyl groups include methyl (also referred to herein as Me), ethyl (also referred to herein as Et), n-propyl, isopropyl (also referred to herein as i-Propyl, i-Pr, or‘Pr), n-butyl, sec- and tert-butyl (also referred to herein as t-Butyl, t-Bu, or *Bu). Any alkyl or alkylene group referred to herein may be substituted with one or more haloatom independently selected from F, Cl, Br, and I.

As used herein‘F’ means fluoride,‘Cl’ means chloride,‘Br’ means bromide, T means iodide.

As used herein, R½, R³ _n, (R³)n and (R³)_n are used interchangeably, and refers to 0, 1, 2, 3, 4 or 5 moieties independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, -CF₃, each of which replaces an aryl hydrogen, and may be located ortho, meta or para to the C-C bond linking the aryl group to the cyclohexanone or cyclohexenone.

As used herein,‘-PO₃H₂’ can also mean -PO₃H , and collectively with the oxygen atom to which it is attached represents a phosphate group. As used herein the term‘-SO₃H’ can also mean -SO₃ and collectively with the oxygen atom to which it is attached represents a sulphate group. In certain embodiments of the invention, the presence of a phosphate group or a sulphate group in compounds of the present invention facilitates formation of a zwitterion wherein the phosphate is deprotonated and thus negatively charged and the amino group is protonated and thus positively charged.

As used herein, the term‘2R,6R-hydroxynorketamine’ refers to 2R,6R-2-(2-Chlorophenyl)- 2-(amino)-6-hydroxycyclohexanone. As used herein, the term ‘2R,6R-hydroxynorketamine L-pyroglutamate’ refers to the acid addition salt formed by the reaction of 2R,6R-2-(2- Chlorophenyl)-2-(amino)-6-hydroxycyclohexanone with L-pyroglutamic acid.

An aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from one or more of a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.

In preferred embodiments of the present invention, the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.

In preferred embodiments of the present invention, the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

In preferred embodiments of the present invention, the psychocognitive disorder is selected from (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.

An aspect of the present invention provides a compound of the present invention for use in treating a disorder of diminished motivation in a patient. In preferred embodiments of the fifth aspect the compound is for use in treating a disorder of diminished motivation in a patient suffering from a comorbid disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder.

As used herein the term‘neurological disorder’ means any disorder of the nervous system, including diseases, conditions, or symptoms resulting from structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves.

As used herein the term‘psychiatric disorder’ is a clinically significant behavioural or psychological pattern that occurs in an individual and that is associated with present distress (eg. a painful symptom), disability (ie. impairment in one or more important areas of functioning) or state of being with significantly increased risk of suffering death, pain, disability, or an important loss of freedom.

As used herein the term‘complex attention’ describes the behavioural and cognitive process of selectively concentrating on a discrete aspect of information, whether deemed subjective or objective, while ignoring other perceivable information. Complex attention may be regarded as a set of processes of cognitive resource allocation, and include basic cognitive processes such as sustained attention, divided attention, selective attention and processing speed.

As used herein the term‘executive function’ refers to a set of cognitive processes that are necessary for the cognitive control of behaviour. Executive functions include basic cognitive processes such as planning, decision making, response to feedback, cognitive inhibition, inhibitory control, working memory, and cognitive flexibility. As used herein the term ‘cognitive control’ means the ability of an individual to select and successfully monitor behaviours that facilitate the attainment of chosen goals. An individual’s elicited behaviour results from an interaction between cognitive control and stimulus control.

As used herein the term‘learning and memory’ is the process of acquiring and storing for future recall of new knowledge, behaviours, skills, values, or preferences, or the modification of those existing. Subdomains involved in learning and memory include free recall, cued recall, recognition memory, semantic and autobiographic long-term memory, and implicit learning.

As used herein the term‘language’ describes a system that consists of the development, acquisition, maintenance and use of complex systems of communication, including object naming, word finding, grammar and syntax, receptive language, and fluency. As used herein the term‘perceptual-motor function’, or simply‘perceptual function’, is a mode of comprehension by organisation, identification, and interpretation of sensory information in order to represent and understand the presented information, or the environment which generated the information. Perceptual-motor function involves subdomains including visual perception, visuocontructional reasoning and perceptual-motor coordination.

As used herein the term‘social cognition’ means a cognitive domain which focuses on how a cognitive subject processes, stores, and applies information about other subjects and social situations. Social cognition includes subdomains including emotional recognition, insight and theory of mind.

In particular, compounds of the present invention have been found to be effective in increasing one or more cognitive domain selected from executive function, perceptual function, learning ability, memory, and attention in a human. Specific subdomains of perceptual function which may be improved by compounds of the present invention include visuoconstructional reasoning and sensory memory. Specific subdomains of learning and memory which may be improved by compounds of the present invention include cued recall, recognition memory, implicit learning, and associative learning. Specific subdomains of attention which may be improved by compounds of the present invention include sustained attention, selective attention, and processing speed. Specific subdomains of executive function which may be improved by compounds of the present invention include working memory, responding to feedback, and sensory memory.

The ability of compounds of the present invention to enhance these particular neurocognitive domains and subdomains render them effective in treating either symptoms or underlying pathology in a patient suffering from one or more neurocognitive, neurodevelopmental, or psychocognitive disorders, in particular the specific disorders described herein.

As used herein, the term‘patient’ refers to a mammal, preferably a human, in need of therapy. The term does not encompass laboratory mammals.

In preferred embodiments of the invention, the composition is non-neurotoxic.

In preferred embodiments of the invention, the composition is non-sedating.

As used herein the term‘non-neurotoxic’ describes a method or composition which does not cause injury or death to nervous tissue.

As used herein the term‘non-sedating’ describes a method or composition which does not assist the induction of sleep.

In particularly preferred embodiments of the invention the composition is for increasing motivation in an individual to whom the method or composition is administered.

Diagnostic criteria for neurocognitive disorders, neurodevelopmental disorders, and psychocognitive disorders referred to herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), the contents of which are incorporated herein by reference.

In preferred embodiments of the present invention, the neurocognitive disorder is selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x)

Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.

As used herein the term‘delirium’ means an acute confusional state, caused by decline from a baseline level of mental function. It often varies in severity over a short period of time, and includes attentional deficits, and disorganisation of behaviour.

As used herein the term‘Alzheimer’s disease’ describes a neurodegenerative disease characterised by the build-up of proteins in the brain to form structures called plaques or tangles. Alzheimer’s disease is the most common cause of dementia. Symptoms can include memory loss and difficulties with thinking, problem-solving or language.

As used herein the term‘pseudodementia’ refers to a disorder which results in a dementia- like phenotype having predominantly cognitive symptoms such as loss of memory, and vagueness, as well as prominent slowing of movement and reduced or slowed speech.

Disorders which can manifest a pseudodementia phenotype include major depressive disorder, mania, bipolar disorder, schizophrenia, dissociative disorders, Ganser syndrome, conversion reaction, and psychoactive drug abuse. A major subcategory of pseudodementia to which the present invention is directed is depressive pseudodementia, also referred to as depressive dementia or major depression with depressive dementia, which is a syndrome in which the patient suffering major depression exhibits symptoms consistent with dementia.

As used herein the term‘frontotemporal neurocognitive disorder’, also referred to as frontotemporal dementia (FTD), refers to a neurocognitive disorder involving the frontal or temporal lobes. Types of frontotemporal neurocognitive disorder include behavioural variant of FTD, primary progressive aphasia (semantic variant or nonfluent agrammatic),

corticobasal syndrome, progressive supranuclear palsy, and FTD associated with motor neuron disease.

As used herein the term‘dementia with Lewy Bodies’ refers to a type of dementia which involves widespread deposits of abnormal clumps of alpha- synuclein protein in neurons, known as Lewy bodies. A feature of dementia with Lewy Bodies is REM sleep behaviour disorder (RBD), in which individuals lose normal muscle paralysis during REM sleep. Other frequent symptoms include visual hallucinations; marked fluctuations in attention or alertness; and slowness of movement, trouble walking, or rigidity.

As used herein the term‘vascular neurocognitive disorder’ refers to cognitive impairment caused by restriction of supply of blood to the brain.

As used herein the term‘multi-infarct dementia’ also known as vascular dementia, or vascular cognitive impairment, is dementia caused by problems in the supply of blood to the brain leading to worsening cognitive decline.

As used herein, a‘tauopathy’ is a disease involving a dysfunction of tau. Examples of tauopathies include Pick disease, argyrophilic grain disease and corticobasal degeneration. As used herein the term‘Pick disease’ refers to a cause of frontotemporal lobar degeneration characterised by build-up of tau proteins in neurons, accumulating into silver-staining, spherical aggregations known as Pick bodies.

As used herein the term‘Parkinson's Disease’ is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain. The reason for this cell death appears to involve the build-up of proteins into Lewy bodies in the neurons. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used to rule out other diseases.

As used herein the term‘Huntingdon's disease’ refers to an inherited disorder that results in death of brain cells, caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin.

As used herein the term‘transmissible spongiform encephalopathy’ refers to a group of progressive, invariably fatal, conditions that affect the brain and nervous system caused by prions, a form of infectious protein. Transmissible spongiform encephalopathies include kuru, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD or nvCJD), Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia.

As used herein the term‘amyotrophic lateral sclerosis’ or ALS, also known as motor neurone disease (MND), and Lou Gehrig's disease, is a specific disease which causes the death of neurons controlling voluntary muscles. ALS is characterised by stiff muscles, muscle twitching, and weakness, resulting in difficulty speaking, swallowing, and eventually breathing.

As used herein the term‘traumatic brain injury’ refers to damage to the brain resulting from external mechanical force.

As used herein the term‘post-concussion syndrome’ is a set of symptoms that may continue for a period of time following a mild traumatic brain injury. The syndrome is charactierised by physical symptoms, such as headache, cognitive symptoms, such as difficulty

concentrating, and emotional and behavioural symptoms, such as irritability.

As used herein the term‘amnesia’ refers to a deficit in memory caused by brain damage, disease, or psychological trauma.

As used herein the term‘substance-induced neurocognitive disorder’ refers to a

neurocognitive disorder which is caused or exacerbated by substance abuse.

As used herein the term‘alcohol-induced neurocognitive disorder’ refers to a neurocognitive disorder which is caused or exacerbated by alcohol abuse.

As used herein the term‘stroke disorder’ refers to a condition in which poor blood flow to the brain results in cell death.

As used herein the term‘hypersomnia’ refers to a disorder of excessive time spent sleeping or excessive sleepiness.

As used herein the term‘clonic perseveration’ refers to a form of motor perseveration in which inappropriate repetition of an action, once initiated, occurs in the absence of an ongoing cue. In preferred embodiments of the present invention, the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

As used herein the term‘intellectual disability’ refers to a neurodevelopmental disorder characterised by significantly impaired intellectual and adaptive functioning. An intellectual disability is typically defined in a person having an IQ under 70 alongside deficits in two or more adaptive behaviours that affect everyday living.

As used herein the term‘learning disability’ refers to a significant general impairment in intellectual functioning acquired during childhood.

As used herein the term‘dyslexia’ refers to difficulty in reading despite normal intelligence.

As used herein the term‘dyscalculia’ refers to difficulty in learning or comprehending arithmetic.

As used herein the term‘dyspraxia’ refers to is a chronic neurological disorder beginning in childhood, which affects the planning of movements and motor co-ordination. It may also affect speech. Dyspraxia is thought to occur as a result of brain messages not being accurately transmitted to the body.

As used herein the term‘dysgraphia’ refers to a deficiency in the ability to write.

As used herein the term‘autism spectrum disorder’ describes a range of developmental conditions, including Asperger syndrome, that affect a person's social interaction,

communication, interests and behaviour as defined by the diagnostic criteria set out in DSM- 5. An individual with an autism spectrum disorder often presents with social problems that include difficulty communicating and interacting with others, repetitive behaviours, as well as limited interests or activities.

As used herein the term‘stereotypic movement disorder’ refers to a motor disorder with onset in childhood involving repetitive, nonfunctional motor behaviour that interferes with normal activities, or results in bodily injury.

As used herein the term‘tic disorder’ refers to a disorder characterised by sudden, rapid, nonrhythmic movements. Tic disorders include Tourette’s syndrome, which is characterised by motor tics alongside at least one vocal tic.

As used herein the term‘cerebral palsy’ refers to a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non progressive disturbances that occurred in the developing foetal or infant brain.

As used herein the term‘fragile X syndrome’ describes a condition typically caused by an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 gene on the X chromosome. This genetic mutation results in a range of developmental problems including learning disabilities and cognitive impairment. Typically males are more severely affected by this disorder than females. Affected individuals usually have delayed development of speech and language, with mild to moderate intellectual disability observed with development. The majority of males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age, including a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles.

As used herein the term‘Down Syndrome’, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21.

As used herein the term‘attention-deficit disorder’ refers to a neurodevelopmental disorder characterised by problems paying attention, excessive activity, or difficulty controlling behaviour which is not appropriate for a person's age. The term encompasses attention-deficit hyperactivity disorder (ADHD), in which symptoms must be present for six months or more to a degree that is much greater than others of the same age. Symptoms are evident prior to the age of 12, and must cause significant problems functioning in at least two settings (e.g., social, school/work, or home). ADHD is divided into three subtypes: predominantly inattentive (ADHD-PI or ADHD-I), predominantly hyperactive-impulsive (ADHD-PH or ADHD-HI), and combined type (ADHD-C).

As used herein the term‘hypogonadotropic hypogonada syndrome’ refers to a condition characterised by hypogonadism due to an impaired secretion of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland in the brain, and in turn decreased gonadotropin levels and a resultant lack of sex steroid production.

As used herein the term‘neurotoxicant poisoning’ refers to an adverse effect on the structure or function of the central and/or peripheral nervous system caused by a biological or chemical agent.

As used herein the term‘foetal alcohol spectrum disorder’ refers to a group of conditions that can occur in a person whose mother drank alcohol during pregnancy. The most severe form of the condition is known as foetal alcohol syndrome (FAS). Other types include partial foetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD).

As used herein the term‘Minamata disease’ refers to a neurological syndrome caused by severe mercury poisoning.

As used herein the term‘Rett syndrome’ refers to a rare (1 in 12,000), severe neurological disorder that affects mostly girls, owing to the fact it is caused by mutations in the MECP2 gene located on the X chromosome. It is usually discovered within the first two years of life.

The clinical features of Rett syndrome include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted. People with Rett syndrome are prone to gastrointestinal disorders and a majority of individuals experience seizures. They typically have no verbal skills, in addition to experiencing problems with muscles and motor coordination meaning they cannot walk.

In preferred embodiments of the present invention, the psychocognitive disorder is selected from an (i) obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.

As used herein the term‘obsessive-compulsive disorder’ is defined by the presence of either obsessions or compulsions, but commonly both. The symptoms can cause significant functional impairment and/or distress. An obsession is defined as an unwanted intrusive thought, image or urge that repeatedly enters the person's mind. Compulsions are repetitive behaviours or mental acts that the person feels driven to perform. Typically

obsessive-compulsive disorder (OCD) manifests as one or more obsession which drives adoption of a compulsion. For example, an obsession with germs may drive a compulsion to clean. A compulsion can either be overt and observable by others, such as checking that a door is locked, or a covert mental act that cannot be observed, such as repeating a certain phrase in one's mind.

As used herein the term‘depressive disorder’ includes major depressive disorder, persistent depressive disorder, bipolar disorder, and bipolar depression.

As used herein the term‘major depressive disorder’ (MDD, also referred to as major depression or clinical depression) is defined as the presence of five or more of the following symptoms over a period of two-weeks or more (also referred to herein as a‘major depressive episode’), most of the day, nearly every day.

• depressed mood, such as feeling sad, empty or tearful (in children and teens,

depressed mood can appear as constant irritability);

• significantly reduced interest or feeling no pleasure in all or most activities;

• significant weight loss when not dieting, weight gain, or decrease or increase in

appetite (in children, failure to gain weight as expected);

• insomnia or increased desire to sleep;

• either restlessness or slowed behaviour that can be observed by others;

• fatigue or loss of energy;

• feelings of worthlessness, or excessive or inappropriate guilt;

• trouble making decisions, or trouble thinking or concentrating;

• recurrent thoughts of death or suicide, or a suicide attempt.

At least one of the symptoms must be either a depressed mood or a loss of interest or pleasure.

Persistent depressive disorder, also known as dysthymia, is defined as a patient exhibiting the following two features:

A. has depressed mood for most the time almost every day for at least two years. Children and adolescents may have irritable mood, and the time frame is at least one year.

B. While depressed, a person experiences at least two of the following symptoms:

• Either overeating or lack of appetite.

• Sleeping too much or having difficulty sleeping.

• Fatigue, lack of energy.

• Poor self-esteem.

• Difficulty with concentration or decision making. As used herein‘bipolar disorder’ also known as manic-depressive illness, is a disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.

There are three defined sub-categories of bipolar disorder; all of them involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely“up,” elated, and energised behaviour (known as manic episodes, and defined further below) to very sad,“down,” or hopeless periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

Bipolar I Disorder— defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that the person needs immediate hospital care. Usually, depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of depression with mixed features (having depression and manic symptoms at the same time) are also possible.

Bipolar II Disorder— defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

As used herein‘bipolar depression’ is defined as an individual who is experiencing depressive symptoms with a previous or coexisting episode of manic symptoms, but does not fit the clinical criteria for bipolar disorder.

As used herein the term‘schizophrenia disorder’ means is a mental disorder characterised by abnormal social behaviour and failure to understand what is real. According to the DSM-5, to meet the criteria for diagnosis of schizophrenia, the patient must have experienced at least 2 of the following symptoms: delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, negative symptoms. At least one of the symptoms must be the presence of delusions, hallucinations, or disorganised speech.

As used herein the term‘a schizotypal disorder’ refers to a disorder characterised by severe social anxiety, thought disorder, paranoid ideation, derealisation, transient psychosis, and often unconventional beliefs.

As used herein the term‘anxiety disorder’ includes generalised anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

‘Generalised anxiety disorder’ (GAD) as used herein means a chronic disorder characterised by long-lasting anxiety that is not focused on any one object or situation. Those suffering from GAD experience non-specific persistent fear and worry, and become overly concerned with everyday matters. GAD is characterised by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

‘Phobia’ is defined as a persistent fear of an object or situation the affected person will go to great lengths to avoid, typically disproportional to the actual danger posed. If the feared object or situation cannot be avoided entirely, the affected person will endure it with marked distress and significant interference in social or occupational activities.

A patient suffering a from a‘panic disorder’ is defined as one who experiences one or more brief attack (also referred to as a panic attack) of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, and/or difficulty breathing. A panic attack is defined as a fear or discomfort that abruptly arises and peaks in less than ten minutes.

‘Social anxiety disorder’ is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests specific physical symptoms, including blushing, sweating, and difficulty speaking.

‘Post-traumatic stress disorder’ (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidant behaviours, anxiety, anger and depression.

As used herein the term‘substance abuse’ means a patterned use of a drug in which the user consumes the substance in amounts or with methods which are harmful to themselves or others.

As used herein the term‘an avolition disorder’ refers to a disorder which includes as a symptom the decrease in motivation to initiate and perform self-directed purposeful activities.

In preferred embodiments of the present invention, the composition is for use in treating a disorder of diminished motivation.

As used herein the term‘a disorder of diminished motivation’ refers to a disorder which manifests in a deficit in a person’s ability to direct behaviour, or in a subject’s ability or desire to repeat a behaviour.

In preferred embodiments, the disorder of diminished motivation is selected from (i) apathy, (ii) aboulia, and (iii) akinetic mutism.

As used herein the term‘apathy’ refers to a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. Apathy levels in a subject may be measured using the Apathy Evaluation Scale (AES), which measures apathy as related to brain-related pathology, as set out in RS Marin, RC Biedrzycki, S Firinciogullari:“Reliability and Validity of the Apathy Evaluation Scale,” Psychiatry Research, 38: 143-162, 1991, the contents of which are incorporated herein by reference.

As used herein the term‘aboulia’ refers to a lack of will or initiative.

As used herein the term‘akinetic mutism’ refers to a disorder in which a subject lacks most motor functions such as speech, facial expressions, and gestures, but demonstrate apparent alertness.

In particularly preferred embodiments of the present invention, the disorder of diminished motivation is apathy and the neurocognitive disorder, neurodevelopmental disorder, or psychocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) a schizophrenia disorder, (v) substance abuse, (vi) attention-deficit hyperactivity disorder, (viii) Alzheimer's disease, (ix) Parkinson's disease, (x) Huntington's disease, (xi) amyotrophic lateral sclerosis, (xii) a stroke disorder, and (xiii) a brain injury disorder. Preferably, the neurocognitive disorder,

neurodevelopmental disorder, or psychocognitive disorder is selected from (i) an obsessive- compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a schizophrenia disorder.

The methods and compositions of the present invention are particularly useful in enhancing a cognitive subdomain selected from (i) visuocontructional reasoning, (ii) cued recall, (iii) recognition memory, (iv) implicit learning, (v) associative learning, (vi) sustained attention, (vii) selective attention, (viii) processing speed, (ix) working memory, and (x) sensory memory.

Compounds according to the present invention may impart their activity via negative modulation of the alpha-7 nicotinic acetylcholine receptor (a7-nAChR). A negative modulator of a7-nAChR may act as a competitive antagonist, an uncompetitive agonist, a non-competitive antagonist, a negative allosteric modulator or a channel blocker.

Accordingly, a thirteenth aspect of the present invention is the use of a compound of Formula I as a negative modulator of a7-nAChR.

As used herein, the term‘competitive antagonist’ refers to a molecule which binds to the acetylcholine binding site but which does not activate the a7-nAChR. A competitive antagonist reversibly interacts with the receptor, in a concentration-dependant and affinity- dependant manner.

As used herein the term‘uncompetitive antagonist’ refers to a type of negative modulator which requires receptor activation before it can bind to a separate allosteric binding site.

As used herein, the term‘non-competitive antagonist’ refers to a molecule which reduces the magnitude of the maximum response that can be attained by activation of the a7-nAChR with acetylcholine. An non-competitive antagonist does not directly compete with the endogenous ligand, through either binding irreversibly to the active site, or by binding to an allosteric site. Thus increasing the concentration of the agonist does not reverse the effect of the non-competitive antagonist.

As used herein, the term‘negative allosteric modulator’ refers to a molecule which binds to a distinctly separate binding site from acetylcholine, thereby reducing the maximum response that can be attained by activation of the a7-nAChR with acetylcholine. A negative allosteric modulator may prevent conformational changes in the receptor required for receptor activation after the agonist binds.

As used herein the term‘channel blocker’ refers to a molecule which inhibits the movement of ions through the ion channel by binding to a binding site within the channel.

An agent may be determined as a negative modulator of a7-nAChR using electrophysiology techniques to determine its IC50 at the a7-nAChR channel. As would be apparent to the person skilled in the art, the a7-nAChR IC50 of any biological or chemical agent may be determined using an appropriate electrophysiological technique on a suitable cell line expressing the a7-nAChR channel.

For example, two-electrode voltage-clamp recordings may be made from Xenopus laevis oocytes stably expressing functional a7-nAChR receptors. Clamped at -70m V, the oocytes should be perfused with standard Ringer solution or test compound using a microcapillary system suitable for rapid solution changes. A concentration of nicotine eliciting 20% of the maximal current (EC20) can used as the nicotine control to reliably measure inhibition of current using, for example, a GeneClamp 500B (Molecular Devices). Test compounds can then be applied for 30s before exposure to nicotine. Inhibition can then be calculated from peak current values as the percentage of the previous nicotine control current (percentage of EC20 Control— Idrug/Icontrol)·

As used herein, the term‘IC50’ means the half maximal inhibitory concentration, and is a quantitative measure of the concentration of an agent required to reduce a function of a7- nAChR (eg. current) by half in an in vitro assay.

Preferably, the compound of the present invention has an a7-nAChR IC50 of less than lmM, preferably less than 100mM, preferably less than 10mM, preferably less than ImM, preferably less than lOOnM, preferably less than lOnM.

An aspect of the present invention provides a compound of Formula I for co-administration with a serotonin modulator for use in increasing executive function or cognitive control in a patient suffering from a psychiatric or neurological disorder. Preferably the patient is suffering from one or more neurocognitive, neurodevelopmental, or psychocognitive disorders described herein.

As used herein, the term‘serotonin modulator’ is defined as any compound which affects the serotonin neurotransmitter (serotonergic system). Serotonin modulators include serotonin receptor agonists, in particular 5HT_2A receptor agonists or partial agonists (eg. ergolines, tryptamines and phenethylamines) and 5HT_2C receptor agonists or partial agonists (eg.

aripiprazole), serotonin stimulators (e.g. vortioxetine), serotonin antagonist and reuptake inhibitors (SARIs; e.g. etoperidone, lorpiprazole, lubazodone, mepiprazole, nefazodone, and trazodone), selective serotonin reuptake inhibitors (SSRIs; e.g. citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g. venlafaxine, milnacipran, duloxetine, levomilnacipran, desvenlafaxine, sibutramine), and noradrenergic and specific serotonergic antidepressants (NaSSAs; e.g. aptazapine, esmirtazapine, mianserin, mirtazapine, setiptiline).

As used herein, the term‘coadministration’ is defined as either the administration of a formulation which contains both the composition of the present invention and the serotonin modulator, or the simultaneous, essentially simultaneous, sequential or separate

administration within a given treatment period of separate formulations containing the composition of the present invention and the serotonin modulator, respectively.

A preferred class of serotonin modulators for use according to the present invention are SSRIs. Preferred SSRIs are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and dapoxetine. Most preferred SSRIs are citalopram or escitalopram.

The compound of the invention may be administered in any formulation suitable for pharmaceutical administration. Preferably the composition of the present invention is in a dosage form selected from a tablet, a pill, a capsule, a caplet, a powder, granules, orodispersible tablet, sterile parenteral solution or suspension, powder for injection, metered aerosol or liquid spray, drops, ampoule, autoinjector, suppository, sublingual spray, sublingual patch, sublingual film, buccal patch, buccal spray, buccal film, intranasal sprayable solution, intranasal sprayable suspension, and intranasal powder. In preferred embodiments of the invention, the dosage form of the compound of the present invention is selected from orodispersible tablet, sublingual spray, sublingual patch, sublingual film, buccal patch, buccal spray, buccal film, intranasal sprayable solution, intranasal sprayable suspension, and intranasal powder, and is preferably a dosage form suitable for intranasal administration.

In embodiments of the invention the solid oral dosage form comprises a crystalline form of the free base or low molecular weight salt of the compound of Formula I.

In embodiments of the invention the solid oral dosage form comprises a diluent blend comprising one or more diluent. In embodiments of the invention the diluent blend comprises microcrystalline cellulose. In embodiments of the invention the diluent blend comprises dicalcium phosphate. In alternative embodiments the solid oral dosage form comprises no diluent.

In embodiments of the invention the solid oral dosage form is a capsule comprising a capsule shell comprising a constituent selected from gelatin and hydroxypropyl methylcellulose.

The compound of the present invention is preferably used an adjunct to behavioural therapy. Behavioural therapy can be particularly effective in disorders described herein when performed in conjunction with pharmaceutical treatment with a compound, composition or dosage form of the present invention.

As used herein the term‘behavioural therapy’ means psychotherapy and/or behaviour analysis falling within a discipline selected from applied behaviour analysis (ABA), the teaching-family model (TFM), positive behaviour support (PBS) and cognitive behaviour therapy (CBT).

In preferred embodiments, the compound of the present invention is for use as a first-line therapy.

As used herein, the term‘first-line therapy’ is defined as the first course of pharmaceutical treatment administered in response to an episode of a disorder, and preferably the first episode of said disorder experienced by the patient. The term‘episode’ refers to a single noteworthy happening, often in the course of a longer series of events, such as one critical period of several during a prolonged disorder.

An aspect of the present invention is a solid oral dosage form comprising a compound of the present invention for use in treating a disorder as described hereinabove.

As used herein, the term‘solid oral dosage form’ is defined as a solid pharmaceutical formulation which can be swallowed whole, chewed and swallowed, or dissolved, dispersed or absorbed via the oral cavity. Solid oral dosage forms include tablets, pills, capsules, caplets, orodispersible tablets, powders, granules and gums. Solid oral dosage forms are not taken to include liquid or aerosol formulations, powders for inhalation, or powders for injection.

In a preferred embodiment, the solid oral dosage form of the present invention is for use in a patient who has not previously been treated. In a preferred embodiment of the invention, the solid oral dosage form is for use in a patient who has failed to achieve adequate control of disorder symptoms using psychotherapy alone. Solid oral dosage forms according to the present invention may be prepared by mixing the principle active agent(s) with a pharmaceutical carrier, e.g. com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, or dicalcium phosphate, and other

pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogenous mixture of the active agent(s). When referring to these preformulation compositions as homogenous, it is meant that the active agent is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. The solid preformulation composition is then subdivided into unit dosage forms of the type described above.

Quantities of weight provided herein refer to the free-form equivalent of a compound of the present invention.

Suitable unit doses of the serotonin modulators for use in aspects of the present invention include the unit doses for these compounds as described in Martindale: The Complete Drug Reference (London, the Pharmaceutical Press, 38^th Edition) and US Pharmacopoeia and National Formulary 2016 Edition.

Suitable unit doses for citalopram include lOmg, 20mg and 40mg. Suitable unit doses for escitalopram include 5mg, lOmg and 20mg. Suitable unit doses for fluoxetine include 20mg and 60mg. Suitable unit doses for fluvoxamine include 50mg and lOOmg. Suitable unit doses for paroxetine include lOmg, 20mg and 30mg. Suitable unit doses for sertraline include 50mg and lOOmg. Suitable unit doses for dapoxetine include 30mg and 60mg.

Solid oral dosage forms according to the present invention are preferably formulated in unit doses for administration between once a day and once a week, or between once every two days and twice a week. In a preferred embodiment the unit dose is for administration once a day.

An aspect of the present invention provides a solid oral dosage form comprising a compound of the present invention for administration in combination with a serotonin modulator, wherein the serotonin modulator is preferably a selective serotonin reuptake inhibitor (SSRI), more preferably selected from Citalopram, Escitalopram, Paroxetine, Fluoxetine,

Fluvoxamine, Sertraline, Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran, Tofenacin, Venlafaxine, Vilazodone, Vortioxetine, Etoperidone, Nefazodone, and Trazodone, or a pharmaceutically acceptable salt thereof, and most preferably selected from Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, and Venlafaxine, or a pharmaceutically acceptable salt thereof.

Preferably the solid oral dosage form comprising a compound of Formula I and the serotonin modulator are for administration simultaneously, sequentially or separately.

An aspect of the present invention provides a method of treating a patient suffering from a disorder selected from a neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder, wherein said method comprises the steps of a. Identifying a deficit in a cognitive domain of said patient, wherein the cognitive domain is selected from executive function, perceptual function, learning ability, memory, and attention, and b. Administering to said patient a composition comprising a compound of Formula I as described hereinabove.

The compound for use according to the method of the present invention is preferably comprised in a pharmaceutical composition, in particular a solid dosage form, as described hereinabove.

In the method of the present invention the patient is preferably suffering from a disorder selected from a neurocognitive disorder selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) a tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform

encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post- concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration; a neurodevelopmental disorder selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebral palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention- deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) foetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome; or a psychocognitive disorder selected from (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.

In preferred embodiments of the method of the present invention, the deficit in said cognitive domain is identified using a computer-based cognitive assessment.

In preferred embodiments of the method of the present invention, the method is effective in increasing motivation. In preferred embodiments of the invention, the method is effective in treating diminished motivation, in particular apathy.

SYNTHETIC SCHEMES

Certain compounds of the present invention may be synthesised through means known in the art. For example, reaction schemes suitable to synthesise certain compounds where X is CHR⁷ or CR⁷ are disclosed in WO2013/056229, the contents of which are incorporated herein by reference.

Alternatively, compounds of Formula I may be synthesised from readily available starting materials following the processes set out in in Schemes 1, 2, 3 and 4 below. In schemes 1 and 2, -L is any suitable leaving group and -Pg¹ is one or more optional protecting group:

Scheme 1

Scheme 2 Compounds of the present invention where X is CR⁷ may be prepared according to the synthesis described in Scheme 3 :

Scheme 3

EXAMPLES

Example 1: Synthesis of (2R,6R)-2-amino-6-hydroxy-2-(3-methoxyphenyl)cyclohexan-l- one (Compound 107)

Compound 107 is synthesised according to the synthesis described in Scheme 3 :

r.t.

1 h

Compound 102

3-Methoxyphenyl cyclopentyl ketone as a solution in ethyl acetate is treated with copper (II) bromide and the suspension heated to reflux over 4 hours. Gases are scrubbed with a water scrubber. The reaction mixture is allowed to cool overnight. The reaction mixture is filtered through a pad of silica and washed with ethyl acetate. The solvent is removed to leave the product 102 as a dark oil.

Compound 103

Compound 102 is stirred in toluene whilst benzylamine is added over 5 minutes. The mixture is stirred over 5 days and then purified by column chromatography to yield crude product 103. Crude 103 is then treated with HC1 in PCME to produce the crystalline iminium salt of 103 in high purity.

Compound 104

Compound 103 is dissolved in isobutanol and heated to l50°C in a microwave for 2 hours. The solvent is removed to leave Compound 104 as a dark oil.

Compound 105

Diisopropylamine is dissolved in dry THF with stirring under an argon atmosphere then the mixture was cooled to -78 °C. n-BuLi is added dropwise over 2 minutes and the reaction mixture is stirred for 15 minutes; after which a solution of 104 in dry THF is added dropwise over 2 minutes and the reaction stirred for 25 minutes. Chlorotrimethylsilane is added to the reaction dropwise and the reaction stirred for 15 minutes at -78 °C then warmed to 0 °C and stirred for 1 h. After this time the reaction is diluted with heptane, washed with NaHCCh and the organic phase is separated and dried over Na₂S0₄, filtered and then concentrated in vacuo to afford crude 105. The crude 105 is purified via column chromatography to afford

Compound 105.

Compound 106

Compound 105 is dissolved in dichloromethane and cooled to -15 °C (ice-lithium chloride), under a nitrogen atmosphere. 3-Chloroperbenzoic acid is then added as a solid. The reaction is stirred for one hour at -15 °C, then the temperature is raised to room temperature and an additional 25 mL of dichloromethane is added. The reaction is stirred a further 0.5 hours. The reaction is then quenched by being poured into a 50/50 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The reaction is extracted into dichloromethane and the solvent removed by rotary evaporation. Then THF is added to the crude material. The reaction is cooled to -5 °C, and tetrabutylbutyl ammonium fluoride is added. The reaction is stirred for 2 minutes, before being quenched by addition to saturated aqueous sodium bicarbonate. Extraction into ethyl acetate, and removal of the solvent by rotary evaporation gives the crude final product 106. Purification by silica gel

chromatography (0% to 70% ethyl acetate in hexanes), gives the purified final product as solid Compound 108.

Compound 107

Compound 106 is transferred into a round bottom flask under an argon atmosphere with a stirrer bar and HC1 (3M in CPME) was added with stirring; and the reaction was stirred under an argon atmosphere for 18 hours. After this time the reaction was filtered to collect the formed precipitate, which was then washed with pentane (3 x 3 mL) and dried under an argon stream to afford Compound 107 as the hydrochloride salt. Example 2: In vivo reduction of perseverative/ repetitive behaviour by 2R,6R- hydroxynorketamine

The marble burying test is one of the most prevalent tests for assessing perseverative and compulsive-like behaviours in mice. It was originally believed that the burying behaviour measured during the test was the result of anxiety triggered by the novel objects. However, the ability of selective serotonin reuptake inhibitors (SSRIs) to reduce burying raised the possibility that the behaviour may be related to obsessive-compulsive disorder (OCD). It is now understood that this test does not selectively measure anxiety alone, as habituation to the marbles does not reduce burying behaviour and the mice did not avoid the marbles when given the chance to do so (Njung'e K, Handley SL. 1991. Evaluation of marble-burying behaviour as a model of anxiety. Pharmacol Biochem Behav 38: 63-7; Broekkamp CL, Rijk HW, Joly-Gelouin D, Lloyd KL. 1986. Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice. Eur J Pharmacol 126: 223-9).

In 2009, Thomas et al undertook a comprehensive study of the marble burying test.

Following a battery of experiments, the authors concluded that the test measured

perseverative, repetitive behaviour (Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R. 2009. Marble burying reflects a repetitive and perseverative behaviour more than novelty-induced anxiety. Psychopharmacology (Berl) 204: 361-73).

Within the present study, the marble burying test was completed as described by Broekkamp et al (1986). Briefly, male Swiss mice (8-10 weeks old, average body weight 39.65g) were placed individually into transparent plastic cages (33 x 21 x 18 cm) containing sawdust 5 cm deep covering the floor and 25 marbles grouped in the centre. Each cage, together with the marbles, was impregnated with mouse odour by leaving 10 mice in the cage for 15 minutes prior to commencement of the test. These mice then played no further role in the experiment. The number of marbles covered by sawdust (a marble is considered as buried if covered by 2/3 or more) were counted at the end of a 30 minute test period.

The effect of 2R,6R-hydroxynorketamine was assessed at 30 and lOOmg/kg (based on weight of active, administered as HC1 salt), administered by oral gavage 60 minutes prior to testing. Dose levels were chosen based on published literature. Vehicle treated (water for injection) and positive control (clobazam 32 mg/kg p.o.) cohorts were used for reference, with vehicle and reference substances administered under the same conditions. The test was performed blind to treatment.

In order to allow interpretation of marble burying data mice were assessed separately for changes in locomotor activity at the same doses used in the marble burying test. 2R,6R- hydroxynorketamine did not result in a change in locomotor activity at either dose.

Results revealed that variation was increased in the treated groups compared with vehicle controls (see Figure 1). Following 30mg/kg 2R,6R-hydroxynorketamine, the number of marbles buried compared to controls fell by 2%, with a 16% reduction in marbles buried seen in the high dose, lOOmg/kg cohort.

Example 3: Evaluation of the effect of 2R,6R-hvdroxynorketamine on cognitive function using the Progressive Ratio Test in the mouse

In order to confirm that the effects observed in Example 2 were a consequence of drug effects on cognitive function, 2R,6R-hydroxynorketamine L-pyroglutamate (2R,6R-HNK) was investigated using a Progressive ratio (PR) schedule.

PR was first described by Hodos in 1961. The schedule requires subjects to perform an incrementally increasing number of responses for the delivery of a single reward (reinforcer). This task is thought to most closely assay motivation and apathy in experimental animals. By challenging the mice to a task in which the difficulty is gradually increased,

one can quantitatively measure the point at which individual mice stop responding (the ‘breakpoint’). PR represents an important tool for assessing dysfunctional motivation behaviour in preclinical studies, including characterisation of rodent models and assessment of candidate therapeutics. Previous studies have demonstrated that PR performance can be affected by pharmacological modulation of a number of neurotransmitter systems, including targets relevant to antidepressant treatment including multiple 5-hydroxytryptamine and dopamine receptor subtypes.

Mice were tested during the dark part of their light/dark cycle. In order to promote reward consumption and therefore facilitate training, mild food restriction was implemented.

Following stabilisation of restricted body weight, animals were familiarised with the reinforcer (strawberry milkshake) and subsequently the apparatus itself. Once habituated to the behavioural equipment, mice were initially trained to emit a set number of responses at the touchscreen for delivery of the reinforcer (fixed ratio schedule). When this behaviour was fully established, mice were tested on sessions which required an increasing number of responses for the delivery of each subsequent reinforcer (progressive ratio schedule; required responses increased by 4 for each trial, from 1 to 5 to 9 etc.). These sessions terminated following either completion of the 60 minute test period or 5 minutes of inactivity. The final number of responses that an animal made for a single reinforcer in a session was termed the ‘breakpoint’ and was taken as an index of motivation and apathy. In addition, the rate of responding (running rate) was analysed to provide further insight into the effect of drug administration on task performance and as an additional indicator of apathy.

A total of 3 dose groups were studied, with a sample number of 16 in each group. 2R,6R- HNK was evaluated at 3 doses administered 20 minutes before the test. The highest dose tested was 300mg/kg. This maximum dose was selected as it corresponded to the highest dose administered in previous studies, as well as falling below the highest dose of 2R,6R- HNK used in the literature (Zanos et al 2016). Ketamine (lOmg/kg) was used as a reference substance. Saline for injection was used as a control, administered under the same

experimental conditions as test compounds. All drugs were dosed via intraperitoneal (IP) injection, chosen based on the experience of the lab and historical data.

Results were analysed by comparing all groups using repeated measures two-way ANOVA or one-way ANOVA, where necessary. RESULTS

Mice performed baseline testing on Day 1 to provide a drug-free reference point, with data used to calculate the fold change in breakpoint after drug treatment. Testing was completed 20 minutes after administration of test, reference or control compound for 4 consecutive days (Tuesday - Friday). This short latency was selected to capture a higher circulating concentration of 2R,6R-HNK as determined in pharmacokinetic studies of 2R,6R-HNK in the mouse.

Under these conditions, 2R,6R-HNK (300mg/kg) produced a significant increase in breakpoint compared to vehicle and ketamine (Figure 2A). This increase in breakpoint remained following normalisation to baseline (Figure 2B).

To investigate possible explanations for the increase in breakpoint, the running rate for each mouse was also determined. This rate was calculated by dividing the number of touches (responses) by the run time (time taken to complete the ratio, excluding the post- reinforcement pause). These values were extracted per animal and fitted with the negative exponential y=a^A(-b*x)). Coefficients for predicted peak response rate (a) and decay of response rate (-b) were extracted and evaluated for between-group significance using a one- way ANOVA or linear mixed-effect models. Running rate measures revealed that following administration of 2R,6R-HNK (300mg/kg), mice maintained a higher rate of responding throughout the 60 minute test session compared to ketamine and vehicle groups (Figure 2C), indicative of increased effort and thus reduced apathy. Average responses per minute performed by 2R,6R-HNK treated mice were 29% higher compared with mice treated only with vehicle, and 59% higher compared with mice treated with ketamine.

In addition to breakpoint (an indicator of motivation) and running rate (a measure of effort, indicative of apathy), the ratio of target to blank touches and percentage of correct touches were calculated, providing a measure of accuracy of task completion indicative of executive function and cognitive control. 2R,6R-HNK (300mg/kg) significantly increased the number of target touches compared to blank touches (Figure 3C) and percentage of correct touches over the 4-day testing period (Figure 3D).

This pattern of improved performance was replicated following a 3-week wash-out period.

As demonstrated previously, 300mg/kg 2R,6R-HNK resulted in a significant increase in breakpoint compared to vehicle and ketamine (Figure 4). The number of target touches

(Figure 5A), the number of target touches to blank touches (Figure 5B) and percent of correct touches (Figure 5D) were also increased, indicating the same improvement in accuracy as seen previously.

2R,6R-HNK was formulated for these assays as a pyroglutamate salt due to its high solubility and easy handling properties. To determine whether pyroglutamate was responsible for the effects observed, sodium L-pyroglutamate (NaPg) was administered as a control (dose matched to 300mg/kg 2R,6R-HNK). NaPg did not significantly affect any measure examined

(Figure 6A and 6B).

CONCLUSION

The results of the Progressive Ratio Task demonstrate that 2R,6R-HNK produces an acute increase in cognitive measures, in particular increased motivation, as evidenced by the increase in breakpoint. The maintenance of an increased running rate over the test hour provides a partial explanation of the increase in breakpoint, and is indicative of increased effort and decreased apathy. Moreover, the rapid and pronounced increase in accuracy in this task among mice exposed to 2R,6R-HNK demonstrates robust cognitive enhancement.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in increasing one or more of executive function, perceptual function, learning ability, memory, and attention in a human;

I wherein n is 0, 1, 2, 3, 4 or 5,

X is selected from CR⁷ and CHR⁷,

R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), OR⁸, benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and C1-C4 alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X from CHR⁷, with the proviso that the compound of Formula I is not selected from 2R,6R- hydroxynorketamine, 2S,6S-hydroxynorketamine, R-5,6-dehydronorketamine and S- 5,6-dehydronorketamine.

2. A compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a disorder selected from a neurocognitive disorder and a neurodevelopmental disorder,

I wherein n is 0, 1, 2, 3, 4 or 5,

R¹, R², R⁴, R⁵, and R⁶ are each independently selected from H and C₁-C₄ alkyl, each R³ is independently selected from OH, 0-(Ci-C₄ alkyl), F, Cl, Br, I, -CF₃, X is CR⁷ and CHR⁷,

R⁷ is selected from H, OH, C1-C4 alkyl, 0-(Ci-C₄ alkyl), OR⁸, benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, Ci-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and Ci-C₄ alkyl,

wherein == is a double bond when X is selected from CR⁷, N, and N(R⁷)⁺, or a single bond when X is selected from CHR⁷, O, NR⁷, and S, with the proviso that the compound of Formula I is not selected from 2R,6R-hydroxynorketamine, 2S,6S- hydroxynorketamine, R-5,6-dehydronorketamine and S-5,6-dehydronorketamine, and wherein

a. the neurocognitive disorder is selected from (i) delirium, (ii) pseudodementia, (iii) frontotemporal neurocognitive disorder, (iv) dementia with Lewy Bodies (v) vascular neurocognitive disorder, (vi) multi-infarct dementia, (vii) A tauopathy, (viii) Parkinson's disease, (ix) Huntingdon's disease, (x) transmissible spongiform encephalopathy, (xi) traumatic brain injury, (xii) post-concussion syndrome, (xiii) amnesia, (xiv) substance-induced neurocognitive disorder, (xv) alcohol-induced neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration, (xvii) brain injury disorder, and (xviii) progressive supranuclear palsy, or b. the neurodevelopmental disorder is selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebal palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) fetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

3. The compound of any one of claims 1 or 2, or a pharmaceutical salt thereof, wherein X is CHR⁷ and R⁷ is selected from OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, 0S0₂R⁸, OSO3R⁸, and OPO3R⁸.

4. The compound of any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein X is either CR⁷, wherein R⁷ is H, or CHR⁷, wherein R⁷ is OH.

5. The compound of any one of claims 1 to 4, or a pharmaceutical salt thereof, wherein n is 1 and R³ is selected from F, Cl, and OMe.

6. The compound of any one of claims 1 to 5, or a pharmaceutical salt thereof, wherein R³ is selected from ortho-Cl and meta-OMe.

7. The compound of any one of claims 1 to 6, or a pharmaceutical salt thereof, wherein R¹ is H and R² is selected from H, Me, or Et.

8. The compound of any one of claims 1 to 7, or a pharmaceutical salt thereof, wherein R⁴, R⁵, and R⁶ are each H.

9. The compound of any one of claims 1 to 8, or a pharmaceutical salt thereof, wherein one or both of R⁴ and R⁶ are Me and R⁵ is H, or R⁴ and R⁶ are H and R⁵ is tBu.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in increasing motivation in a human or patient.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in treating a neurocognitive disorder selected from (i) delirium, (ii) Alzheimer’s disease, (iii) pseudodementia, (iv) frontotemporal neurocognitive disorder, (v) dementia with Lewy Bodies (vi) vascular neurocognitive disorder, (vii) multi-infarct dementia, (viii) A tauopathy, (ix) Parkinson's Disease, (x) Huntingdon's disease, (xi) transmissible spongiform encephalopathy, (xii) amyotrophic lateral sclerosis, (xiii) traumatic brain injury, (xiv) post-concussion syndrome, (xv) amnesia, (xvi) substance-induced neurocognitive disorder, (xvii) alcohol-induced

neurocognitive disorder, and (xviii) stroke disorder, (xix) hypersomnia, and (xx) clonic perseveration.

12. The compound of any one of claims lto 10, or a pharmaceutically acceptable salt thereof, for use in treating a neurodevelopmental disorder selected from (i) intellectual disability, (ii) learning disability, (iii) dyslexia, (iv) dyscalculia, (v) dyspraxia, (vi) dysgraphia, (vii) autism-spectrum disorder, (viii) stereotypic movement disorder, (ix) tic disorder, (x) cerebal palsy (xi) fragile-X syndrome, (xii) Down Syndrome, (xiii) attention-deficit disorder, (xiv) hypogonadotropic hypogonadal syndrome (xv) neurotoxicant poisoning, (xvi) fetal alcohol spectrum disorder, (xvii) Minamata disease, and (xviii) Rett Syndrome.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in treating a psychocognitive disorder selected from (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) a schizophrenia disorder, (iv) a schizotypal disorder, (v) an anxiety disorder, (vi) substance abuse, and (vii) an avolition disorder.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in treating a disorder of diminished motivation selected from (i) apathy, (ii) aboulia, and (iii) akinetic mutism.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein the disorder of diminished motivation is apathy and the neurocognitive disorder, neurodevelopmental disorder, or psychocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) a schizophrenia disorder, (v) substance abuse, (vi) attention-deficit hyperactivity disorder, (viii) Alzheimer's disease, (ix) Parkinson's disease, (x) Huntington's disease, (xi) amyotrophic lateral sclerosis, (xii) a stroke disorder, and (xiii) a brain injury disorder.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the neurocognitive disorder, neurodevelopmental disorder, or psychocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, and (iv) a schizophrenia disorder.

17. The compound of any previous claim, or a pharmaceutically acceptable salt thereof, for use in enhancing one or more cognitive subdomain selected from (i)

visuocontructional reasoning, (ii) cued recall, (iii) recognition memory, (iv) implicit learning, (v) associative learning, (vi) sustained attention, (vii) selective attention, (viii) processing speed, (ix) working memory, and (x) sensory memory.

18. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

19. A solid oral dosage form comprising the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

20. The solid oral dosage form of claim 19 wherein the dosage form is selected from a capsule and a tablet.

21. The composition of claim 20 or the solid oral dosage form of claim 19 or 20 for use in combination with a serotonin modulator.

22. The composition or dosage form for use according to claim 21 wherein the serotonin modulator is a selective serotonin reuptake inhibitor (SSRI).

23. The composition or dosage form according to claim 21 or 22 wherein said

composition or dosage form and said serotonin modulator are administered

simultaneously, sequentially or separately.

24. The composition or dosage form according to any one of claims 21 to 23 wherein said serotonin modulator is selected from Citalopram, Escitalopram, Paroxetine,

Fluoxetine, Fluvoxamine, Sertraline, Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran, Tofenacin, Venlafaxine, Vilazodone, Vortioxetine, Etoperidone, Nefazodone, and Trazodone, or a pharmaceutically acceptable salt thereof.

25. The composition or dosage form according to any one of claims 21 to 24 wherein the serotonin modulator is selected from Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, Vortioxietine and Venlafaxine, or a pharmaceutically acceptable salt thereof.

26. The compound, composition or dosage form of any preceding claim for use as a first- line therapy.

27. The compound, composition or dosage form of any preceding claim for use as an adjunct to behavioural therapy.

28. A method of treating a patient suffering from a disorder selected from a

neurocognitive disorder, a neurodevelopmental disorder, and a psychocognitive disorder, wherein said method comprises the steps of a. Identifying a deficit in a cognitive domain of said patient, wherein the

cognitive domain is selected from executive function, perceptual function, learning ability, memory, and attention, and b. Administering to said patient a compound of Formula I, or a pharmaceutically acceptable salt thereof;

I wherein n is 0, 1, 2, 3, 4 or 5,

X is selected from CR⁷ and CHR⁷,

R⁷ is selected from H, OH, Ci-C₄ alkyl, 0-(Ci-C₄ alkyl), OR⁸, benzyl, 0(C=0)-R⁸, 0(C=0)0-R⁸, 0(C=0)NR⁸R⁹, OSO2R⁸, OSO3R⁸, OPO3R⁸ wherein R⁸ is selected from H, Ci-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₆-Cio aryl, C₆-Cio heteroaryl, and R⁹ is selected from H and Ci-C₄ alkyl,

wherein == is a double bond when X is CR⁷, or a single bond when X is CHR⁷, with the proviso that the compound of Formula I is not selected from 2R,6R- hydroxynorketamine, 2S,6S-hydroxynorketamine, R-5,6-dehydronorketamine and S- 5,6-dehydronorketamine.

29. The method of claim 28, wherein the compound of Formula I is the compound of any one of claims 1 to 17, 26 or 27.

30. The method of claim 28 or 29 wherein the compound of Formula I is administered in a composition or solid oral dosage form according to any one of claims 18 to 27.

31. The method of any one of claims 28 to 30 wherein the deficit in said cognitive domain is identified using a computer-based cognitive assessment.