A GABA receptor modulator for use in the treatment of tremor

Abstract

Provided herein are methods for treating and / or preventing tremor, as well as diseases and disorders associated with tremor, such as essential tremor.

Description

[0001] P7475PC00

[0002] A GABA receptor modulator for use in the treatment of tremor

[0003] Technical field

[0004] The present invention relates to the use of GABAA-03 subtype selective compounds for treating and / or preventing tremor. Moreover, the present invention relates to the use of GABAA-03 selective compounds for treating and / or preventing disorders associated with tremor.

[0005] Background

[0006] Tremor is a common movement disorder that includes shaking or trembling movements in one or more parts of the body, including the hands, head, tongue, legs, and the voice. Tremor is categorized based on when and how the tremor is activated, and includes both rest and action tremor, which occurs respectively when the muscle is at rest (resting tremor) or when the muscle is moved voluntarily (action tremor).

[0007] Essential tremor (ET) is a chronic and progressive neurological disease whose main symptom is tremor. The etiology of ET is largely unknown, but it has been suggested that the GABAA receptor plays a role in the pathophysiology of ET, and that dysfunction in the GABAergic system, particularly involving GABAA receptors, contributes to the abnormal neural activity underlying ET.

[0008] Benzodiazepines, which non-selectively enhance the effect of GABA at the GABAA receptors containing a1 , a2, a3, and a5 subunits, have been shown to be effective in the treatment of ET. However, their clinical utility is limited by adverse effects such as sedation, ataxia, tolerance development, and memory impairment. Preclinically, activation of distinct GABAA receptors containing different a-subtypes has been associated with well-known effects such as sedation (a1), muscle relaxation (a2), anxiolysis (a2 / 3), and memory impairment (a5). Furthermore, it has been demonstrated that GABAA a2 / 3 subtype selective modulator NS16085 significantly and dose- dependently inhibits harmaline-induced tremors in rats, indicating that potentiation of a2- and a3-containing GABAA receptors is sufficient to ameliorate harmaline-induced tremors (Amrutkar, D.V. et al., The Cerebellum (2020) 19:265-274).

[0009] The mechanisms underlying tremor pathology are poorly understood, and existing therapeutic agents are hampered by either inadequate efficacies or intolerable side P7475PC00 effects. Thus, there is a need for improved tremorolytic compounds, for treatment of tremors, as well as diseases and disorders associated with tremor.

[0010] Summary

[0011] The invention concerns methods for treatment and prevention of tremor. The present inventors have surprisingly found that 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, Compound 1 , which is a GABAA-QS subtype selective positive allosteric modulator, reduces tremor. Hence, it has surprisingly been demonstrated that functional activity at the GABAA O2-subunit is dispensable for the anti-tremor effect in a model of ET.

[0012] Compound 1 : 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7-imidazo[4,5- b]pyridin-6-yl)propan-2-ol

[0013] In one aspect, the present invention relates to Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of tremor as well as diseases and disorders associated with tremor, such as essential tremor.

[0014] Description of Figures

[0015] Figure 1. Effect of Compound 1 on harmaline induced tremor in rats. Compound 1 dose dependently reduces harmaline-induced tremor in rats.

[0016] Figure 2. Compound 1 inhibited harmaline-induced tremors in rats. Data is presented as a motion power percentage (%MP), which is the ratio of the Percent Energy Spent P7475PC00 at tremor frequency (11-13Hz) I all frequency (0-30Hz) (Martine FC et al., 2005; Adrian- Hanforth etal . , 2012). Compound 1 decreased %MP to the same magnitude as that of primidone. Reproducible results are observed with 3 mg / kg, dose of Compound 1. The minimal effective dose is 1 mg / kg.

[0017] Figures 3A-3B. Harmaline-induced tremors were quantified in rats using tremor boxes. Significantly, as shown in Figs. 3A-3B, Compound 1 , as well as decreasing the harmaline-induced tremors similar to the efficacy observed with primidone, also reversed harmaline-induced effects in the 4-8 Hz range, something which is not ameliorated by primidone. Tremor monitors differentiate tremor events from ambulatory / stereotyped movements by using an ultrasensitive movement sensor, and motion activity is measured by piezoelectric disc attached to the bottom of animal enclosure in the tremor box. Percentage Energy Spent: this measure typically refers to the proportion of signal energy within a certain frequency range relative to the total energy across all frequencies. For tremor analysis, it helps to identify the frequency range where the tremor is most pronounced. dBV (Decibels Relative to 1 Volt) provides information about the strength of the tremor signal (severity of the tremor).

[0018] Figure 4. Orthogonal cross sections of co-registered PET and MR images from subject 3001 (Fig. 4A), 3002 (Fig. 4B), and 3003 (Fig. 4C). From left to right columns, images are PET1 , PET2, PET3 and structural (T1 weighted) MRI. PET images are shown as SUV summed from 10 - 90 minutes.

[0019] Figure 5. Brain GABAA receptor occupancy data plotted against measured plasma concentration of Compound 1. The plotted curve fit is to Equation 3; the dashed vertical line shows the estimated ECso value, and the vertical dotted lines the corresponding 95% confidence interval.

[0020] Figure 6. Effects of Compound 1 and Diazepam on exploratory locomotor activity of rats. (6A) Compound 1 (3, 10, 30 mg / kg, po) or vehicle treatment did not affect the explorative locomotion of rats. Data is presented as mean ± S.E.M. of total distance travelled over 30 minutes. *P<0.05, vs. vehicle (one way ANOVA followed by Fisher’s LSD post hoc test) n=7 / group. (6B) Diazepam (1 , 3, 6 mg / kg, po) treatment dose dependently decreased the explorative locomotion of rats. Data is presented as mean ± S.E.M. of total distance travelled over 30 minutes. *P<0.05, vs. vehicle (one way ANOVA followed by Fisher’s LSD post hoc test) n=7 / group. P7475PC00

[0021] Detailed description

[0022] The present invention is based, at least in part, on the finding that administration of Compound 1 , which is a GABAA-03 subtype selective PAM, provides for reduction of tremor. In Example 1 , it is demonstrated that Compound 1 provides for significant and dose-dependent inhibition of harmaline-induced tremor in rats indicating the potential for alleviation of essential tremors in humans . Example 2 demonstrates that, not only does Compound 1 reduce harmaline-induced tremor, but it also normalizes the percentage energy spent pattern in the lower frequency range, in contrast to, for example, primidone. Moreover, it is demonstrated in Example 5 that Compound 1 is devoid of sedative activity in rats.

[0023] Furthermore, as demonstrated in Example 4, orally dosed Compound 1 can engage a significant proportion of brain GABAA receptors in humans.

[0024] Tremor

[0025] Tremor is a movement disorder that includes involuntary oscillations (shaking or trembling movements) in one or more parts of the body, most commonly affecting a person’s hands. It can also occur in the arms, legs, head, neck vocal cords, and torso. The tremor may be constant, or only happen sometimes. Tremor can occur on its own or as a result of another disorder, or drug treatment of another disorder. Moreover, tremor can occur when the muscle is at rest (resting tremor) or when the muscle is moved voluntarily (action tremor).

[0026] Tremor is not life threatening, but may cause challenges with daily life tasks such as writing, typing, eating, shaving, and dressing, or even lead to disabilities. Several tremor syndromes exist, including essential tremor, dystonic tremor, cerebellar tremor, functional tremor, enhanced physiologic tremor, parkinsonian tremor and orthostatic tremor. The tremor syndromes are defined based on the pattern of the tremor, as well as the type of tremor.

[0027] The type of tremor is commonly classified according to the behavioural circumstances in which it occurs. The main categories are action tremor and rest tremor, as further defined below.

[0028] Action tremor P7475PC00

[0029] Action tremor occurs when a muscle is moved voluntarily. There are several subclassifications of action tremor, many of which overlap, including:

[0030] • Postural tremor, which occurs when holding a position against gravity, such as holding the arms outstretched.

[0031] • Kinetic tremor, which is associated with any voluntary movement, such as moving the wrists up and down or closing and opening your eyes. o Intention tremor, which starts when the person makes an intended movement toward a target, such as lifting a finger to touch their nose. o Task-specific tremor, which only appears when performing goal-oriented tasks such as handwriting or speaking.

[0032] • Isometric tremor, which occurs during a voluntary muscle contraction that is not accompanied by any movement, such as when holding a heavy book in the same position.

[0033] Rest tremor

[0034] Resting tremors happen while the patient is sitting or lying down and relaxed. People who have a resting tremor can usually stop the tremor by deliberately moving the affected body part, as rest tremor typically goes away with movement.

[0035] Rest tremor is the type of tremor typically experienced by people with Parkinson’s disease.

[0036] Disorders associated with tremor, according to ICD-11 , includes:

[0037] - Essential tremor (8A04.1)

[0038] - Enhanced physiological tremor (8A04.0)

[0039] - Functional tremor (8A04.4)

[0040] - Secondary tremor (8A04.3), including:

[0041] - Tremor due to metabolic disorders (8A04.30)

[0042] - Tremor due to chronic or acute substance use (8A04.31)

[0043] - Tremor due to drug withdrawal (8A04.32)

[0044] - Tremor due to certain specified central nervous system diseases (8A04.33)

[0045] - Other specified secondary tremor (8A04.3Y)

[0046] - Unspecified secondary tremor (8A04.3Z)

[0047] - Rest tremor (8A04.2)

[0048] - Other specified disorders associated with tremor (8A04.Y) P7475PC00

[0049] - Unspecified disorders associated with tremor (8A04.Z)

[0050] Essential tremor

[0051] Essential tremor (ET), previously called “familial tremor” or “benign essential tremor,” is a chronic and progressive neurological disease whose main symptom is tremor with a frequency ranging from 4 to 12 Hz in humans.

[0052] The tremors in ET affect various parts of the body, including the hands (approximately 95% of patients), head (at minimum, 34%), tongue (about 30%), legs (approximately 30%), as well as the voice (at minimum, 12%), face / chin (about 7%), neck and torso (approximately 5%). Although ET usually does not reduce life expectancy or cause other symptoms, many patients have severe psychosocial disability, as tremor often increases with anxiety, stress, and in situations involving interaction with others (Pal, 2011).

[0053] Essential tremor affects approximately 1% of the population, and 5-6% of people aged over 65 years. The prevalence increases with age, but the condition can appear in early adulthood in those who have a family history of essential tremor.

[0054] As life expectancy increases, the prevalence of essential tremor increases. The disease is progressive, with a gradual increase in symptoms, such as increased tremor amplitude.

[0055] Essential tremor is characterised by action tremors, and typically involves kinetic, intention tremors and / or postural tremors. Essential tremor should be differentiated from other types of tremors, especially Parkinson's disease which is characterised by rest tremors.

[0056] Animal models of Essential tremor

[0057] The most common animal model used in the preclinical screening of potential ET therapies is the Harmaline-induced tremor model (Martin, F.C. et al., 2005). Harmaline- induced tremor is an action tremor (kinetic and postural tremor), which as essential tremor is intensified during movement. Concordance in the anti-tremor effect between the harmaline model and patients with essential tremor has been demonstrated for propranolol, primidone, clonazepam, zonisamide, and gabapentin, among others. P7475PC00

[0058] Other models include genetic models. These models are known to be less reliable (Kosmowska and Wardas, 2021).

[0059] Treatment of tremor

[0060] Current therapies used to help manage symptoms of essential tremor include propranolol (a nonselective beta-adrenergic antagonist) and primidone (an antiepileptic drug, a derivative of barbituric acid), however, their use is associated with adverse effects like hypotension, depression, and cognitive impairments. Moreover, it has been shown that benzodiazepines are effective in treating ET. Their use, however, is limited due to sedation, ataxia, tolerance development and memory impairment. Alternative treatment strategies include brain surgery, such as deep brain stimulation of the motor thalamus, and botulinum toxin injection to relevant muscles (Kosmowska and Wardas, 2021). The treatment strategies are hampered from inadequate efficacies or intolerable side effects.

[0061] As demonstrated in Example 1 , Compound 1, which is a GABAA-03 subtype selective PAM, provides for significant and dose-dependent inhibition of harmaline-induced tremor in rats indicating the potential for alleviation of essential tremors in humans.

[0062] In one aspect, the present invention relates to a GABAA-03 subtype selective PAMs for use in the treatment or prevention of tremor. In one aspect, the present invention relates to Compound 1, or a pharmaceutically acceptable salt thereof or hydrate thereof, for use in the treatment or prevention of tremor. In one aspect, the present invention relates to Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of tremor.

[0063] In one aspect, the present invention relates to a method for treating and / or preventing tremor, the method comprising administering a GABAA-03 subtype selective PAM to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing tremor, the method comprising administering Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing tremor, the method comprising administering Compound 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. P7475PC00

[0064] In one aspect, the present invention relates to a method of reducing tremor in a subject, said method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof to the subject in need thereof.

[0065] In one aspect, the present invention relates to use of a GA BAA-OS subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject.

[0066] In some embodiments, the tremor is hand tremor, head tremor, leg tremor, voice tremor, tongue tremors, face tremor, chin tremor, neck tremor and / or torso tremor.

[0067] In some embodiments, the tremor is action tremor. In some embodiments, the action tremor is postural tremor, kinetic tremor and / or isometric tremor. In some embodiments, the action tremor is postural tremor and / or kinetic tremor.

[0068] In some embodiments, the tremor is kinetic tremor, such as intention tremor and / or task-specific tremor.

[0069] In some embodiments, the tremor is increased by anxiety and / or stress. In some embodiments, the tremor is induced by drugs. In some embodiments, the tremor is worsened by drugs.

[0070] In some embodiments, the disease or disorder associated with tremor is essential tremor, enhanced physiological tremor, functional tremor, secondary tremor and / or rest tremor. In some embodiments, the disease or disorder associated with tremor is essential tremor. In some embodiments, the essential tremor is hereditary essential tremor. In some embodiments, the essential tremor is familial essential tremor. P7475PC00

[0071] In one aspect, the present invention relates to a GABAA-03 subtype selective PAM for use in the treatment and / or prevention of essential tremor. In one aspect, the present invention relates to Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, for use in the treatment and / or prevention of essential tremor. In one aspect, the present invention relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of essential tremor.

[0072] In one aspect, the present invention relates to a method for treating and / or preventing essential tremor, the method comprising administering a GABAA-03 subtype selective PAM to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing essential tremor, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing essential tremor, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0073] As demonstrated in Example 2, Compound 1 can be used to treat essential tremors without side effects such as sedation. Compound 1 decreased the harmaline-induced tremors similar to the efficacy observed with primidone (Figure 3). Moreover, Compound 1 also reversed harmaline-induced effects in the lower frequence range (4- 8 Hz), which was not ameliorated by primidone. Compound 1 ameliorates the harmaline induced effects, not only in the frequence range that tremors are induced. Thus, Compound 1 normalizes the percentage energy spent pattern.

[0074] In some embodiments, the compound reduces tremor without significantly causing sedation. In some embodiments, the compound reduces tremor without significantly causing sedation in the 4-8 Hz frequency range. In some embodiments, the compound reduces tremor without significantly causing sedation in the 4-8 Hz range in the Harmaline-induced Tremor rat model. In one aspect, the present invention relates to a method for treating and / or preventing tremor without eliciting sedation in a subject, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the sedation is not elicited in the tremor 4-8 Hz frequency range. In some embodiments, the sedation is elicited by P7475PC00 harmaline and not relieved or ameliorated by primidone. In some embodiments, the compound reduces tremor primarily in the 8-15 Hz range, such as primarily in the IQ- 14 Hz range, such as primarily in the 11-13 Hz range in the Harmaline-lnduced Tremor rat model. In some embodiments, the compound reduces tremor primarily in the 8-12 Hz range. In some embodiments, the tremor reduction is reduction in tremor amplitude. In some embodiments, the tremor reduction is measured in terms of motion power. In some embodiment, the tremor reduction is measured in terms of strength / severity of the tremor, e.g. in Decibels Relative to 1 Volt (dBV).

[0075] In one aspect, the present invention relates to use of a GABAA-QS subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of essential tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of essential tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of essential tremor in a subject.

[0076] In one aspect, the present invention relates to a GABAA-03 subtype selective PAM for use in the treatment or prevention of a disease or disorder associated with tremor. In one aspect, the present invention relates to Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, for use in the treatment or prevention of a disease or disorder associated with tremor. In one aspect, the present invention relates to Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder associated with tremor.

[0077] In one aspect, the present invention relates to a method for treating and / or preventing a disease or disorder associated with tremor, the method comprising administering a GABAA-03 subtype selective PAM to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing a disease or disorder associated with tremor, the method comprising administering Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof. In one aspect, the present invention relates to a method for treating and / or preventing a disease or disorder associated with tremor, the method comprising P7475PC00 administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0078] In one aspect, the present invention relates to use of a GA BAA-OS subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of tremor and / or a disease or disorder associated with tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor and / or a disease or disorder associated with tremor in a subject. In one aspect, the present invention relates to use of Compound 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor and / or a disease or disorder associated with tremor in a subject.

[0079] In some embodiments, the disease or disorder associated with tremor is not Parkinson’s disease. In some embodiments, the disease or disorder associated with rest tremor is not Parkinson’s disease. In one embodiment the tremor is not rest tremor.

[0080] Any appropriate method may be used to evaluate the severity of tremor. Examples of methods that can be used to evaluate the severity of a movement disorder and / or a symptom of a movement disorder include, without limitation, measurements of activities of daily living (e.g., as measured using TETRAS), clinician global impression of improvement (e.g., as measured using CGI-I), patient global impression of change (e.g., as measured using PGIC), tremor specific goal attainment (e.g., as measured using GAS), quality of life (e.g., as measured using QUEST tremor medication satisfaction sub-item), and Archimedes spiral (e.g., as measured using pen and paper as in the TETRAS-PS sub-item and / or measured digitally using a tablet and stylus such as in iMotor). For example, the severity, frequency, and impact of tremor may be measured using one or more method selected from clinical rating scales, objective tools, and patient-reported outcomes. Clinical rating scales include but are not limited to The Tremor Rating Scale (TRS), The Fahn-Tolosa-Marin (FTM) Tremor Rating Scale, and Activities of Daily Living (ADL) Scales. Objective tools include but are not limited to accelerometry, electromyography (EMG), Motion Capture Systems, and Digitized Spiral Analysis. Patient-reported outcomes include but are not limited to P7475PC00

[0081] Tremor Impact Scale (TIS), and Quality of Life in Essential Tremor Questionnaire (QUEST). Further, the severity, frequency, and impact of tremor may be measured using video recordings reviewed by trained clinicians to rate tremor severity using scales like the TRS or FTM; and / or functional assessments such as drinking from a cup and writing a sentence. Moreover, technologies like wearables devices can be used to monitor tremor continuously in real-life settings, providing data on frequency and severity; and machine learning algorithms may be used to analyze large datasets from motion sensors or accelerometers, improving accuracy in tremor characterization.

[0082] The efficacy of the compound or composition disclosed herein for treating tremor can be measured by methods known in the art. Examples of such methods are presented elsewhere in this application. In some embodiments, the the tremor is reduced with at least 10%, such as 20%, such as 30%, such as 40%, such as 50%, such as 60%, such as 70%. In some embodiments, the tremor is reduced with at least about 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75% following treatment onset.

[0083] In some embodiments, the methods described herein result in at least 25% reduction in the upper limb tremor score, wherein the tremor score may be converted to amplitude, as compared to a baseline. For example, in certain embodiments, the methods described herein result in about 40% mean reduction in tremor amplitude as measured by The Essential Tremor Rating Assessment Scale (TETRAS) upper limb score, described, for example, in Elble, R.J., “The Essential Tremor Rating Assessment Scale,” J. Neurol. Neuromed. 2016; l(4):34-38. In some embodiments, the methods described herein result in at least 25% reduction in TETRAS performance score as compared to the baseline. In some embodiments, the methods described herein result in at least 35% average reduction in symptom severity as compared to the baseline, as measured by TETRAS performance score.

[0084] In some embodiments, efficacy of the treatment may be assessed by Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) (Elble 2008). TETRAS consists of a 12-item activities of daily living (ADL) subscale, and a 9-item performance subscale (PS). In some embodiments, efficacy of the treatment may be assessed by Tremor Research Group Essential Tremor Rating Assessment Scale - Activities of Daily Living (TETRAS-ADL) subscale. TETRAS-ADL subscale is a patient-rated scale P7475PC00 of the impact of tremor on day-to-day functioning that is administered by a trained interviewer. The TETRAS-ADL directly measures how a patient functions by assessing activities impacted by tremor, such as eating and drinking, dressing and personal hygiene, carrying items, and finer motor skills (Elble 2012). The ADL subscale includes many of the items assessed in previously developed scales for the evaluation of tremor (Fahn 1993; Louis 2000; Bain 1993), including eating and drinking, dressing and personal hygiene, carrying items and finer motor skills. Each item in the TETRAS-ADL is rated on a 0 to 4 scale, with 0 representing normal activity and 4 representing severe abnormality. The sum of the individual scores provides the overall score, ranging from 0 to 48.

[0085] In some embodiments, the subject has an initial TETRAS ADL subscale total score of at least 12 prior to treatment onset. In some embodiments, the subject has an initial TETRAS ADL subscale total score of less than about 28 prior to treatment onset. In some embodiments, the subject has an initial TETRAS ADL subscale total score of at least about 20 prior to treatment onset. In some embodiments, the subject has an initial TETRAS ADL subscale total score of at least about 24 prior to treatment onset. In some embodiments, the subject has an initial TETRAS ADL subscale total score of at least about 28 prior to treatment onset.

[0086] The TETRAS ADL performance subscale includes 9 metrics or characteristics, wherein each metric or characteristic is scored 0 to 4. Some metrics or characteristics are performed on both right and left limbs and / or include multiple subitems. The 9 metrics or characteristics include: 1) Head tremor, 2) Face (including jaw) tremor, 3) Voice tremor, 4) Upper limb tremor, 5) Lower limb tremor, 6) Archimedes spirals, 7) Handwriting, 8) Dot approximation task, and 9) Standing tremor.

[0087] As used herein, "The Essential Tremor Rating Assessment Scale (TETRAS) performance subscale part 4 upper limb tremor total score" refers to the "upper limb tremor" under metric or characteristic 4 of the TETRAS performance subscale set forth above. Each of the three tasks are performed on each limb to give a total of 6 tasks, wherein each task is scored 0, 1, 1.5, 2, 2.5, 3, 3.5, or 4, and each score is added to give a total score no greater than 24. P7475PC00

[0088] In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of no greater than 12 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 4 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 6 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 8 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 10 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 12 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 20 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 24 prior to treatment onset. In some embodiments, the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 28 prior to treatment onset.

[0089] In one aspect, the present invention provides a method of treating essential tremor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, wherein the subject experiences a reduction in TETRAS activities of daily living (ADL) subscale total score following treatment onset.

[0090] In some embodiments, the subject experiences a reduction in TETRAS ADL subscale total score of at least about 5% following treatment onset. For example, the subject experiences a reduction in TETRAS ADL subscale total score of at least about 10% following treatment onset. In other examples, the subject experiences a reduction in TETRAS ADL subscale total score of at least about 15% following treatment onset. In other examples, the subject experiences a reduction in TETRAS ADL subscale total score of at least about 20% following treatment onset.

[0091] In some embodiments, the subject experiences the reduction in TETRAS ADL subscale total score about 8 days following treatment onset. In some embodiments, the P7475PC00 subject experiences a reduction in TETRAS ADL subscale total score about 10 days following treatment onset. In some embodiments, the subject experiences a reduction in TETRAS ADL subscale total score about 15 days following treatment onset. In some embodiments, the subject experiences a reduction in TETRAS ADL subscale total score about 20 days following treatment onset. In some embodiments, the subject experiences a reduction in TETRAS ADL subscale total score about 25 days following treatment onset. In some embodiments, the subject experiences a reduction in TETRAS ADL subscale total score about 30 days following treatment onset.

[0092] In some embodiments, the tremor amplitude is reduced following treatment onset. In some embodiments, the amplitude is reduced with at least about 5%, such as at least 15%, such as at least 30%, such as at least 50%, such as at least 75% following treatment onset.

[0093] Reduction in tremor amplitude may be calculated based on the following formula (Elble R.J., Tremor Other Hyperkinet. Mov. (2018), 8:600):

[0094] J T. _ — Tl- =10a(Rf-Ri) / N _1

[0095] Ti wherein

[0096] Tf is a final tremor amplitude:

[0097] Tj is an initial tremor amplitude;

[0098] Rf is a final tremor rating;

[0099] Ri is an initial tremor rating; a is 0.05; and

[0100] N = 6, for 6 tasks in TETRAS performance subscale part 4 upper limb tremor total score.

[0101] Tremor amplitude can be measured using any method or apparatus known in the art. Examples of apparatus for measurement of tremor amplitude include, but are not limited to, accelerometers or gyroscopes (Hess and Pullman, Tremor Other Hyperkinet Mov. (2012) 28;2).

[0102] In some embodiments, the tremor is reduced within 60 minutes after administration, such as within 30 minutes after administration. P7475PC00

[0103] In some embodiments, the tremor is decreased for at least 3 hours after administration, such as 4 hours, such as 5 hours, such as 6 hours, such as 7 hours, such as 10 hours, such as 12 hours, such as 18 hours, such as 24 hours.

[0104] In some embodiments, the subject experiences a reduction in tremor amplitude about 5 days following treatment onset. In some embodiments, the subject experiences a reduction in tremor amplitude about 8 days following treatment onset. For example, the subject experiences a reduction in tremor amplitude about 10 days, about 12 days, about 14 days, about 16 days, about 18 days, about 20 days, about 25 days, about 30 days, or about 40 days following treatment onset.

[0105] In some embodiments, the treatment is acute. In some embodiments, the treatment is prophylactic. In some embodiments, the treatment is preventive. In some embodiments, the treatment by is ameliorative. In some embodiments, the treatment is symptomatic.

[0106] Preferably, the subject is a mammal, such as a human.

[0107] In one embodiments, the subject is suffering from tremor. In one embodiments, the subject is suffering from a disease or disorder associated with tremor.

[0108] In some embodiments, the subject is having, is suspected of having, or at risk of developing tremor. In some embodiments, the subject is a human subject having, suspected of having, or at risk of developing tremor. In some embodiments, the subject is having, is suspected of having, or at risk of developing essential tremor. In some embodiments, the subject is a human subject having, suspected of having, or at risk of developing essential tremor.

[0109] In some embodiments, the subject is a human having, suspected of having, or at risk of developing tremor. In one embodiment, the subject is a human having, suspected of having, or at risk of developing a disease or disorder associated with tremor. In one embodiment, the subject is a human having, suspected of having, or at risk of developing essential tremor. In one embodiment, the subject is genetically related to a human subject having essential tremor. P7475PC00

[0110] In one embodiment, the subject is above 30 years old, such as above 40 years old, such as above 50 years old, such as above 60 years old.

[0111] In some embodiments, the subject is administered a dose of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 0.001 - 100 mg / kg. In some embodiments, Compound 1 is administered to the subject as a dose ranging from 0.001 mg / kg - 100 mg / kg, such as 0.001 - 0.01 mg / kg, such as 0.01 - 0.05 mg / kg, such as 0.05 - 1.0 mg / kg, such as 1 - 5 mg / kg, such as 5 - 10 mg / kg, such as 10 - 25 mg / kg, such as 25 - 50 mg / kg, such as 50 - 100 mg / kg. In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, is administrated by the oral route. In one embodiment of the present invention, the treatment by Compound 1 is administered perorally to a subject as a dose ranging from 0.001 mg / kg - 100 mg / kg, such as 0.001 - 0.01 mg / kg, such as 0.01 - 0.05 mg / kg, such as 0.05 - 1.0 mg / kg, such as 1 - 5 mg / kg, such as 5 - 10 mg / kg, such as 10 - 25 mg / kg, such as 25 - 50 mg / kg, such as 50 - 100 mg / kg.

[0112] In some embodiments, the subject is administered a daily dose of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 1 to 500 mg, such as 10 to 250 mg, such as 50 to 150 mg. In some embodiments, the subject is administered a daily dose of Compound 1, or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 10 to 130 mg, such as 20 to 120 mg, such as 30 to 120 mg, such as 40 to 120 mg, such as 50 to 120 mg, such as 10 to 110 mg, such as 10 to 100 mg, such as 30 to 70 mg, such as 40 to 80 mg, such as 50 to 120 mg, such as 50 to 130 mg. In some embodiments, the subject is administered a daily dose of Compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 40 to 150 mg, such as 50 to 150 mg, such as 60 to 150 mg, such as 75 to 150 mg, such as 100 to 150 mg.

[0113] In some embodiments, the daily dose is 1 mg. In some embodiments, the daily dose is 10 mg. In some embodiments, the daily dose is 20 mg. In some embodiments, the daily dose is 25 mg. In some embodiments, the daily dose is 30 mg. In some embodiments, the daily dose is 35 mg. In some embodiments, the daily dose is 40 mg. In some embodiments, the daily dose is 41 mg.

[0114] In some embodiments, the daily dose is 42 mg. In some embodiments, the daily dose is 43 mg. In some embodiments, the daily dose is 44 mg. In some embodiments, the P7475PC00 daily dose is 45 mg. In some embodiments, the daily dose is 46 mg. In some embodiments, the daily dose is 47 mg. In some embodiments, the daily dose is 48 mg In some embodiments, the daily dose is 49 mg. In some embodiments, the daily dose is 50 mg. In some embodiments, the daily dose is 51 mg. In some embodiments, the daily dose is 52 mg. In some embodiments, the daily dose is 53 mg. In some embodiments, the daily dose is 54 mg. In some embodiments, the daily dose is 55 mg In some embodiments, the daily dose is 56 mg. In some embodiments, the daily dose is 57 mg. In some embodiments, the daily dose is 58 mg. In some embodiments, the daily dose is 59 mg. In some embodiments, the daily dose is 60 mg. In some embodiments, the daily dose is 61 mg. In some embodiments, the daily dose is 62 mg In some embodiments, the daily dose is 63 mg. In some embodiments, the daily dose is 64 mg. In some embodiments, the daily dose is 65 mg. In some embodiments, the daily dose is 66 mg. In some embodiments, the daily dose is 67 mg. In some embodiments, the daily dose is 68 mg. In some embodiments, the daily dose is 69 mg In some embodiments, the daily dose is 70 mg. In some embodiments, the daily dose is 71 mg. In some embodiments, the daily dose is 72 mg. In some embodiments, the daily dose is 73 mg. In some embodiments, the daily dose is 74 mg. In some embodiments, the daily dose is 75 mg. In some embodiments, the daily dose is 76 mg In some embodiments, the daily dose is 77 mg. In some embodiments, the daily dose is 78 mg. In some embodiments, the daily dose is 79 mg. In some embodiments, the daily dose is 80 mg. In some embodiments, the daily dose is 81 mg. In some embodiments, the daily dose is 82 mg. In some embodiments, the daily dose is 83 mg In some embodiments, the daily dose is 84 mg. In some embodiments, the daily dose is 85 mg. In some embodiments, the daily dose is 86 mg. In some embodiments, the daily dose is 87 mg. In some embodiments, the daily dose is 88 mg. In some embodiments, the daily dose is 89 mg. In some embodiments, the daily dose is 90 mg In some embodiments, the daily dose is 91 mg. In some embodiments, the daily dose is 92 mg. In some embodiments, the daily dose is 93 mg. In some embodiments, the daily dose is 94 mg. In some embodiments, the daily dose is 95 mg. In some embodiments, the daily dose is 96 mg. In some embodiments, the daily dose is 97 mg In some embodiments, the daily dose is 98 mg. In some embodiments, the daily dose is 99 mg. In some embodiments, the daily dose is 100 mg. In some embodiments, the daily dose is 101 mg. In some embodiments, the daily dose is 102 mg. In some embodiments, the daily dose is 103 mg. In some embodiments, the daily dose is 104 mg. In some embodiments, the daily dose is 105 mg. In some embodiments, the daily P7475PC00 dose is 106 mg. In some embodiments, the daily dose is 107 mg. In some embodiments, the daily dose is 108 mg. In some embodiments, the daily dose is 109 mg. In some embodiments, the daily dose is 110 mg. In some embodiments, the daily dose is 111 mg. In some embodiments, the daily dose is 112 mg. In some embodiments, the daily dose is 113 mg. In some embodiments, the daily dose is 114 mg. In some embodiments, the daily dose is 115 mg. In some embodiments, the daily dose is 116 mg. In some embodiments, the daily dose is 117 mg. In some embodiments, the daily dose is 118 mg. In some embodiments, the daily dose is 119 mg. In some embodiments, the daily dose is 120 mg. In some embodiments, the daily dose is 121 mg. In some embodiments, the daily dose is 122 mg. In some embodiments, the daily dose is 123 mg. In some embodiments, the daily dose is 124 mg. In some embodiments, the daily dose is 125 mg. In some embodiments, the daily dose is 126 mg. In some embodiments, the daily dose is 127 mg. In some embodiments, the daily dose is 128 mg. In some embodiments, the daily dose is 129 mg. In some embodiments, the daily dose is 130 mg. In some embodiments, the daily dose is 131 mg. In some embodiments, the daily dose is 132 mg. In some embodiments, the daily dose is 133 mg. In some embodiments, the daily dose is 134 mg. In some embodiments, the daily dose is 135 mg. In some embodiments, the daily dose is 136 mg. In some embodiments, the daily dose is 137 mg. In some embodiments, the daily dose is 138 mg. In some embodiments, the daily dose is 139 mg. In some embodiments, the daily dose is 140 mg. In some embodiments, the daily dose is 145 mg. In some embodiments, the daily dose is 150 mg. In some embodiments, the daily dose is 155 mg. In some embodiments, the daily dose is 160 mg. In some embodiments, the daily dose is 165 mg. In some embodiments, the daily dose is 170 mg. In some embodiments, the daily dose is 175 mg. In some embodiments, the daily dose is 180 mg. In some embodiments, the daily dose is 185 mg. In some embodiments, the daily dose is 190 mg. In some embodiments, the daily dose is 195 mg. In some embodiments, the daily dose is 200 mg. In some embodiments, the daily dose is 205 mg. In some embodiments, the daily dose is 210 mg. In some embodiments, the daily dose is 215 mg. In some embodiments, the daily dose is 220 mg. In some embodiments, the daily dose is 225 mg. In some embodiments, the daily dose is 230 mg. In some embodiments, the daily dose is 235 mg. In some embodiments, the daily dose is 240 mg. In some embodiments, the daily dose is 245 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the daily dose is 260 mg. In some embodiments, the daily dose is 265 P7475PC00 mg. In some embodiments, the daily dose is 270 mg. In some embodiments, the daily dose is 275 mg. In some embodiments, the daily dose is 280 mg. In some embodiments, the daily dose is 285 mg. In some embodiments, the daily dose is 290 mg. In some embodiments, the daily dose is 295 mg. In some embodiments, the daily dose is 300 mg. In some embodiments, the daily dose is 310 mg. In some embodiments, the daily dose is 320 mg. In some embodiments, the daily dose is 330 mg. In some embodiments, the daily dose is 340 mg. In some embodiments, the daily dose is 350 mg. In some embodiments, the daily dose is 360 mg. In some embodiments, the daily dose is 370 mg. In some embodiments, the daily dose is 380 mg. In some embodiments, the daily dose is 390 mg. In some embodiments, the daily dose is 400 mg. In some embodiments, the daily dose is 410 mg. In some embodiments, the daily dose is 420 mg. In some embodiments, the daily dose is 430 mg. In some embodiments, the daily dose is 440 mg. In some embodiments, the daily dose is 450 mg. In some embodiments, the daily dose is 460 mg. In some embodiments, the daily dose is 470 mg. In some embodiments, the daily dose is 480 mg. In some embodiments, the daily dose is 490 mg. In some embodiments, the daily dose is 500 mg.

[0115] GABA receptor

[0116] The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA). The GABAA receptors are ligand gated ion channels which exists in multiple isoforms. Each receptor is a pentameric complex comprising subunits drawn from ai-6, P1-3, Y1-3, 6, £ and 0 subunit isoforms. The majority of GABAA receptors present in the CNS contain two a, two p, and one y subunit, with GABAA receptor subtypes such as 0C1 2Y2, 0C2 2Y2, 0.3 272 and 0C5 2Y2.

[0117] The pharmacological effects of activating a GABAA receptor depend mainly on which type of subunits the receptor contains. The classical anxiolytic benzodiazepines show no GABAA subtype selectivity, i.e. they non-selectively enhance the effect of GABA at the GABAA a1 / 2 / 3 / 5 receptors. It has been suggested that one of the key elements in the disadvantages of the classical benzodiazepines, such as sedation, dependency, and cognitive impairment, relates to activation of the 01 subunit of the GABAA receptor. Thus, compounds with selectivity for the 02 and / or 03 subunits over the 01 subunit, such as compounds with selectivity for the GABAA-03 subunits, are expected to have an improved side effect profile. P7475PC00

[0118] GABAA-O3 subtype selective compounds

[0119] The compounds of the present invention are GABAA-03 subtype selective positive allosteric modulators (PAMs). A GABAA-03 subtype selective PAM is compound that binds allosterically to GABAA receptors and enhances GABA-induced chloride currents preferentially at receptors containing the 03 subunit (e.g. 03 372 oro302Y2), with minimal modulation of receptors containing other a isoforms. The term “GABAA-03 subtype selective PAM” as used herein refers to compound which fulfills the below criteria:

[0120] - The GABAA-03 subtype selective PAMs of the present invention bind to the benzodiazepine site of GABAA receptors and as a result of binding causes the displacement of radioligands, including but not limited to [3H]flunitrazepam or [3H]flumazenil radioligands, from cortical tissue or recombinant GABAA receptors expressed in cell lines with an Kj<1 M.

[0121] - The GABAA-03 subtype selective PAMs of the present invention moreover demonstrates the following efficacies:

[0122] (i) from -10% to 10% modulation of GABAA-OI;

[0123] (ii) from 0% to 15% modulation of GABAA-02;

[0124] (iii) above 25% modulation of GABAA-OS; and

[0125] (iv) from -5% to 25% modulation of GABAA-OS.

[0126] The efficacies can be measured and calculated as described in the assay protocol set forth in Example 3.

[0127] In some embodiments, the modulation of GABAA-OI is the modulation of OI02Y2 GABAA. In some embodiments, the modulation of GABAA-02 is the modulation of O202Y2 GABAA. In some embodiments, the modulation of GABAA-03 is the modulation of O302Y2 GABAA. In some embodiments, the modulation of GABAA-OS is the modulation of O502Y2 GABAA.

[0128] Thus, the GABAA-03 subtype selective PAMs of the present invention demonstrates the following efficacies when measured and calculated as described in the assay protocol set forth in Example 3:

[0129] (i) from -10% to 10% modulation of QI02Y2 GABAA;

[0130] (ii) from 0% to 15% modulation of Q202Y2 GABAA;

[0131] (iii) above 25% modulation of Q302Y2 GABAA; and

[0132] (iv) from -5% to 25% modulation of O502Y2 GABAA. P7475PC00

[0133] In some embodiments, the GABAA-03 subtype selective PAM demonstrates from -5% to 5% modulation of GABAA-OI. In some embodiments, the GABAA-03 subtype selective PAM demonstrates from -2% to 2% modulation of GABAA-OI. In some embodiments, the GABAA-03 subtype selective PAM demonstrates less than 10% modulation of GABAA-02. In some embodiments, the GABAA-03 subtype selective PAM demonstrates 0% to 10% modulation of GABAA-02. In some embodiments, the GABAA-03 subtype selective PAM demonstrates less than 15% modulation of GABAA-OS. In some embodiments, the GABAA-03 subtype selective PAM demonstrates less than 10% modulation of GABAA-OS. In some embodiments, the GABAA-03 subtype selective PAM demonstrates 0% to 10% modulation of GABAA-OS. In some embodiments, the GABAA- 03 subtype selective PAM demonstrates more than 30% modulation of GABAA-03. In some embodiments, the GABAA-03 subtype selective PAM demonstrates at least twice as much modulation of GABAA-03 compared to GABAA-02. In some embodiments, the GABAA-03 subtype selective PAM demonstrates at least 30% modulation of GABAA-03 and no more than 15% modulation of GABAA-02. In some embodiments, the GABAA-03 subtype selective PAM demonstrates at least 25% modulation of GABAA-03 and no more than 12% modulation of GABAA-02.

[0134] In some embodiments, the GABAA-03 subtype selective PAMs of the present invention demonstrates the following efficacies:

[0135] (i) from -5% to 5% modulation of GABAA-OI;

[0136] (ii) from 0% to 12% modulation of GABAA-02;

[0137] (iii) above 25% modulation of GABAA-OS; and

[0138] (iv) from -5% to 10% modulation of GABAA-OS.

[0139] In one embodiment, the compound is selective for GABAA-03 over GABAA-OI, GABAA- 02 and GABAA-OS. In one embodiment, the the compound shows the following efficacies:

[0140] (i) from -10% to 10% modulation of GABAA-OI.

[0141] (ii) from 0% to 15% modulation of GABAA-02;

[0142] (iii) above 25% modulation of GABAA-OS; and

[0143] (iv) from -5% to 25% modulation of GABAA-OS. P7475PC00

[0144] In one embodiment, the efficacies are measured by the oocyte assay as presented in Example 3.

[0145] Compound 1 is known to be capable of modulation the GABAA receptor complex, and is a proven positive allosteric modulator (PAM) of GABAA receptors, selective for GABAA receptors containing the 03 subunit (WO 2020 / 053377). Thus, in some embodiments, the GABAA-03 subtype selective PAM is compound 1.

[0146] Pharmaceutically Acceptable Salts

[0147] The chemical compound of the invention may be provided in any form suitable for the intended administration, including pharmaceutically (i.e. physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, adipate, aminosalicylate, ascorbate, aspartate, benzamidoacetate benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, camphorate, camphorsulfonate, camsylate, carbonate, cinnamate, citrate, cyclamate, dodecylsulfonate, decanoate, dichloroacetate, dihydroxybenzoate, edetate, edisylate, embonate, enantate, esylate, fumarate, galactarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulphonate, methyl bisulfate, mucate, naphthalene disulphonate, naphthalene- 2-sulphonate, nicotinate, nitrate, oxoglutarate, octanoate, oleate, palmitate, pamoate, pantothenate, polygalacturonate, propionate, phthalate, pyroglutamate, salicylate, sebacate, sorbate, stearate, succinate, tartrate, teoclate, thiocyanate, toluene-p- sulphonate, undecenoate, and the like. Such salts may be formed by procedures well known and described in the art. Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.

[0148] Examples of pharmaceutically acceptable cationic salts of compound 1 of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the P7475PC00 zinc, the aluminium, the lithium, the choline, the lysinium, the argininium, the benzathinium, the diethanolaminium, the ethanolaminium, the ethylenediaminium, histidinium, the megluminium, and the ammonium salt, and the like, of compound 1 of the invention containing an anionic group. Such cationic salts may be formed by procedures well known and described in the art. In the context of this invention the "onium salts" of / V-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkylonium salts, and the cycloalkylalkyl-onium salts.

[0149] Labelled Compounds

[0150] The chemical compound of the present invention may be used in its labelled or unlabelled form. In the context of this invention the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound.

[0151] The labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging. The labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from2H (deuterium),3H (tritium),11C,13C,14C,13N,15O131l,125l,123l, and18F.

[0152] The physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.

[0153] Pharmaceutical compositions

[0154] The invention also provides use of pharmaceutical compositions comprising a GABAA- 03 selective compound, such as compound 1 , or a pharmaceutically acceptable salt thereof or hydrate thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent. P7475PC00

[0155] While the GABAA-03 selective compound of the present invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0156] In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt thereof or hydrate thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.

[0157] The GABAA-03 selective compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Compound 1 of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active P7475PC00 component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.

[0158] In some embodiments, Compound 1 is placed into the form of a pharmaceutical composition. Thus, in one aspect, the present invention relates to a pharmaceutical composition comprising Compound 1 for use in the treatment and / or prevention of tremor in a subject. In some embodiments, the pharmaceutical composition is in the form of solid dosage unit(s). In some embodiments, Compound 1 is administered in the form of a tablet. In some embodiments, Compound 1 is administered in the form of a capsule. In some embodiments, Compound 1 is administered in the form of a powder, such as a powder for oral solution.

[0159] For preparing pharmaceutical compositions from a GABAA-03 selective compound, such as compound 1 , of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0160] In one embodiment of the present invention, the GABAA-QS selective compound, or the pharmaceutically acceptable salt thereof, is the only active pharmaceutical ingredient. In one embodiment of the present invention, the GABAA-QS selective compound is within a pharmaceutical composition, wherein the composition comprises one or more adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliaries. In one embodiment of the present invention, the pharmaceutical composition consists of a GABAA-03 selective compound, such as Compound 1 , or the pharmaceutically acceptable salt thereof, and one or more adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliaries.

[0161] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, P7475PC00 cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0162] A therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.

[0163] The dose administered may be adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage can be determined by the practitioner.

[0164] The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.1 to about 10.000 mg of active ingredient per individual dose, preferably of from about 1 to about 1000 mg, most preferred of from about 1 to about 500 mg, are suitable for therapeutic treatments. In some embodiments, the dosage unit comprises the daily dose of the compound. In some embodiments, the dosage unit comprises half of the daily dose of the compound. The active ingredient may be administered in one or several doses per day. A satisfactory result may, in certain instances, be obtained at a dosage as low as 0.1 pg / kg i.v. and 1 pg / kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from about 0.1 pg / kg to about 10 mg / kg / day i.v., and from about 1 pg / kg to about 100 mg / kg / day p.o.

[0165] The compound of the present invention is suitable for use as a pharmaceutical agent. Hence, in some embodiments, the compound exhibits desirable pharmacological properties, such as target efficacy, affinity, and / or selectivity. For example, compound acts as a GABAA-C(3 subtype selective PAM, thereby enhancing GABAergic P7475PC00 neurotransmission in a receptor-subtype-specific manner. Such selectivity is advantageous in providing therapeutic efficacy in the treatment or prevention of essential tremor, while minimizing adverse effects associated with non-selective GABAA modulation, such as sedation, ataxia, or cognitive impairment.

[0166] In some embodiments, the compound demonstrates suitable absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. For example, in some embodiments, the compound exhibits acceptable metabolic stability and reduced liability for the formation of reactive metabolites. In some embodiments, the compound does not react with glutathione (GSH) under physiological or simulated metabolic conditions. In some embodiments, the compound has low electrophilic reactivity.

[0167] In some embodiments, the compound exhibits acceptable safety and tolerability, including low off-target activity, and low levels of genotoxicity, carcinogenicity, and / or hepatotoxicity.

[0168] In some embodiments, the compound demonstrates suitable pharmacokinetic properties, such as desirable oral bioavailability, plasma half-life, clearance, and brain penetration sufficient to achieve therapeutic concentrations at central GABAA-C(3 receptors. In some embodiments, the compound exhibits favorable pharmacodynamic properties, such as high potency and consistent efficacy in relevant in vitro and in vivo models of essential tremor.

[0169] In some embodiments, the compound demonstrates chemical and metabolic stability under storage and physiological conditions, including resistance to oxidative and conjugative metabolism. Said parameters may be assessed using conventional in vitro assays, in vivo animal studies, and / or clinical evaluations, as known to the skilled person.

[0170] In some embodiments, the compound demonstrates suitable characteristics for oral formulation using pharmaceutically acceptable excipients. For example, in some embodiments, the compound exhibits adequate solubility and dissolution in relevant biopharmaceutical media, and maintains chemical integrity during formulation and storage. P7475PC00

[0171] Definitions

[0172] The term " treatment" as used herein to describe the present invention, means that the compound or pharmaceutical composition is administered to a subject to stop or reduce the relevant condition or symptom of said condition from occurring in a subject. Thus, unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition (or any symptom thereof), or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment").

[0173] The term "preventive treatment" as used herein to describe the present invention, means that the compound, or pharmaceutical composition, is administered to a subject to reduce the extent of or development of the relevant condition or symptom of said condition from occurring in a subject. The term "preventive treatment" thus also includes that the compound, or pharmaceutical composition, is administered to a subject to inhibit or stop or reduce the risk of the relevant condition or symptom of said condition from occurring in a subject.

[0174] The term “ameliorative treatment” as used herein to describe the present invention, refers to the treatment of subjects having, or at risk of having a specified symptom, wherein the subjects are presently having or experiencing the symptoms of the condition.

[0175] The term “symptomatic treatment” as used herein to describe the present invention, refers to ameliorating a specified condition or disorder or symptoms accompanied therewith to a significant extent.

[0176] P7475PC00

[0177] Items

[0178] 1. A compound for use in the treatment or prevention of tremor in a subject, wherein the compound is a GABAA-03 subtype selective positive allosteric modulator (PAM).

[0179] 2. A compound for use in the treatment or prevention of tremor in a subject, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof.

[0180] 3. A compound for use in the treatment or prevention of tremor in a subject, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof.

[0181] 4. A compound for use in the treatment and / or prevention of essential tremor, wherein the compound is a GABAA-03 subtype selective PAM.

[0182] 5. A compound for use in the treatment and / or prevention of essential tremor, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof.

[0183] 6. A compound for use in the treatment and / or prevention of essential tremor, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof.

[0184] 7. A compound for use in the treatment or prevention of a disease or disorder associated with tremor, wherein the compound is a GABAA-03 subtype selective PAM.

[0185] 8. A compound for use in the treatment or prevention of a disease or disorder associated with tremor, wherein the compound is 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof.

[0186] 9. A compound for use in the treatment or prevention of a disease or disorder associated with tremor, wherein the compound is 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof. P7475PC00

[0187] 10. The compound for use according to any one of the preceding items, wherein the tremor is hand tremor, head tremor, leg tremor, voice tremor, tongue tremors, face tremor, chin tremor, neck tremor and / or torso tremor.

[0188] 11. The compound for use according to any one of the preceding items, wherein the tremor is action tremor.

[0189] 12. The compound for use according to any one of the preceding items, wherein, the action tremor is postural tremor, kinetic tremor and / or isometric tremor.

[0190] 13. The compound for use according to any one of the preceding items, wherein the action tremor is postural tremor and / or kinetic tremor.

[0191] 14. The compound for use according to any one of the preceding items, wherein the tremor is kinetic tremor, such as intention tremor and / or task-specific tremor.

[0192] 15. The compound for use according to any one of the preceding items, wherein the tremor is increased by anxiety and / or stress.

[0193] 16. The compound for use according to any one of the preceding items, wherein the tremor is induced by drugs.

[0194] 17. The compound for use according to any one of the preceding items, wherein the tremor is worsened by drugs.

[0195] 18. The compound for use according to any one of the preceding items, wherein the disease or disorder associated with tremor is essential tremor, enhanced physiological tremor, functional tremor, secondary tremor and / or rest tremor.

[0196] 19. The compound for use according to any one of the preceding items, wherein the disease or disorder associated with tremor is essential tremor.

[0197] 20. The compound for use according to any one of the preceding items, wherein the essential tremor is hereditary essential tremor.

[0198] 21. The compound for use according to any one of the preceding items, wherein the essential tremor is familial essential tremor.

[0199] 22. The compound for use according to any one of the preceding items, wherein the disease or disorder associated with tremor is not Parkinson’s disease.

[0200] 23. The compound for use according to any one of the preceding items, wherein the disease or disorder associated with rest tremor is not Parkinson’s disease

[0201] 24. The compound for use according to any one of the preceding items, wherein the tremor is not rest tremor. P7475PC00

[0202] 25. The compound for use according to any one of the preceding items, wherein the the tremor is reduced with at least 10%, such as 20%, such as 30%, such as 40%, such as 50%, such as 60%, such as 70%.

[0203] 26. The compound for use according to any one of the preceding items, wherein the tremor is reduced with at least about 5%, such as at least 10%, such as at least 15%, such as at least 20%, such as at least 25%, such as at least 30%, such as at least 50%, such as at least 75% following treatment onset.

[0204] 27. The compound for use according to any one of the preceding items, wherein the treatment results in at least 25% reduction in the upper limb tremor score, wherein the tremor score may be converted to amplitude, as compared to a baseline.

[0205] 28. The compound for use according to any one of the preceding items, wherein the treatment results in about 40% mean reduction in tremor amplitude as measured by The Essential Tremor Rating Assessment Scale (TETRAS) upper limb score.

[0206] 29. The compound for use according to any one of the preceding items, wherein the treatment results in at least 25% reduction in TETRAS performance score as compared to the baseline.

[0207] 30. The compound for use according to any one of the preceding items, wherein the treatment results in at least 35% average reduction in symptom severity as compared to the baseline, as measured by TETRAS performance score.

[0208] 31. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS ADL subscale total score of at least 12 prior to treatment onset.

[0209] 32. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS ADL subscale total score of less than about 28 prior to treatment onset.

[0210] 33. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS ADL subscale total score of at least about 20 prior to treatment onset.

[0211] 34. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS ADL subscale total score of at least about 24 prior to treatment onset. P7475PC00

[0212] 35. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS ADL subscale total score of at least about 28 prior to treatment onset.

[0213] 36. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of no greater than 12 prior to treatment onset.

[0214] 37. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 4 prior to treatment onset.

[0215] 38. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 6 prior to treatment onset.

[0216] 39. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 8 prior to treatment onset.

[0217] 40. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 10 prior to treatment onset.

[0218] 41. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 12 prior to treatment onset.

[0219] 42. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 20 prior to treatment onset.

[0220] 43. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 24 prior to treatment onset.

[0221] 44. The compound for use according to any one of the preceding items, wherein the subject has an initial TETRAS performance subscale part 4 upper limb tremor total score of at least about 28 prior to treatment onset.

[0222] 45. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score of at least about 5% following treatment onset. P7475PC00

[0223] 46. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score of at least about 10% following treatment onset.

[0224] 47. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score of at least about 15% following treatment onset.

[0225] 48. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score of at least about 20% following treatment onset.

[0226] 49. The compound for use according to any one of the preceding items, wherein the subject experiences the reduction in TETRAS ADL subscale total score about 8 days following treatment onset.

[0227] 50. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score about 10 days following treatment onset.

[0228] 51. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score about 15 days following treatment onset.

[0229] 52. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score about 20 days following treatment onset.

[0230] 53. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score about 25 days following treatment onset.

[0231] 54. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in TETRAS ADL subscale total score about 30 days following treatment onset.

[0232] 55. The compound for use according to any one of the preceding items, wherein the tremor amplitude is reduced following treatment onset.

[0233] 56. The compound for use according to any one of the preceding items, wherein the amplitude is reduced with at least about 5%, such as at least 15%, such as at least 30%, such as at least 50%, such as at least 75% following treatment onset. P7475PC00

[0234] 57. The compound for use according to any one of the preceding items, wherein the tremor is reduced within 60 minutes after administration of the compound, such as within 30 minutes after administration.

[0235] 58. The compound for use according to any one of the preceding items, wherein the tremor is decreased for at least 3 hours after administration of the compound, such as 4 hours, such as 5 hours, such as 6 hours, such as 7 hours, such as 10 hours, such as 12 hours, such as 18 hours, such as 24 hours.

[0236] 59. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in tremor amplitude about 5 days following treatment onset.

[0237] 60. The compound for use according to any one of the preceding items, wherein the subject experiences a reduction in tremor amplitude about 8 days following treatment onset.

[0238] 61. The compound for use according to any one of the preceding items, wherein, the subject experiences a reduction in tremor amplitude about 10 days, about 12 days, about 14 days, about 16 days, about 18 days, about 20 days, about 25 days, about 30 days, or about 40 days following treatment onset.

[0239] 62. The compound for use according to any one of the preceding items, wherein the compound reduces tremor without significantly causing sedation.

[0240] 63. The compound for use according to any one of the preceding items, wherein the compound reduces tremor without significantly causing sedation in a 4-8Hz range.

[0241] 64. The compound for use according to any one of the preceding items, wherein the treatment is acute.

[0242] 65. The compound for use according to any one of the preceding items, wherein the treatment is prophylactic.

[0243] 66. The compound for use according to any one of the preceding items, wherein the treatment is preventive.

[0244] 67. The compound for use according to any one of the preceding items, wherein the treatment by is ameliorative.

[0245] 68. The compound for use according to any one of the preceding items, wherein the treatment is symptomatic.

[0246] 69. The compound for use according to any one of the preceding items, wherein the subject is a mammal. P7475PC00

[0247] 70. The compound for use according to any one of the preceding items, wherein the subject is a human.

[0248] 71. The compound for use according to any one of the preceding items, wherein the subject is suffering from tremor.

[0249] 72. The compound for use according to any one of the preceding items, wherein the subject is suffering from a disease or disorder associated with tremor.

[0250] 73. The compound for use according to any one of the preceding items, wherein the subject is having, is suspected of having, or at risk of developing tremor.

[0251] 74. The compound for use according to any one of the preceding items, wherein the subject is a human subject having, suspected of having, or at risk of developing tremor.

[0252] 75. The compound for use according to any one of the preceding items, wherein the subject is having, is suspected of having, or at risk of developing essential tremor.

[0253] 76. The compound for use according to any one of the preceding items, wherein the subject is a human subject having, suspected of having, or at risk of developing essential tremor.

[0254] 77. The compound for use according to any one of the preceding items, wherein the subject is a human having, suspected of having, or at risk of developing tremor.

[0255] 78. The compound for use according to any one of the preceding items, wherein the subject is a human having, suspected of having, or at risk of developing a disease or disorder associated with tremor.

[0256] 79. The compound for use according to any one of the preceding items, wherein the subject is a human having, suspected of having, or at risk of developing essential tremor.

[0257] 80. The compound for use according to any one of the preceding items, wherein the subject is genetically related to a human subject having essential tremor.

[0258] 81. The compound for use according to any one of the preceding items, wherein the subject is above 30 years old, such as above 40 years old, such as above 50 years old, such as above 60 years old.

[0259] 82. The compound for use according to any one of the preceding items, wherein the subject is administered a dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 0.001 - 100 mg / kg. P7475PC00

[0260] 83. The compound for use according to any one of the preceding items, wherein the subject is administered a dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, in the range of 0.001 - 100 mg / kg.

[0261] 84. The compound for use according to any one of the preceding items, wherein 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol is administered to the subject as a dose ranging from 0.001 mg / kg - 100 mg / kg, such as 0.001 - 0.01 mg / kg, such as 0.01 - 0.05 mg / kg, such as 0.05 - 1.0 mg / kg, such as 1 - 5 mg / kg, such as 5 - 10 mg / kg, such as 10 - 25 mg / kg, such as 25 - 50 mg / kg, such as 50 - 100 mg / kg.

[0262] 85. The compound for use according to any one of the preceding items, wherein 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, is administrated by the oral route.

[0263] 86. The compound for use according to any one of the preceding items, wherein 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, is administrated by the oral route.

[0264] 87. The compound for use according to any one of the preceding items, wherein 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, is administered perorally to a subject as a dose ranging from 0.001 mg / kg - 100 mg / kg, such as 0.001 - 0.01 mg / kg, such as 0.01 - 0.05 mg / kg, such as 0.05 - 1.0 mg / kg, such as 1 - 5 mg / kg, such as 5 - 10 mg / kg, such as 10 - 25 mg / kg, such as 25 - 50 mg / kg, such as 50 - 100 mg / kg calculated based on 2-(3-(3- (2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol.

[0265] 88. The compound for use according to any one of the preceding items, wherein 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, is administered perorally to a subject as a dose ranging from 0.001 mg / kg - 100 mg / kg, such as 0.001 - 0.01 mg / kg, such as 0.01 - 0.05 mg / kg, such as 0.05 - 1.0 mg / kg, such as 1 - 5 mg / kg, such as 5 - 10 mg / kg, such as 10 - 25 mg / kg, such as 25 - 50 mg / kg, such as 50 - 100 mg / kg.

[0266] 89. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- P7475PC00 yl) phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol , or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 1 to 500 mg, such as 10 to 250 mg, such as 50 to 150 mg calculated based on 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol.

[0267] 90. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, in the range of 1 to 500 mg, such as 10 to 250 mg, such as 50 to 150 mg.

[0268] 91. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 10 to 130 mg, such as 20 to 120 mg, such as 30 to 120 mg, such as 40 to 120 mg, such as 50 to 120 mg, such as 10 to 110 mg, such as 10 to 100 mg, such as 30 to 70 mg, such as 40 to 80 mg, such as 50 to 120 mg, such as 50 to 130 mg calculated based on 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol.

[0269] 92. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, in the range of 10 to 130 mg, such as 20 to 120 mg, such as 30 to 120 mg, such as 40 to 120 mg, such as 50 to 120 mg, such as 10 to 110 mg, such as 10 to 100 mg, such as 30 to 70 mg, such as 40 to 80 mg, such as 50 to 120 mg, such as 50 to 130 mg.

[0270] 93. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, in the range of 40 to 150 mg, such as 50 to 150 mg, such as 60 to 150 mg, such as 75 to 150 mg, such as 100 to 150 mg calculated based on 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol.

[0271] 94. The compound for use according to any one of the preceding items, wherein the subject is administered a daily dose of 2-(3-(3-(2,4-dimethoxypyrimidin-5- yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically P7475PC00 acceptable salt thereof, in the range of 40 to 150 mg, such as 50 to 150 mg, such as 60 to 150 mg, such as 75 to 150 mg, such as 100 to 150 mg.

[0272] 95. The compound for use according to any one of the preceding items, wherein the daily dose is 1 mg.

[0273] 96. The compound for use according to any one of the preceding items, wherein the daily dose is 10 mg.

[0274] 97. The compound for use according to any one of the preceding items, wherein the daily dose is 20 mg.

[0275] 98. The compound for use according to any one of the preceding items, wherein the daily dose is 25 mg.

[0276] 99. The compound for use according to any one of the preceding items, wherein the daily dose is 30 mg.

[0277] 100. The compound for use according to any one of the preceding items, wherein the daily dose is 35 mg.

[0278] 101 . The compound for use according to any one of the preceding items, wherein the daily dose is 40 mg.

[0279] 102. The compound for use according to any one of the preceding items, wherein the daily dose is 41 mg.

[0280] 103. The compound for use according to any one of the preceding items, wherein the daily dose is 42 mg.

[0281] 104. The compound for use according to any one of the preceding items, wherein the daily dose is 43 mg.

[0282] 105. The compound for use according to any one of the preceding items, wherein the daily dose is 44 mg.

[0283] 106. The compound for use according to any one of the preceding items, wherein the daily dose is 45 mg.

[0284] 107. The compound for use according to any one of the preceding items, wherein the daily dose is 46 mg.

[0285] 108. The compound for use according to any one of the preceding items, wherein the daily dose is 47 mg.

[0286] 109. The compound for use according to any one of the preceding items, wherein the daily dose is 48 mg.

[0287] 110. The compound for use according to any one of the preceding items, wherein the daily dose is 49 mg. P7475PC00

[0288] 111. The compound for use according to any one of the preceding items, wherein the daily dose is 50 mg.

[0289] 112. The compound for use according to any one of the preceding items, wherein the daily dose is 51 mg.

[0290] 113. The compound for use according to any one of the preceding items, wherein the daily dose is 52 mg.

[0291] 114. The compound for use according to any one of the preceding items, wherein the daily dose is 53 mg.

[0292] 115. The compound for use according to any one of the preceding items, wherein the daily dose is 54 mg.

[0293] 116. The compound for use according to any one of the preceding items, wherein the daily dose is 55 mg.

[0294] 117. The compound for use according to any one of the preceding items, wherein the daily dose is 56 mg.

[0295] 118. The compound for use according to any one of the preceding items, wherein the daily dose is 57 mg.

[0296] 119. The compound for use according to any one of the preceding items, wherein the daily dose is 58 mg.

[0297] 120. The compound for use according to any one of the preceding items, wherein the daily dose is 59 mg.

[0298] 121. The compound for use according to any one of the preceding items, wherein the daily dose is 60 mg.

[0299] 122. The compound for use according to any one of the preceding items, wherein the daily dose is 61 mg.

[0300] 123. The compound for use according to any one of the preceding items, wherein the daily dose is 62 mg.

[0301] 124. The compound for use according to any one of the preceding items, wherein the daily dose is 63 mg.

[0302] 125. The compound for use according to any one of the preceding items, wherein the daily dose is 64 mg.

[0303] 126. The compound for use according to any one of the preceding items, wherein the daily dose is 65 mg.

[0304] 127. The compound for use according to any one of the preceding items, wherein the daily dose is 66 mg. P7475PC00

[0305] 128. The compound for use according to any one of the preceding items, wherein the daily dose is 67 mg.

[0306] 129. The compound for use according to any one of the preceding items, wherein the daily dose is 68 mg.

[0307] 130. The compound for use according to any one of the preceding items, wherein the daily dose is 69 mg.

[0308] 131. The compound for use according to any one of the preceding items, wherein the daily dose is 70 mg.

[0309] 132. The compound for use according to any one of the preceding items, wherein the daily dose is 71 mg.

[0310] 133. The compound for use according to any one of the preceding items, wherein the daily dose is 72 mg.

[0311] 134. The compound for use according to any one of the preceding items, wherein the daily dose is 73 mg.

[0312] 135. The compound for use according to any one of the preceding items, wherein the daily dose is 74 mg.

[0313] 136. The compound for use according to any one of the preceding items, wherein the daily dose is 75 mg.

[0314] 137. The compound for use according to any one of the preceding items, wherein the daily dose is 76 mg.

[0315] 138. The compound for use according to any one of the preceding items, wherein the daily dose is 77 mg.

[0316] 139. The compound for use according to any one of the preceding items, wherein the daily dose is 78 mg.

[0317] 140. The compound for use according to any one of the preceding items, wherein the daily dose is 79 mg.

[0318] 141. The compound for use according to any one of the preceding items, wherein the daily dose is 80 mg.

[0319] 142. The compound for use according to any one of the preceding items, wherein the daily dose is 81 mg.

[0320] 143. The compound for use according to any one of the preceding items, wherein the daily dose is 82 mg.

[0321] 144. The compound for use according to any one of the preceding items, wherein the daily dose is 83 mg. P7475PC00

[0322] 145. The compound for use according to any one of the preceding items, wherein the daily dose is 84 mg.

[0323] 146. The compound for use according to any one of the preceding items, wherein the daily dose is 85 mg.

[0324] 147. The compound for use according to any one of the preceding items, wherein the daily dose is 86 mg.

[0325] 148. The compound for use according to any one of the preceding items, wherein the daily dose is 87 mg.

[0326] 149. The compound for use according to any one of the preceding items, wherein the daily dose is 88 mg.

[0327] 150. The compound for use according to any one of the preceding items, wherein the daily dose is 89 mg.

[0328] 151. The compound for use according to any one of the preceding items, wherein the daily dose is 90 mg.

[0329] 152. The compound for use according to any one of the preceding items, wherein the daily dose is 91 mg.

[0330] 153. The compound for use according to any one of the preceding items, wherein the daily dose is 92 mg.

[0331] 154. The compound for use according to any one of the preceding items, wherein the daily dose is 93 mg.

[0332] 155. The compound for use according to any one of the preceding items, wherein the daily dose is 94 mg.

[0333] 156. The compound for use according to any one of the preceding items, wherein the daily dose is 95 mg.

[0334] 157. The compound for use according to any one of the preceding items, wherein the daily dose is 96 mg.

[0335] 158. The compound for use according to any one of the preceding items, wherein the daily dose is 97 mg.

[0336] 159. The compound for use according to any one of the preceding items, wherein the daily dose is 98 mg.

[0337] 160. The compound for use according to any one of the preceding items, wherein the daily dose is 99 mg.

[0338] 161. The compound for use according to any one of the preceding items, wherein the daily dose is 100 mg. P7475PC00

[0339] 162. The compound for use according to any one of the preceding items, wherein the daily dose is 101 mg.

[0340] 163. The compound for use according to any one of the preceding items, wherein the daily dose is 102 mg.

[0341] 164. The compound for use according to any one of the preceding items, wherein the daily dose is 103 mg.

[0342] 165. The compound for use according to any one of the preceding items, wherein the daily dose is 104 mg.

[0343] 166. The compound for use according to any one of the preceding items, wherein the daily dose is 105 mg.

[0344] 167. The compound for use according to any one of the preceding items, wherein the daily dose is 106 mg.

[0345] 168. The compound for use according to any one of the preceding items, wherein the daily dose is 107 mg.

[0346] 169. The compound for use according to any one of the preceding items, wherein the daily dose is 108 mg.

[0347] 170. The compound for use according to any one of the preceding items, wherein the daily dose is 109 mg.

[0348] 171. The compound for use according to any one of the preceding items, wherein the daily dose is 110 mg.

[0349] 172. The compound for use according to any one of the preceding items, wherein the daily dose is 111 mg.

[0350] 173. The compound for use according to any one of the preceding items, wherein the daily dose is 112 mg.

[0351] 174. The compound for use according to any one of the preceding items, wherein the daily dose is 113 mg.

[0352] 175. The compound for use according to any one of the preceding items, wherein the daily dose is 114 mg.

[0353] 176. The compound for use according to any one of the preceding items, wherein the daily dose is 115 mg.

[0354] 177. The compound for use according to any one of the preceding items, wherein the daily dose is 116 mg.

[0355] 178. The compound for use according to any one of the preceding items, wherein the daily dose is 117 mg. P7475PC00

[0356] 179. The compound for use according to any one of the preceding items, wherein the daily dose is 118 mg.

[0357] 180. The compound for use according to any one of the preceding items, wherein the daily dose is 119 mg.

[0358] 181. The compound for use according to any one of the preceding items, wherein the daily dose is 120 mg.

[0359] 182. The compound for use according to any one of the preceding items, wherein the daily dose is 121 mg.

[0360] 183. The compound for use according to any one of the preceding items, wherein the daily dose is 122 mg.

[0361] 184. The compound for use according to any one of the preceding items, wherein the daily dose is 123 mg.

[0362] 185. The compound for use according to any one of the preceding items, wherein the daily dose is 124 mg.

[0363] 186. The compound for use according to any one of the preceding items, wherein the daily dose is 125 mg.

[0364] 187. The compound for use according to any one of the preceding items, wherein the daily dose is 126 mg.

[0365] 188. The compound for use according to any one of the preceding items, wherein the daily dose is 127 mg.

[0366] 189. The compound for use according to any one of the preceding items, wherein the daily dose is 128 mg.

[0367] 190. The compound for use according to any one of the preceding items, wherein the daily dose is 129 mg.

[0368] 191. The compound for use according to any one of the preceding items, wherein the daily dose is 130 mg.

[0369] 192. The compound for use according to any one of the preceding items, wherein the daily dose is 131 mg.

[0370] 193. The compound for use according to any one of the preceding items, wherein the daily dose is 132 mg.

[0371] 194. The compound for use according to any one of the preceding items, wherein the daily dose is 133 mg.

[0372] 195. The compound for use according to any one of the preceding items, wherein the daily dose is 134 mg. P7475PC00

[0373] 196. The compound for use according to any one of the preceding items, wherein the daily dose is 135 mg.

[0374] 197. The compound for use according to any one of the preceding items, wherein the daily dose is 136 mg.

[0375] 198. The compound for use according to any one of the preceding items, wherein the daily dose is 137 mg.

[0376] 199. The compound for use according to any one of the preceding items, wherein the daily dose is 138 mg.

[0377] 200. The compound for use according to any one of the preceding items, wherein the daily dose is 139 mg.

[0378] 201. The compound for use according to any one of the preceding items, wherein the daily dose is 140 mg.

[0379] 202. The compound for use according to any one of the preceding items, wherein the daily dose is 145 mg.

[0380] 203. The compound for use according to any one of the preceding items, wherein the daily dose is 150 mg.

[0381] 204. The compound for use according to any one of the preceding items, wherein the daily dose is 155 mg.

[0382] 205. The compound for use according to any one of the preceding items, wherein the daily dose is 160 mg.

[0383] 206. The compound for use according to any one of the preceding items, wherein the daily dose is 165 mg.

[0384] 207. The compound for use according to any one of the preceding items, wherein the daily dose is 170 mg.

[0385] 208. The compound for use according to any one of the preceding items, wherein the daily dose is 175 mg.

[0386] 209. The compound for use according to any one of the preceding items, wherein the daily dose is 180 mg.

[0387] 210. The compound for use according to any one of the preceding items, wherein the daily dose is 185 mg.

[0388] 211. The compound for use according to any one of the preceding items, wherein the daily dose is 190 mg.

[0389] 212. The compound for use according to any one of the preceding items, wherein the daily dose is 195 mg. P7475PC00

[0390] 213. The compound for use according to any one of the preceding items, wherein the daily dose is 200 mg.

[0391] 214. The compound for use according to any one of the preceding items, wherein the daily dose is 205 mg.

[0392] 215. The compound for use according to any one of the preceding items, wherein the daily dose is 210 mg.

[0393] 216. The compound for use according to any one of the preceding items, wherein the daily dose is 215 mg.

[0394] 217. The compound for use according to any one of the preceding items, wherein the daily dose is 220 mg.

[0395] 218. The compound for use according to any one of the preceding items, wherein the daily dose is 225 mg.

[0396] 219. The compound for use according to any one of the preceding items, wherein the daily dose is 230 mg.

[0397] 220. The compound for use according to any one of the preceding items, wherein the daily dose is 235 mg.

[0398] 221. The compound for use according to any one of the preceding items, wherein the daily dose is 240 mg.

[0399] 222. The compound for use according to any one of the preceding items, wherein the daily dose is 245 mg.

[0400] 223. The compound for use according to any one of the preceding items, wherein the daily dose is 250 mg.

[0401] 224. The compound for use according to any one of the preceding items, wherein the daily dose is 260 mg.

[0402] 225. The compound for use according to any one of the preceding items, wherein the daily dose is 265 mg.

[0403] 226. The compound for use according to any one of the preceding items, wherein the daily dose is 270 mg.

[0404] 227. The compound for use according to any one of the preceding items, wherein the daily dose is 275 mg.

[0405] 228. The compound for use according to any one of the preceding items, wherein the daily dose is 280 mg.

[0406] 229. The compound for use according to any one of the preceding items, wherein the daily dose is 285 mg. P7475PC00

[0407] 230. The compound for use according to any one of the preceding items, wherein the daily dose is 290 mg.

[0408] 231. The compound for use according to any one of the preceding items, wherein the daily dose is 295 mg.

[0409] 232. The compound for use according to any one of the preceding items, wherein the daily dose is 300 mg.

[0410] 233. The compound for use according to any one of the preceding items, wherein the daily dose is 310 mg.

[0411] 234. The compound for use according to any one of the preceding items, wherein the daily dose is 320 mg.

[0412] 235. The compound for use according to any one of the preceding items, wherein the daily dose is 330 mg.

[0413] 236. The compound for use according to any one of the preceding items, wherein the daily dose is 340 mg.

[0414] 237. The compound for use according to any one of the preceding items, wherein the daily dose is 350 mg.

[0415] 238. The compound for use according to any one of the preceding items, wherein the daily dose is 360 mg.

[0416] 239. The compound for use according to any one of the preceding items, wherein the daily dose is 370 mg.

[0417] 240. The compound for use according to any one of the preceding items, wherein the daily dose is 380 mg.

[0418] 241. The compound for use according to any one of the preceding items, wherein the daily dose is 390 mg.

[0419] 242. The compound for use according to any one of the preceding items, wherein the daily dose is 400 mg.

[0420] 243. The compound for use according to any one of the preceding items, wherein the daily dose is 410 mg.

[0421] 244. The compound for use according to any one of the preceding items, wherein the daily dose is 420 mg.

[0422] 245. The compound for use according to any one of the preceding items, wherein the daily dose is 430 mg.

[0423] 246. The compound for use according to any one of the preceding items, wherein the daily dose is 440 mg. P7475PC00

[0424] 247. The compound for use according to any one of the preceding items, wherein the daily dose is 450 mg.

[0425] 248. The compound for use according to any one of the preceding items, wherein the daily dose is 460 mg.

[0426] 249. The compound for use according to any one of the preceding items, wherein the daily dose is 470 mg.

[0427] 250. The compound for use according to any one of the preceding items, wherein the daily dose is 480 mg.

[0428] 251 . The compound for use according to any one of the preceding items, wherein the daily dose is 490 mg.

[0429] 252. The compound for use according to any one of the preceding items, wherein the daily dose is 500 mg.

[0430] 253. The compound for use according to any one of the preceding items, wherein the compound is placed in a pharmaceutical composition.

[0431] 254. The compound for use according to any one of the preceding items, wherein the pharmaceutical composition is in the form of dosage unit(s).

[0432] 255. The compound for use according to any one of the preceding items, wherein the dosage unit(s) is solid dosage unit(s).

[0433] 256. The compound for use according to any one of the preceding items, wherein the solid dosage unit is a tablet.

[0434] 257. The compound for use according to any one of the preceding items, wherein the solid dosage unit is a capsule.

[0435] 258. The compound for use according to any one of the preceding items, wherein the solid dosage unit is a powder, such as a powder for oral solution.

[0436] 259. The compound for use according to any one of the preceding items, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, provided in the form of a tablet.

[0437] 260. The compound for use according to any one of the preceding items, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, provided in the form of a capsule.

[0438] 261 . The compound for use according to any one of the preceding items, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7- P7475PC00 imidazo[4,5-jb]pyridin-6-yl)propan-2-ol , or a pharmaceutically acceptable salt thereof or hydrate thereof, provided in the form of a powder.

[0439] 262. The compound for use according to any one of the preceding items, wherein a dosage unit comprises the daily dose of the compound.

[0440] 263. The compound for use according to any one of the preceding items, wherein a dosage unit comprises half of the daily dose of the compound.

[0441] 264. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM binds to the benzodiazepine site of GABAA receptors and as a result of binding causes the displacement of radioligands, including but not limited to [3H]flunitrazepam or [3H]flumazenil radioligands, from cortical tissue or recombinant GABAA receptors expressed in cell lines with an Kj<1 M.

[0442] 265. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates the following efficacies:

[0443] (i) from -10% to 10% modulation of GABAA-CU;

[0444] (ii) from 0% to 15% modulation of GABAA-02;

[0445] (iii) above 25% modulation of GABAA-OS; and

[0446] (iv) from -5% to 25% modulation of GABAA-OS.

[0447] 266. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates from -5% to 5% modulation of GABAA-CU.

[0448] 267. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates from -2% to 2% modulation of GABAA-CU.

[0449] 268. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates less than 10% modulation of GABAA-02.

[0450] 269. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates 0% to 10% modulation of GABAA-02.

[0451] 270. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates less than 15% modulation of GABAA-OS. P7475PC00

[0452] 271. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates less than 10% modulation of GABAA-OS.

[0453] 272. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates 0% to 10% modulation of GABAA-OS.

[0454] 273. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates more than 30% modulation of GABAA-03.

[0455] 274. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates at least twice as much modulation of GABAA-03 compared to GABAA-02.

[0456] 275. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates at least 30% modulation of GABAA-03 and no more than 15% modulation of GABAA-02.

[0457] 276. The compound for use according to any one of the preceding items, wherein the GABAA-03 subtype selective PAM demonstrates at least 25% modulation of GABAA-03 and no more than 12% modulation of GABAA-02.

[0458] 277. The compound for use according to any one of the preceding items, wherein the compound demonstrates the following efficacies:

[0459] (i) from -5% to 5% modulation of GABAA-OI;

[0460] (ii) from 0% to 12% modulation of GABAA-02;

[0461] (iii) above 25% modulation of GABAA-OS; and

[0462] (iv) from -5% to 10% modulation of GABAA-OS.

[0463] 278. The compound for use according to any one of the preceding items, wherein the compound is selective for GABAA-OS over GABAA-OI, GABAA-02 and GABAA-OS.

[0464] 279. The compound for use according to any one of the preceding items, wherein the GABAA-OS subtype selective PAM is 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol.

[0465] 280. A method for treating and / or preventing tremor, the method comprising administering a GABAA-OS subtype selective PAM to a subject in need thereof.

[0466] 281. A method for treating and / or preventing tremor, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5- P7475PC00 b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof.

[0467] 282. Use of a GABAA-C(3 subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject.

[0468] 283. Use of 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5- b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject.

[0469] 284. A method for treating and / or preventing essential tremor, the method comprising administering a GABAA-03 subtype selective PAM to a subject in need thereof.

[0470] 285. A method for treating and / or preventing essential tremor, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0471] 286. Use of a GABAA-C(3 subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of essential tremor in a subject.

[0472] 287. Use of 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5- b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of essential tremor in a subject.

[0473] 288. A method for treating and / or preventing a disease or disorder associated with tremor, the method comprising administering a GABAA-03 subtype selective PAM to a subject in need thereof.

[0474] 289. A method for treating and / or preventing a disease or disorder associated with tremor, the method comprising administering 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof.

[0475] 290. Use of a GABAA-C(3 subtype selective PAM for the manufacture of a medicament for the treatment and / or prevention of tremor and / or a disease or disorder associated with tremor in a subject.

[0476] 291. Use of 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5- b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or P7475PC00 prevention of tremor and / or a disease or disorder associated with tremor in a subject.

[0477] 292. A method of treating essential tremor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2- (3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6- yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, wherein the subject experiences a reduction in The Essential Tremor Rating Assessment Scale (TETRAS) activities of daily living (ADL) subscale total score following treatment onset.

[0478] 293. A method for treating and / or preventing tremor without eliciting sedation in a subject, the method comprising administering 2-(3-(3-(2,4- dimethoxypyrimidin-5-yl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof, to a subject in need thereof.

[0479] 294. The method according to item 293, wherein the sedation is not elicited in the tremor 4-8 Hz frequency range.

[0480] 295. The method according to any one of items 293 or 294, wherein the sedation is elicited by harmaline and not relieved or ameliorated by primidone.

[0481] Examples

[0482] Example 1: Effect on Harmaline-lnduced Tremor

[0483] Materials and methods:

[0484] Animals

[0485] Male Sprague-Dawley (SD) rats (Ntac:SD) weighing 230-300 g were purchased from Taconic, Denmark. Animals were acclimatized to the inhouse conditions for 1 week before subjected to experiments. Rats were group housed 4 by 4 in standard macroIon cages (20x40x18 cm), equipped with standard soft bedding. The rats were allowed access to food and water ad libitum. The animals were kept at a 12h day and night cycle (lights on at 7:00 am and off at 7:00 pm) in temperature- and humidity-regulated rooms (20 ± 2 °C and 45 ± 5%, respectively). The experiments were carried out according to P7475PC00 the 3Rs guiding principles for more ethical use of animals in testing and the experimental license obtained from The Danish Animals Experiments Inspectorate, The Danish Veterinary and Food administration.

[0486] Drug preparations and administration

[0487] Compound 1 and primidone were dissolved in 5% dimethyl sulfoxide (DMSO) and 30% hydroxypropyl beta-cyclodextrin (HPbCD) in MilliQ water. Hydrochloride salts of harmaline and propranolol were dissolved in physiological saline solution. The dosing solutions for harmaline and propanol were prepared by adjusting the weight of the salt to the free base while other compounds were dosed to the free base weight. Harmaline was injected subcutaneously (sc) by using 27G needles in 1 ml / kg volume. Propranolol was administered ip 30 minutes before the harmaline injection in a volume of 3 ml / kg. All other compounds were given po 60 minutes before harmaline injection in a volume of 10 ml / kg.

[0488] Automatic quantification of harmaline induced tremors in rats using tremor monitors: Rats were pretreated with vehicle, reference, or test compounds 30-60 minutes prior to harmaline injection. Immediately after harmaline injection, rats were placed individually in transparent acrylic enclosures (20(L)x9(ID) cm) positioned in the tremor monitors (38(W)x35(D)x45(H) cm, SDI, San Diego USA). After 5 minutes of acclimatization in the monitors, tremors were registered continuously for 20 minutes. House lights and fans located within the tremor monitor boxes were switched on during the entire period of tremor measurement. Two rats were monitored parallelly at each session. Tremor monitors differentiate tremor events from ambulatory / stereotyped movements by using an ultrasensitive movement sensor.

[0489] The raw waveforms were transferred by fast Fourier transformations into power spectra, by the provided software from SDI. The power spectra were then condensed to 1 Hz bins and averaged across all rats in the given treatment group. The data were exported as percentage energy spent (PES) at a given frequency summarized over 20 minutes and presented as a motion power percentage (%MP), which is defined as the ratio of PES at tremor frequency bandwidth divided by overall motion power across all frequencies as done in previous studies (Martin et al, 2005) This ratio is (11-13 Hz power) I (0 to 30 Hz) x 100. Rats were sacrificed immediately after completing the experiments and brains and blood were sampled for analysis of harmaline and test compound concentrations. P7475PC00

[0490] Statistical Analysis

[0491] %MP was analyzed by one-way ANOVA followed by Fisher’s LSD post hoc test. The level of significance was set at P<0.05. All the analyses were performed using Graph Pad prism 7.0 software (GraphPad Software, San Diego, CA) and data is presented as mean ± SEM.

[0492] Results

[0493] Subcutaneous administration of 5 mg / kg of Harmaline caused a highly statistically significant increase of tremors in rats, monitored as an increase in % motion power (p<0.0001 vs. Vehicle). Pretreatment with the positive control, Propranolol, at a dose level of 30 mg / kg (ip) markedly reduced the harmaline-induced tremors (p< 0.0001 vs. Harmaline per se). Similarly, peroral dosing with increasing doses of Compound 1 resulted in a dose-related reduction of the harmaline-induced tremors, reaching statistical significance at a dose level of 1- and 3 mg / kg (p< 0.001 and p< 0.03 vs. Harmaline per se, respectively).

[0494] Conclusions

[0495] Harmaline resulted in the expected increase in tremors, measured as % motion power, in rats. Peroral treatment with Compound 1 caused a significant- and dose-dependent reduction of the Harmaline-induced tremors with 1 mg / kg as the minimal efficacious dose level. The data suggests that Compound 1 alleviates tremors in patients with tremors, such as essential tremor.

[0496] Example 2:

[0497] Compound 1 inhibited harmaline-induced tremors in rats, comparable to primidone. Data is presented as a motion power percentage (%MP), which is the ratio of the Percent Energy Spent at tremor frequency (11-13Hz) I all frequency (0-30Hz) (Martin FC et al., 2005;). Compound 1 decreased %MP to the same magnitude as that of primidone. Reproducible results are observed with 3mg / kg, dose of Compound 1. The minimal effective dose is 1 mg / kg.

[0498] Significantly, as shown in Figs. 3A-3B, Compound 1 , as well as decreasing the harmaline-induced tremors similar to the efficacy observed with primidone, also reversed harmaline-induced unspecific effects (see 4-8Hz), likely sedation- something which is not ameliorated by primidone. Tremor monitors differentiate tremor events P7475PC00 from ambulatory / stereotyped movements by using an ultrasensitive movement sensor, and motion activity is measured by piezoelectric disc attached to the bottom of animal enclosure in the tremor box. Percentage Energy Spent: this measure typically refers to the proportion of signal energy within a certain frequency range relative to the total energy across all frequencies. For tremor analysis, it helps to identify the frequency range where the tremor is most pronounced. dBV (Decibels Relative to 1 Volt) provides information about the strength of the tremor signal (severity of the tremor).

[0499] The results suggest that Compound 1 can be used to treat essential tremors with novel mechanism of action without side effects (e.g., sedation) and / or tolerance development like benzodiazepines and other gaba-ergic treatment like primidone.

[0500] Example 3: Selectivity for GABAA receptor subtypes

[0501] This assay is designed to determine the in vitro functional potency and efficacy of modulators of GABAA receptor subtypes aiP2 / 2, 0C2P2Y2, 0C3P2Y2 and 0^272 expressed in Xenopus laevis oocytes. The assay is especially suitable for comparing a compound’s modulation of GABAA ai, a2, as, and as subunits to assess efficacy selectivity of compounds for the different a subunits (the P272 is constant).

[0502] A full concentration response profile is determined on a control GABA concentration set at 5-20% of the maximal GABA-evoked response.

[0503] Materials:

[0504] Xenopus Laevis Oocytes

[0505] Collagenase defolliculated X. laevis oocytes are obtained from Ecocyte Bioscience. For injection, the oocytes are placed in a custom designed chamber in Mod. Barth’s solution (90 mM NaCI, 1 mM KCI, 0.66 mM NaNO3, 2.4 mM NaHCO3, 0.74 mM CaCI2, 0.82 mM MgCh, 100 pg / ml Gentamicin and 10 mM HEPES adjusted to pH 7.55) and injected with 25-50 nl of cRNA mixture using a Pico Pump (WPI). The cRNA mixture contain GABAAR subunits ax, P2, and 72s in the ratio of 5:1 :5 and in a total concentration of 0.5 pg / pl. Following injection, oocytes are maintained at 18°C in Mod. Barth’s for 2-5 days.

[0506] Compound solutions

[0507] Compounds are initially dissolved at 10 mM in 100% DMSO and then diluted in the experimental solutions. Typically, the maximal compound concentration tested is 10 or P7475PC00

[0508] 31.6 |iM and from this solution a serial dilution row is produced in the experimental assay solution (OR2).

[0509] Two-Electrode Voltage Clamp Experiments

[0510] Electrophysiological responses from X. laevis oocytes are measured using the two- electrode voltage clamp technique. Single oocytes are placed in custom designed recording chambers that are continuously perfused with > 2 ml / min OR2 (90 mM NaCI, 2.5 mM KCI, 2.5 mM CaCh, 1 mM MgCh and 5 mM HEPES pH 7.4). The experimental assay solution is a standard OR2 buffer solution which has a measured osmolarity of approximately 180mOsm. Recording electrodes are fabricated from borosilicate glass tubings with filament (Sutter BF150-110-10) using a DMZ-Universal puller (Zeitz Instrument), backfilled with 2 M KCI and when submerged into OR2 solution the electrode resistances are in the range of 0.5-1 MQ. The oocyte is impaled using manual micro manipulators and allowed to equilibrate at a holding potential of -50 mV to -80 mV for at least 1 min to ensure a maximal leak current of 100 nA before the experiment is initiated. The holding potential is normally set at -60 mV, which is significantly lower than a typical resting potential of -25 mV. In case current amplitudes are low in a batch of oocytes, a holding potential of -80 mV is used provided that the leak current does not exceed 100 nA. Currents are amplified by a Geneclamp 500B amplifier (Axon), low-pass filtered at 20Hz, digitized at 200 Hz by a Digidata 1322A (Axon) and then recorded as well as analyzed by a PC (Compaq Evo) using the pClamp9 suite (Axon).

[0511] Compound solutions are applied through a capillary tube, with an inner diameter of 1.5 mm (Modulohm 214813), placed approximately 2 mm from the oocyte and connected through Teflon tubing to a Gilson 233XL autosampler. Gilson 735 software suite was used to control all the Gilson equipment (233XL autosampler, 402 diluter and Minipuls 3 pumps) and to trigger recording by pCLAMP9. A flow rate of 2.5 ml / min through the capillary tube during applications ensures a rapid exchange of liquid surrounding the oocyte. The application length is set to last 60 s which is sufficient to obtain peak currents. The time interval between recordings is 5 min, during which the oocyte is perfused with OR2 through the capillary tube as well.

[0512] Experimental data

[0513] For each experimental data set, GABA is dissolved in OR2 in a concentration known to give rise to EC5-EC20 elicited currents for a given GABAA receptor subtype combination P7475PC00

[0514] (usually 0.5-5 pM) and this solution is then used for controls as well as a stock solution for dissolving the compounds to test in the experiment. A complete experimental set contain control traces of GABA, a reference trace (0.5 pM diazepam + test concentration of GABA), GABA control traces once again and finally test traces of a compound in increasing concentrations. The individual oocytes are discarded after one experimental set.

[0515] Experimental quality criteria

[0516] Oocytes with leak currents exceeding 250 nA at a holding potential of -50 mV to -80 mV are discarded. Oocytes with receptor expression levels giving rise to a control GABA evoked whole-cell currents either below or above the range of 250 nA to 2000 nA are discarded. Finally, run-down or run-up is evaluated by calculating the linear slope of the last 3-4 control traces before compound addition and if the slope value exceeds 2.5% of the last control the experiment is discarded.

[0517] Data analysis

[0518] Using Clampex or Matlab, all traces are background subtracted and peak current values are read. If used, reference potentiation is calculated in percent by comparing the reference trace to the control trace immediately before the reference trace.

[0519] Likewise, modulatory effects of compound in the test traces are obtained by comparing to the control trace immediately before the test traces.

[0520] C = GABA (Control)

[0521] T = GABA + Compound (Test)

[0522] R = GABA + Diazepam (0.5 pM) (Reference)

[0523] Positive modulatory effect is calculated as:

[0524] % PAM = 100 x (T-C)Z(R-C)

[0525] Negative modulatory effect is calculated as:

[0526] % NAM = 100 x (T-C)ZC

[0527] Potential leak current is assessed throughout the experiment and if the leak current changes dramatically during an experiment this is then discarded. Data points are fitted to the empirical Hill equation by non-linear regression using GraphPadPrism or Matlab. Potencies and efficacies are derived from this fitting routine. P7475PC00

[0528] Example 4: Phase 1 study, GABAA receptor occupancy

[0529] A phase 1 study was conducted to assess the safety and tolerability of single and multiple ascending doses of Compound 1 in healthy participants and to determine GABAA receptor occupancy using Positron-emission Tomography (PET).

[0530] [11C]-flumazenil is a well-established PET tracer for human use. It is well validated for use in occupancy studies in humans and has been used for more than 20 years (Lassen et al., Journal of Cerebral Blood Flow and Metabolism (1995), 15, 153-165, Benzodiazepine Receptor Quantification In Vivo in Humans Using [ CJFIumazenil and PET: Application of the Steady-State Principle). It has recently been shown that11C flumazenil can be used in evaluation of allosteric subtype modulators for occupancy measurements (Nickoils et al., British Journal of Pharmacology (2018), 175, 708-725, Pharmacology in translation: the preclinical and early clinical profile of the novel a2 / 3 functionally selective GABAA receptor positive allosteric modulator PF-06372865).

[0531] Study and subjects

[0532] The demographics of a total of 3 participants was shown in the Table 1 below.

[0533] Table 1. Demographic table for 3 participants.

[0534] Each subject had magnetic resonance imaging (MRI) scans as part of screening procedures. Each subject had three PET imaging sessions, with one PET scan in each session. The PET 1 was taken as a baseline scan. After a single oral dose of Compound 1 , the PET 2 and PET 3 were performed at two different pose-dose time points. Subjects received an intravenous dose of the radiolabelled tracer, [11C]- flumazenil, at the start of each PET scan. P7475PC00

[0535] MRI acquisition

[0536] Structural MRI acquisition for each subject was performed using a 3 Tesla Siemens clinical MRI system. Structural imaging data were acquired in the sagittal plane, utilising a 3D magnetization prepared rapid Acquisition gradient echo (MP-RAGE) scan with the following parameters: TR repetition time = 2300 ms, TE echo delay time = 2.98 ms, flip angle = 9°, isotropic voxels = 1.0 mm x 1.0 mm x 1.0 mm, 160 slices, total scanning time = 5 min, 3 sec. Scans were reviewed by a neuroradiologist to exclude any clinically relevant brain abnormalities. T1 MRI data were used as part of the PET data analysis as described below. f11Cl-flumazenil preparation

[0537] [11C]-flumazenil was prepared by reacting [11C]-methyl iodide with the desmethylflumazenil precursor, followed by purification by semi-preparative HPLC and reformulation in ethanol and phosphate buffered saline.

[0538] PET acquisition

[0539] Dynamic PET scans were performed using Siemens PET / CT scanners (two similar scanners used: Hi-Rez Biograph 6 and Biograph 6 TruePoint with TrueV, Siemens Healthcare, Erlangen, Germany). A low dose CT scan was performed before each PET study to correct for the attenuation of emitted radiation. Subjects then received an intravenous bolus injection of up 300 MBq MBq of the [11C]-flumazenil radioligand. Dynamic emission data were recorded for 90 minutes after injection of the radioligand. The dynamic images were reconstructed (frame durations: 8 x 15s, 3 x 60s, 5 x 120s, 5 x 300s, 5 x 600s), using Fourier rebinning and a 2D filtered discrete inverse Fourier transform algorithm with 5 mm isotropic Gaussian filter on a 128 x 128 matrix with 2.6 zoom giving 2 mm isotropic voxels. Corrections were applied for attenuation, randoms and scatter.

[0540] Arterial blood data

[0541] The analyses of arterial blood were performed on11C-radioactivity, with discernment of11Cflumazenil and its metabolites to get a kinetic profile for the tracer. Prior to each PET scan the radial artery of the subject’s arm was cannulated under local anaesthesia, to enable arterial blood sampling during the scan. Arterial cannulation took place following satisfactory findings in Allen’s test, platelet count and clotting screen. P7475PC00

[0542] Continuous blood data were scaled (i.e. calibrated) to match overlapping discrete whole blood samples, and then merged with the remaining discrete whole blood data to form a whole blood activity curve covering the 90 minutes of the scan. Activity measurements from the discrete plasma samples were divided by the corresponding whole blood data to form plasma-overblood (POB) data. The POB data were fitted to a linear model to interpolate the relationship. The POB model fit curve was multiplied by the whole blood curve to give an estimated total plasma curve.

[0543] Plasma samples were analysed by HPLC to determine the parent fraction. Parent fraction (metabolite) data were fitted to a sigmoid model. The resulting fitted parent fraction profile was multiplied by the total plasma curve and then smoothed postpeak using a multi-exponential fit to give the required parent plasma input function. For each scan, a time delay was fitted and applied to the input function to account for any delay between blood sampling measurements and tissue data from the PET tomography. The resulting parent plasma input function was used as input for the kinetic modelling processes.

[0544] Analysis methods

[0545] PET data analysis was performed using Invicro's in-house MIAKATTM software package (MIAKAT_release_4.4.3.1). MIAKATTM is implemented using MATLAB (version R2016a; The Mathworks Inc., Natick, MA, USA), and makes use of SPM12 (Wellcome Trust Centre for Neuroimaging, http: / / www.fil.ion.ucl.ac.uk / spm) for image segmentation and registration.

[0546] Image processing

[0547] Each subject's structural MRI image underwent a grey matter segmentation, followed by a registration to a standard reference space (Grabner et al., Ramanujan J (2006), 12, 439-454, Analysis of some new partition statistics (MN1152)). The MNI152 template brain image and associated atlas (CIC atlas) , was nonlinearly warped to the subject's MR image to enable automated definition of regions of interest (ROIs). A set of ROIs was selected based on the expected distribution of [11C]-flumazenil signal and emerging data from this study: frontal lobe, temporal lobe, parietal lobe, occipital lobe, insular cortex, posterior cingulate gyrus, anterior cingulate, caudate, putamen, P7475PC00 accumbens, thalamus, amygdala, hippocampus, ventral cerebellum, cerebral white matter, and pons.

[0548] Dynamic PET images were generated on the PET scanners using the manufacturer's recommended reconstruction settings. These were then registered to each subject's MRI scan and corrected for motion using a frame-to-frame registration process with a normalised mutual information cost function. ROIs defined on the MRI images were applied to the dynamic PET data to derive regional time-activity curves (TACs), with activity concentrations expressed as standardised uptake values (SUV), given by:

[0549] Equation 1 where Act is the measured radioactivity concentration (kBq / ml), IA is the injected radioactivity (MBq) and BW is the subject's bodyweight (kg).

[0550] Kinetic modelling

[0551] The derived tissue TACs were analysed using kinetic modelling methods that employ a metabolite-corrected plasma input function. The model used was the two tissue compartment (2TC) model (Gunn, Gunn & Cunningham, Journal of Cerebral Blood Flow and Metabolism (2001), 21 , 635-652, Positron Emission Tomography Compartmental Models). The 2TC model describes the target tissue signal via two compartments, one consisting of free (F) and non-specifically (NS) bound radiotracer and the other containing specifically bound (SB) radiotracer.

[0552] The primary outcome parameter from the 2TC model is the PET total T, which is a measure of the total (i.e. both non-displaceable and specific binding) distribution into the tissue. MIAKATTM fits the 2TC model to the data using nonlinear optimisation techniques to estimate the rate constants Ki , k2, k3and k4, then calculates Vi-via Equation 2. As part of the 2TC model fitting a fixed blood volume fraction of 5% was used to correct for the contribution of whole blood signal to tissue TACs.

[0553] Equation 2

[0554] Occupancy analysis

[0555] Decreases in T from baseline to post-dose scans were interpreted as an effect of

[0556] GABAA occupancy by Compound 1. The Lassen plot (Cunningham et al., Journal of P7475PC00

[0557] Cerebral Blood Flow & Metabolism (2010), 30, 46-50, Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited ) was used to estimate the target occupancy by calculating the changes of VT between baseline and post-dose against baseline VT for 16 ROI brain regions. VND (distribution volume of non- displaceable) was constrained to be equal for all scans within subject.

[0558] PK-occupancy analysis

[0559] Occupancy estimates were plotted against plasma concentrations of Compound 1 , corresponding to the start of each post-dose PET scan. The following model was fitted to the occupancy data set:

[0560] Occ = 100 Equation 3 where Occ is estimated occupancy (%), Cpis the measured plasma concentration of Compound 1 (ng / ml) and ECso is the plasma concentration of Compound 1 that corresponds to 50% occupancy.

[0561] Results

[0562] Image data

[0563] Image data were successfully acquired for 9 PET scans in the 3 participants at baseline and at two time points following single doses of Compound 1. Subject 3001 was scanned 2.4 hours and 24.1 hours after 94 mg Compound 1, subject 3002 was scanned 2.3 hours and 24.1 hours after 128 mg Compound 1 and subject 3003 was scanned 0.6 hours and 23.0 hours after 157 mg Compound 1. Table 2 shows dose and image acquisition times and dates.

[0564] Table 2. Dose and scan events data. P7475PC00

[0565] Images for all three subjects are shown in Figure 4. Tissue time-activity curves were generated successfully for all scans. In all three subjects, the baseline image showed regional heterogeneity consistent with the expected signal distribution. This was significantly reduced 0.6 - 2.4 hours after administration of Compound 1 in PET2. For PET3, the signal reduction relative to baseline appears to be less profound around 24 hours after the drug administration.

[0566] Kinetic modelling with the reversible two tissue compartmental model with fixed blood volume correction produced acceptable model fits to tissue time-activity curve data in all cases. VT data were reported for each subject, scan and region of interest.

[0567] Calculated VT values for 8 representative ROIs are detailed in Table 3.

[0568] Table 3. T data estimated for 3 subjects. Regions of interest were reported for frontal lobe (Frontal), temporal lobe (Temporal), posterior cingulate (PostCing), caudate (Cau), amygdala (Amg), hippocampus (Hippo), cerebral white matter (CWM) and pons.

[0569] Occupancy analysis

[0570] The Lassen plot based on 2TC model-derived VT data was used to estimate the drug occupancy (%) for each scan by plotting the VT difference between the baseline and P7475PC00 post-dose scans against the baseline VT, fitted with VND constrained to be equal for all scans within-subject. Estimated [11C]-flumazenil occupancy values are presented in Table 4 along with the corresponding plasma concentrations of Compound 1.

[0571] Table 4. Estimated GABAA receptor occupancy data. The Lassen plot was used to estimate the brain occupancy using 16 brain regions. Doses are given as mass of Compound 1 administered. Scan times are relative to the time of Compound 1 administration. Plasma concentration is that of Compound 1 , corresponding to the start of the PET scan.

[0572] PK-RO analysis

[0573] Equation 3 was fitted to the calculated occupancy values and the corresponding Compound 1 plasma concentration data. Target occupancy was plotted against plasma concentration (measured near to the start time of the PET scan) and appeared to fit a standard occupancy model well (see Figure 5) and produced an estimated ECso of

[0574] 301.1 ng / ml, with 95% confidence interval of 212.9 - 389.3 ng / ml in terms of total Compound 1 in plasma.

[0575] Conclusions

[0576] This study demonstrates that brain occupancy increased with the plasma concentration of Compound 1. Further, a consistent relationship between Compound 1 plasma concentration and GABAA RO was observed over the time periods explored (0.6 to

[0577] 24.1 hours post-dose). The ECso for Compound 1 at the GABAA receptor was estimated to be 301.1 ng / mL (95% Cl: 212.9 to 389.3 ng / mL) in terms of total Compound 1 in plasma. P7475PC00

[0578] Example 5: Effect on explorative motility of rats

[0579] Drugs used to treat central nervous system disease / disorder are accompanied by unwanted effects like sedation, muscle relaxation etc. Exploratory behaviour is assessed to test for drug induced sedation by measuring distance travelled while effect on the muscle can be assessed by studying the rearing behaviour. Animals placed in a novel environment will show exploratory behaviour and gradually habituate. In recorded activity counts this will be observed as initially high activity and later (15-30 min after start) low activity counts. Compounds that decrease initial high activity counts may be classified as sedative compounds.

[0580] Animals

[0581] Male SD rats of body weight 140-160 g were used for the study. Animals were habituated for minimum 1 week in the animal’s house and at least 24h in the experimental room before the experiment. Rats were kept in group of 4 per cage.

[0582] Procedure

[0583] Rats were acclimatized to the experimental room for 24h prior to the experiment. After 2h and 1h treatment with Compound 1 (3, 10, 30 mg / kg perorally), Diazepam (1, 3, 6 mg / kg perorally) respectively or vehicle, rats were returned to their home cage for 30 min. Rats were then placed individually in transparent home cages placed in a frame (30 x 20 x 25 cm, TSE Systems, Bad Homburg, Germany) equipped with 12 infrared sensors (6 x 2). Locomotor activity, measured as a distance travelled (m), was monitored automatically in the chambers via the interruption of two consecutive infrared sensors. Interruptions were detected by a control unit and recorded via a computer running ActiMot software (TSE Systems). Raw data obtained via 5 min sampling intervals was summed for the 30 min duration of the experiment and expressed as distance travelled (m).

[0584] Results

[0585] The data is presented in figures 6A and 6B. The tested doses Compound 1 is devoid of sedative activity unlike Diazepam in rats. P7475PC00

[0586] References

[0587] Amrutkar, D.V. et al., The Cerebellum (2020) 19:265-274, Anti-Tremor Action of Subtype Selective Positive Allosteric Modulators of GABAA Receptors in a Rat Model of Essential Tremor

[0588] Kosmowska B, Wardas J., Biomolecules (2021), 11 (12):1813, The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models Martin FC, Thu le A, Handforth A., Mov Disord. (2005);20(3):298-305, Harmaline- induced tremor as a potential preclinical screening method for essential tremor medications

[0589] Pal PK., Ann Indian Acad Neurol. 2011 Jul; 14 (Suppl 1):S25-8, Guidelines for management of essential tremor

Claims

67P7475PC00Claims1. A compound for use in the treatment and / or prevention of tremor in a subject, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7- imidazo[4,5-b]pyridin-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof or hydrate thereof.

2. The compound, salt, or hydrate for use according to claim 1 , wherein the tremor is essential tremor, enhanced physiological tremor, functional tremor, secondary tremor and / or rest tremor.

3. The compound, salt or hydrate for use according to any one of the preceding claims, wherein the tremor is essential tremor.

4. The compound, salt, or hydrate for use according to any one of the preceding claims, wherein the tremor is action tremor, such as postural tremor, kinetic tremor and / or isometric tremor.

5. The compound, salt, or hydrate for use according to any one of the preceding claims, wherein the tremor is postural tremor and / or kinetic tremor.

6. The compound, salt, or hydrate for use according to any one of the preceding claims, wherein the tremor is hand tremor, head tremor, leg tremor, voice tremor, tongue tremors, face tremor, chin tremor, neck tremor and / or torso tremor.

7. The compound, salt or hydrate for use according to any one of the preceding claims, wherein the tremor is reduced, such as reduced with at least about 5%, such as at least 10%, such as at least 15%, such as at least 25%.

8. The compound, salt, or hydrate for use according to any one of the preceding, wherein the compound reduces tremor without significantly causing sedation.68P7475PC009. The compound, salt, or hydrate for use according to claim 8, wherein the compound reduces tremor without significantly causing sedation in the 4-8 Hz range.

10. A method for treating and / or preventing tremor, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7-imidazo[4,5- b]pyridin-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof or a hydrate thereof, to a subject in need thereof.11 . The method according to claim 10, wherein the tremor is essential tremor, enhanced physiological tremor, functional tremor, secondary tremor and / or rest tremor.

12. The method according to any one of the claims 10 or 11 , wherein the tremor is essential tremor.

13. The method according to any one of the claims 10 to 12, wherein the tremor is action tremor, such as postural tremor, kinetic tremor and / or isometric tremor.

14. The method according to any one of the claims 10 to 13, wherein the tremor is postural tremor and / or kinetic tremor.

15. The method according to any one of claims 10 to 14, wherein the tremor is hand tremor, head tremor, leg tremor, voice tremor, tongue tremors, face tremor, chin tremor, neck tremor and / or torso tremor.

16. The method according to any one of claims 10 to 15, wherein the tremor is reduced, such as reduced with at least about 5%, such as at least 10%, such as at least 15%, such as at least 25%.

17. The method according to any one of claims 10 to 16, wherein the compound reduces tremor without significantly causing sedation.

18. The method according to claim 10, wherein the subject is having, is suspected of having, or at risk of developing essential tremor.P7475PC0019. The method according to any one of claims 10 to 18, wherein the subject is human.

20. Use of 2-(3-(3-(2,4-dimethoxypyrimidin-5-yl)phenyl)-3 / 7-imidazo[4,5-b]pyridin-6- yl)propan-2-ol or a pharmaceutically acceptable salt thereof or hydrate thereof, for the manufacture of a medicament for the treatment and / or prevention of tremor in a subject.

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