KV3 modulators for use in the treatment or prophylaxis of amyotrophic lateral sclerosis (ALS)

Abstract

The invention provides, inter alia, a method for the treatment or prophylaxis of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing total Kv3 channel activity in the subject.

Description

[0001] KV3 MODULATORS FOR USE IN THE TREATMENT OR PROPHYLAXIS OF AMYOTROPHIC LATERAL SCLEROSIS (ALS) Field of the invention

[0002] The invention relates to methods for the treatment or prophylaxis of amyotrophic lateral sclerosis (ALS) by modulating Kv3 channel activity.

[0003] Background of the invention

[0004] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, affects around 1 in 400 people, with 1,200 (UK) and 6,000 (USA) new diagnoses per year on average. The disease is characterised by degeneration of motoneurons causing a progressive paralysis and death within 2-5 years of symptom onset, usually due to respiratory complications.

[0005] Approximately 10% of ALS cases show a Mendelian pattern of inheritance, mainly in an autosomal dominant manner, and have been linked to gene mutations in one of several known causative genes (SOD1, fus, C9orf72, TDP43 and SQSTM1). The remaining 90% of cases are considered “sporadic”, although they may involve certain risk genes, such as TBK1. Diverse pathogenic mechanisms have been implicated in the degeneration of motoneurons, including exci totoxi city, oxidative stress, aberrant protein aggregation, defective axonal transport, mitochondrial dysfunction and altered RNA metabolism. In addition, there are competing theories suggesting an active role for muscle in the earliest pathophysiology of ALS. Riluzole and edaravone are the only licenced treatments, with modest benefit on survival.

[0006] There remains a need for new approaches to the treatment or prophylaxis of ALS, such approaches may demonstrate high in vivo efficacy, reduction in the dose required for effect in vivo, or efficacy associated with an improved safety profile / reduced side effects, or the like.

[0007] Summary of the invention

[0008] The invention provides a method for the treatment of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing total Kv3 channel activity in the subject. The invention also provides a method for the treatment of ALS in a subject, the method comprising the steps of:

[0009] i) diagnosing the subject with ALS; and

[0010] ii) increasing total Kv3 channel activity in the subject.

[0011] The invention also provides a method for the treatment of ALS in a subject who may be susceptible to treatment by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0012] i) identifying that the ALS may be susceptible to treatment by increasing total Kv3 channel activity in the subject; and

[0013] ii) increasing total Kv3 channel activity in the subject. The invention also provides a method for the treatment of ALS in a subject, the method comprising the steps of:

[0014] i) providing a sample from the subject;

[0015] ii) using the sample to diagnose the subject with ALS; and iii) increasing total Kv3 channel activity in the subject.

[0016] The invention also provides a method for the treatment of ALS in a subject who may be susceptible to treatment by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0017] i) providing a sample from the subject;

[0018] ii) using the sample to identify that the ALS may be susceptible to treatment by increasing total Kv3 channel activity; and

[0019] iii) increasing total Kv3 channel activity in the subject.

[0020] The invention also provides a method for the prophylaxis of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing total Kv3 channel activity in the subject.

[0021] The invention also provides a method for the prophylaxis of ALS in a subject, the method comprising the steps of:

[0022] i) establishing that the subject is at significant risk of developing ALS; and ii) increasing total Kv3 channel activity in the subject.

[0023] The invention also provides a method for the prophylaxis of ALS in a subject at significant risk of developing ALS who may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0024] i) identifying that the ALS may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject; and

[0025] ii) increasing total Kv3 channel activity in the subject.

[0026] The invention also provides a method for the prophylaxis of ALS in a subject, the method comprising the steps of:

[0027] i) providing a sample from the subject;

[0028] ii) using the sample establish that the subject is at significant risk of developing ALS; and

[0029] iii) increasing total Kv3 channel activity in the subject.

[0030] The invention also provides a method for the prophylaxis of ALS in a subject at significant risk of developing ALS who may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0031] i) providing a sample from the subject;

[0032] ii) using the sample to identify that the ALS may be susceptible to prophylaxis by increasing total Kv3 channel activity; and iii) increasing total Kv3 channel activity in the subject.

[0033] The invention also provides a Kv3 modulator for use in the treatment of ALS in a subject.

[0034] The invention also provides a pharmaceutical composition comprising a Kv3 modulator for use in the treatment of ALS in a subject.

[0035] The invention also provides a pharmaceutical composition comprising a Kv3 modulator and a pharmaceutically acceptable excipient or carrier for use in the treatment of ALS in a subject.

[0036] The invention also provides the use of a Kv3 modulator in the manufacture of a medicament for the treatment of ALS in a subject.

[0037] The invention also provides a Kv3 modulator for use in the prophylaxis of ALS in a subject.

[0038] The invention also provides a pharmaceutical composition comprising a Kv3 modulator for use in the prophylaxis of ALS in a subject.

[0039] The invention also provides a pharmaceutical composition comprising a Kv3 modulator and a pharmaceutically acceptable excipient or carrier for use in the prophylaxis of ALS in a subject.

[0040] The invention also provides the use of a Kv3 modulator in the manufacture of a medicament for the prophylaxis of ALS in a subject.

[0041] Further embodiments of the invention will be apparent from the description below.

[0042] Summary of the figures

[0043] Fig. 1: Kv3.1 mRNA levels (fold change) in the anterios tibialis, extensor digitorium longus and soleus muscles from a mouse ALS model (at 40 days, 63 days and 85 days).

[0044] Fig. 2: Kv3.4 mRNA levels (fold change) in the anterios tibialis, extensor digitorium longus and soleus muscles from a mouse ALS model (at 40 days, 63 days and 85 days).

[0045] Fig. 3: Kv3.1; Kv3.3 and Kv3.4 mRNA levels (fold change) in the anterios tibialis at the end stage (at 120 days) of the disease in a mouse ALS model.

[0046] Fig. 4: Kv3.1; Kv3.3 and Kv3.4 mRNA levels (fold change) in the spinal cord at the end stage (at 120 days) of the disease in a mouse ALS model.

[0047] Fig. 5: Expression of members of the miR-17-92 complex (19a and 19b) and a member of the C2MC complex (miR669c (“669c”)) at the end stage (120 days) of disease in a mouse ALS model.

[0048] Fig. 6: Mouse model Nissl positive motor neuron count in lumbar-1 of Group 2 (SOD1G93Aand vehicle).

[0049] Fig. 7: Mouse model astrogliosis in lumbar-1 quantified by mean intensity of GFAP staining (intensity of Group 1 to Group 4). Fig. 8: Mouse model microgliosis in lumbar-1 quantified by mean intensity of Iba1 staining (intensity of Group 1 to Group 4).

[0050] Fig. 9: Mouse model Nf-L level in plasma in Group 1 to Group 4.

[0051] Figs. 10A and 10B: Human sporadic ALS patient Kv3.4 mRNA expression in Vastus Lateralis (VL) muscle.

[0052] Fig. 11: Kv3.1 and Kv3.4 localisation studies in muscle samples (microscopy images).

[0053] Fig. 12: Kv3.1 and Kv3.4 localisation studies in muscle samples (fluorescence measurements).

[0054] Fig. 13: Percentage of Kv3.1 or Kv3.4-positive Ila, I lx and lib muscle fibers.

[0055] Fig. 14: Impact of motor unit damage on expression of Kv3 family members and regulation of genes associated with muscle denervation.

[0056] Fig. 15: Effect of nerve cutting, BoNT injection and BaCl2injection on transversal sections of quadriceps muscle shown by hematoxylin / eosin staining.

[0057] Detailed description of the invention

[0058] The inventors have identified that increasing total Kv3 channel activity may be of use in the treatment or prophylaxis of amyotrophic lateral sclerosis (ALS).

[0059] Kv3 modulation

[0060] Methods of the invention comprise increasing total Kv3 channel activity in a subject. Total Kv3 channel activity may be increased by, for example, (a) increasing the number of Kv3 channels (i.e. influencing expression of the channels) and / or (b) increasing the activity of specific Kv3 channels (i.e. potentiating channel function). In one embodiment, total Kv3 channel activity is increased in muscle or in the brain. In a particular embodiment, total Kv3 channel activity is increased in the muscle.

[0061] Expression of Kv3 channels

[0062] Increasing the number of Kv3 channels may be achieved in a specific tissue type, or in the plasma membrane of a specific cell type. The number of Kv3 channels may be increased by increasing expression of the channels. Suitably expression of Kv3 channels is increased after treatment by increasing the quantity of relevant transcription activation factors, increasing the number of copies of relevant genes, or other epigenetic modifications to histone (e.g. acetylation, methylation), chromatin or nucleic acids (e.g. methylation). In some embodiments, increasing Kv3 channel expression comprises “overexpressing” a transcription activation factor, i.e., increasing expression of the transcription activation factor above the endogenous expression level of the transcription factor in the cell.

[0063] Expression of Kv3 channels may be increased by gene therapy, for example using DNA or RNA. A suitable gene therapy may comprise administering a vector (e.g. a viral vector) to the subject which encodes and is cable of resulting in the expression of Kv3 channels.

[0064] Expression of Kv3 channels may be increased by regulating gene expression. Certain micro RNAs (miRNAs) target Kv3 channel-encoding mRNA, reducing translation of Kv3 channels. Therefore, one method of regulating gene expression to increase Kv3 channels is to deliver to the subject an agent such as a small molecule which targets such miRNAs and prevents binding to Kv3 channel-encoding mRNA. Such miRNAs are referred to herein as “anti-Kv3 channel-encoding mRNA miRNAs”. Suitable miRNAs include members of the miR-17-92 complex, such as miR19a and miR19b, and also miR669c.

[0065] An increase in Kv3 channel numbers may refer to a relative increase or an absolute increase. Such outcomes may improve the disease state or reduce symptoms of disease. An increase in Kv3 channel expression may also refer to a reduction in the rate of decline of Kv3 channels as compared to untreated subjects with the disease. Such an outcome may retard the progression of disease or reduce symptoms of disease.

[0066] In some embodiments, Kv3 channel expression in the subject is considered to be increased if the quantity of the channels expressed in a specific tissue type (e.g. muscle fibers) or in the plasma membrane of a specific cell type (e.g. muscle fiber cells), most suitably at the plasma membrane of a specific cell type, is increased.

[0067] As discussed above, treatment may increase the level of Kv3 channel expression. The increase may be relative to the level of Kv3 channel expression in the subject before treatment. Accordingly, the level of Kv3 channel expression may be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 300%, at least 400% or at least 500% relative to the level of Kv3 channel expression before treatment.

[0068] Alternatively, the increase may be relative to the level of Kv3 channel expression in a control. Accordingly, the level of Kv3 channel expression after treatment may be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% relative to the level of Kv3 channel expression in a control. Alternatively, the level of Kv3 channel expression may be increased to at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300% or at least 400% of the level of Kv3 channel expression in a control.

[0069] A suitable control may be a sample of healthy tissue or a healthy cell which has not received treatment. Desirably, the level of Kv3 channel expression after treatment does not substantially exceed the level of Kv3 channel expression in the control. In one embodiment the level of Kv3 channel expression exceeds the level of Kv3 channel expression in the control by no more than 1%, such as 5%, such as 10%.

[0070] As discussed above, treatment may retard the progression of disease, such as by reducing the rate of decline of Kv3 channels. A reduction in the rate of decline of Kv3 channels is achieved where, before treatment, the quantity of Kv3 channels was declining and after treatment, the rate of decline has reduced or the quantity of Kv3 channels has substantially stabilised (e.g. in line with that of a healthy control). Suitably the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150% or at least 200% relative to the rate of decline before treatment.

[0071] Alternatively, a reduction in the rate of decline of Kv3 channels is achieved where the rate of decline has reduced, compared to a healthy control. Suitably the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150% or at least 200% relative to the rate of decline in a healthy control.

[0072] The level of Kv3 channel expression may be quantified, for example, by (a) RNA isolation from the subject and real time qPCR e.g. to establish the level of Kv3 channel mRNA, or (b) micro-RNA retro-transcription and q-PCR e.g. to establish the level of micro RNAs targeting Kv3 channel transcripts (e.g. members of the miR-17-92 complex, such as miR19a and miR19b, and also miR669c). These methods may be carried out more specifically as set out in Example 1 “RNA isolation and real time qPCR” and “Micro-RNA retro-transcription and q-PCR” below.

[0073] Function of Kv3 channels

[0074] Potentiating channel function is also referred to herein as increasing channel function. An increase in Kv3 channel function may refer to a relative increase or an absolute increase. Such outcomes may improve the disease state or reduce symptoms of disease. An increase in Kv3 channel function may also refer to a reduction in the rate of decline of Kv3 channel function as compared to untreated subjects with the disease. Such an outcome may retard the progression of disease or reduce symptoms of disease.

[0075] In some embodiments, Kv3 channel function in the subject is considered to be increased if the function of the channels expressed in a specific tissue type (e.g. muscle fibers) or in the plasma membrane of a specific cell type (e.g. muscle fiber cells), most suitably at the plasma membrane of a specific cell type, is increased. As discussed above, treatment may increase Kv3 channel function. The increase may be relative to the function of Kv3 channels in the subject before treatment. Accordingly, the function of channels may be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190% or at least 200% relative to the function of Kv3 channels before treatment.

[0076] Alternatively, the increase may be relative to the function of Kv3 channels in a control. Accordingly, the level of Kv3 channel function may be increased after treatment by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% relative to the level of Kv3 channel function in a control.

[0077] Alternatively, the level of Kv3 channel function after treatment may be increased to at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% of the level of Kv3 channel function in a control.

[0078] A suitable control may be a sample of healthy tissue or a healthy cell which has not received treatment. Desirably, the level of Kv3 channel function after treatment does not substantially exceed the level of Kv3 channel function in the control. In one embodiment the level of Kv3 channel function exceeds the level of Kv3 channel function in the control by no more than 1%, such as 5%, such as 10%.

[0079] As discussed above, treatment may retard the progression of disease, such as by reducing the rate of decline of Kv3 channel function. A reduction in the rate of decline of Kv3 channel function is achieved where, before treatment, the function of Kv3 channels was declining and after treatment, the rate of decline has reduced or the function of Kv3 channels has substantially stabilised (e.g. in line with that of a healthy control). Suitably the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140% or at least 150% relative to the rate of decline before treatment.

[0080] Alternatively, a reduction in the rate of decline of Kv3 channel function is achieved where the rate of decline has reduced, compared to a healthy control. Suitably the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140% or at least 150% relative to the rate of decline in a healthy control.

[0081] Kv3 channel function may be increased by administering an agent which increases Kv3 channel function. An agent which acts directly on Kv3 channels to potentiate the associated currents, thereby increasing Kv3 channel function is referred to herein as a Kv3 modulator. Kv3 modulators may include polynucleotides (e.g. DNA, RNA (e.g. siRNA, miRNA, IncRNA)), polypeptides or small molecules.

[0082] Suitably the Kv3 modulator is selected from the list consisting of one or more of a modulator of Kv3.1, Kv3.2, Kv3.3 and Kv3.4 (such as: a modulator of Kv3.1; a modulator of Kv3.1 and Kv3.2; a modulator of Kv3.1 and / or Kv3.4. In one embodiment the Kv3 modulator is a modulator of Kv3.1. In one embodiment the Kv3 modulator is a modulator of Kv3.4.

[0083] Suitably a Kv3 modulator refers to an agent which is capable of producing at least 10% potentiation, and more suitably at least 20% potentiation of whole-cell currents mediated by Kv3 channels. Suitably the Kv3 channels are human Kv3 channels. Suitably the Kv3 channels are recombinantly expressed (e.g. in mammalian cells).

[0084] In one embodiment the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by human Kv3.1 channels recombinantly expressed in mammalian cells. Suitably the pEC50of the modulator is in the range of 4-8 (such as 5-7.5). Suitably the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0085] In one embodiment the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by human Kv3.1 channels recombinantly expressed in mammalian cells. Suitably the pEC50of the modulator is in the range of 4-8 (such as 5-7.5). Suitably the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0086] In one embodiment the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by human Kv3.2 channels recombinantly expressed in mammalian cells. Suitably the pEC50of the modulator is in the range of 4-8 (such as 5-7.5). Suitably the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0087] In one embodiment the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by human Kv3.3 channels recombinantly expressed in mammalian cells. Suitably the pEC50of the modulator is in the range of 4-8 (such as 5-7.5). Suitably the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0088] In one embodiment the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by human Kv3.4 channels recombinantly expressed in mammalian cells. Suitably the pEC50of the modulator is in the range of 4-8 (such as 5-7.5). Suitably the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0089] Suitably the percentage potentiation of whole-cell currents is established in the assay set out below under ‘Potentiation Assay (Measurement of Kv3 Channel Modulation)’.

[0090] Particular Kv3 modulators

[0091] Suitably, the Kv3 modulator may be selected from the following compounds:

[0092] A compound of formula (I):

[0093]

[0094] wherein:

[0095] R1is halo, C1-4 alkyl, C1-4 alkoxy, halo-Ci-4 alkyl, halo-C1-4alkoxy, or cyano; R2is H, halo, cyano, C1-4 alkyl or C1-4 alkoxy; with the proviso that when R2is H, R1 is not in the para position;

[0096] X is C or N;

[0097] Y is C or N;

[0098] R3is C1-4 alkyl;

[0099] R4is H, deuterium, or C1-4 alkyl; or R3and R4can be fused to form a C3-4 spiro carbocyclyl group;

[0100] or a pharmaceutically acceptable salt and / or solvate thereof.

[0101] More suitably, the Kv3 modulator is selected from the following compounds (‘List A’): (5R)-5-methyl-3-{4-[(3-methylphenyl)oxy]phenyl}-2,4-imidazolidinedione;

[0102] (5R)-5-methyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0103] (5R)-3-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-imidazolidinedione;

[0104] (5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0105] (5R)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0106] (5S)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0107] (5R)-5-methyl-3-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0108] (5R)-3-{6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0109] (5R)-3-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0110] (5R)-3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0111] (5R)-3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0112] (5R)-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0113] (5R)-5-methyl-3-(6-{[2-methyl-5-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0114] (5R)-5-methyl-3-(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0115] (5R)-5-ethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0116] (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0117] (5S)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0118] (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; 5,5-dimethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0119] 3-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0120] 3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0121] 3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0122] (5R)-5-(1-methylethyl)-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0123] (5R)-5-methyl-3-(2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione; (5R)-5-ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

[0124] (5R)-5-(1, 1 -dimethylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0125] (5R)-5-ethyl-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0126] 7-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-5,7-diazaspiro[3.4]octane-6,8-dione;

[0127] 6-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-4,6-diazaspiro[2.4]heptane-5,7-dione; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(1-methylethyl)benzonitrile;

[0128] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(trifluoromethyl)oxy]benzonitrile;

[0129] 3-{6-[(4-fluoro-3-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione; 3-{6-[(4-fluoro-2-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione; 5.5-dimethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0130] (5R)-5-(1-methylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0131] 3-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione; 3-(2-{[2-(1,1-dimethylethyl)phenyl]oxy}-5-pyrimidinyl)-5,5-dimethyl-2,4-imidazolidinedione;

[0132] (5R)-5-ethyl-5-methyl-3-(2-{[4-methyl-3-(methyloxy)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

[0133] (5R)-5-ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-5-methyl-2,4-imidazolidinedione;

[0134] 5.5-dimethyl-3-[6-({3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0135] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-ethylbenzonitrile; 2-chloro-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile; 5.5-dimethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0136] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(methyloxy)benzonitrile;

[0137] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-methylbenzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(trifluoromethyl)benzonitrile;

[0138] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-ethylbenzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-2-ethylbenzonitrile; 3-cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0139] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(1,1-dimethylethyl)benzonitrile;

[0140] 2-[(cyclopropylmethyl)oxy]-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0141] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(ethyloxy)benzonitrile; 2-cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1 -imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0142] 5,5-dimethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4-imidazolidinedione;

[0143] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-3-(1,1-dimethylethyl)benzonitrile;

[0144] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(1-methylethyl)oxy]benzonitrile;

[0145] 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1-methylethyl)oxy]benzonitrile;

[0146] 3-cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0147] 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitrile;

[0148] 2-cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0149] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4-imidazolidinedione;

[0150] 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile;

[0151] 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0152] 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(methyloxy)benzonitrile; 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(ethyloxy)benzonitrile; 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(ethyloxy)benzonitrile; 3-cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0153] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2- (methyloxy)benzonitrile;

[0154] 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(methyloxy)benzonitrile; 2-[(cyclopropylmethyl)oxy]-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0155] (5R)-5-ethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0156] 2-cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0157] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0158] (5R)-5-ethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4-imidazolidinedione;

[0159] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1-methylethyl)oxy]benzonitrile;

[0160] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-3-methylbenzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitrile;

[0161] 3-ethyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)-3-methylbenzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile; and

[0162] 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0163] or a pharmaceutically acceptable salt and / or solvate thereof.

[0164] Most suitably, the Kv3 modulator is:

[0165] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[0166]

[0167] or a pharmaceutically acceptable salt and / or solvate thereof.

[0168] Such Kv3 modulators are disclosed in PCT publication number WO2011069951 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 8 of WO2011069951 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Example 1 to 86 of WO2011069951 or a pharmaceutically acceptable salt and / or solvate thereof.

[0169] Alternatively, the Kv3 modulator is compound of formula (II):

[0170]

[0171] wherein:

[0172] Ri is H, or Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, haloCi-4alkoxy;

[0173] R2is H, Ci-4alkyl, C3-4 spiro carbocyclyl, haloCi-4alkyl or halo;

[0174] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0175] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0176] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group to form a tricycle when considered together with the phenyl;

[0177] X is C or N;

[0178] Y is C or N;

[0179] R4 is C1-4 alkyl;

[0180] R5 is H, Deuterium, C1-4 alkyl;

[0181] or R4 and Rs can be fused to form C3-4 spiro carbocyclyl;

[0182] wherein R2 and R3 may be attached to the same or a different ring atom; and wherein R2 may be attached to a fused ring atom;

[0183] or a pharmaceutically acceptable salt and / or solvate thereof.

[0184] More suitably, the Kv3 modulator is selected from the following compounds (‘List B’): (5R)-3-[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione; (5R)-5-methyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2,4-imidazolidinedione;

[0185] (5R)-3-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0186] 5,5-dimethyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2,4-imidazolidinedione; (5R)-5-ethyl-3-{6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

[0187] (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; (5 / ?)-3-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0188] (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0189] (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-2,4-imidazolidinedione;

[0190] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-2,4-imidazolidinedione;

[0191] 7-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5,7-diazaspiro[3.4]octane-6, 8-dione;

[0192] 6-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-4,6-diazaspiro[2.4]heptane-5, 7-dione;

[0193] 3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0194] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-(1,1-dimethylethyl)-2,4-imidazolidinedione;

[0195] (5R)-5-ethyl-3-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0196] 5.5-dimethyl-3-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0197] (5R)-5-ethyl-5-methyl-3-[6-(spiro[1 -benzofuran-3, 1 '-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0198] (5R)-5-ethyl-3-(6-{[(3S / R)-3-methyl-1,3-dihydro-2-benzofuran-4-yl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (diastereoisomeric mixture);

[0199] (5R)-5-ethyl-3-{6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2);

[0200] (5R)-5-ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (distereoisomeric mixture);

[0201] (5R)-5-ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2);

[0202] 5.5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (racemate mixture);

[0203] 5.5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (enantiomers 1 and enantiomer 2);

[0204] 5.5-dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione; 5.5-dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (enantiomer 1 and enantiomer 2);

[0205] (5R)-5-ethyl-5-methyl-3-[6-(1 / 7-spiro[2-benzopyran-4,1'-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0206] 3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0207] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-(1-methylethyl)-2,4-imidazolidinedione;

[0208] (5R)-3-{6-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-2,4-imidazolidinedione;

[0209] 5.5-dimethyl-3-[6-(1 / 7-spiro[2-benzopyran-4,1'-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0210] (5R)-3-[2-(2,3-dihydrospiro[chromene-4, T-cyclopropan]-5-yloxy)-5-pyrimidinyl]-5-ethyl-5-methyl-2,4-imidazolidinedione;

[0211] 5.5-dimethyl-3-{6-[(4-methyl-3,4-dihydro-2 / 7-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (racemate mixture, enantiomer 1, enantiomer 2);

[0212] (5R)-5-ethyl-5-methyl-3-{6-[(3-methyl-3,4-dihydro-2 / 7-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[0213] (5R)-5-ethyl-5-methyl-3-[6-(1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridinyl]-2,4-imidazolidinedione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[0214] 3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione (racemate mixture, enantiomer 1, enantiomer 2);

[0215] (5R)-5-ethyl-5-methyl-3-[2-(4-methylchroman-5-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[0216] (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[0217] (5R)-3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0218] (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[0219] (5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;

[0220] (5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione;

[0221] (5R)-3-{2-[(2,2-difluoro-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione; (5R)-5-ethyl-5-methyl-3-{2-[(2,4,4-trimethyl-4H-3,1-benzoxazin-5-yl)oxy]-5-pyrimidinyl}- 2.4-imidazolidinedione;

[0222] 5.5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[0223] 3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0224] 5.5-dimethyl-3-[2-(7-methylspiro[1H-isobenzofuran-3, T-cyclobutane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[0225] (5R)-5-ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[0226] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[0227] (5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

[0228] (5R)-5-ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;

[0229] (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[0230] (5R)-3-[6-(3,3-dimethylisochroman-5-yl)oxy-3-pyridyl]-5-ethyl-5-methyl-imidazolidine- 2.4-dione;

[0231] (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-4-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0232] (5R)-5-ethyl-5-methyl-3-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]imidazolidine-2, 4-dione;

[0233] (5R)-3-{6-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione; and

[0234] 5.5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[0235] or a pharmaceutically acceptable salt and / or solvate thereof.

[0236] Most suitably, the Kv3 modulator is:

[0237] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione

[0238]

[0239] or a pharmaceutically acceptable salt and / or solvate thereof.

[0240] Most suitably, the Kv3 modulator is:

[0241] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[0242]

[0243] or a pharmaceutically acceptable salt and / or solvate thereof.

[0244] Such Kv3 modulators are disclosed in PCT publication number W02012007877 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 41 of WO2012007877 ora pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 70 of W02012007877 or a pharmaceutically acceptable salt and / or solvate thereof.

[0245] Alternatively, the Kv3 modulator is compound of formula (III):

[0246]

[0247] wherein:

[0248] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[0249] R2is H, Ci-5alkyl, C3-5 spiro carbocyclyl, haloCi-5alkyl or halo;

[0250] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0251] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0252] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0253] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[0254] X is CH or N;

[0255] Y is CR15 or N; R15 is H or Ci-4alkyl;

[0256] R4 is C1-4 alkyl;

[0257] R5 is H, Deuterium, C1-4 alkyl;

[0258] or R4 and R5 can be fused to form C3-4 spiro carbocyclyl;

[0259] wherein R2 and R3 may be attached to the same or a different ring atom; wherein R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0260] or a pharmaceutically acceptable salt and / or solvate thereof.

[0261] More suitably, the Kv3 modulator is selected from the following compounds (‘List C’): 3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[0262] 3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0263] 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[0264] 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[0265] 5,5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 1);

[0266] 5.5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 2);

[0267] 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[0268] 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[0269] 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[0270] 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[0271] 5.5-dimethyl-3-(2-spiro[1H-isobenzofuran-3, T-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[0272] 5.5-dimethyl-3-(2-spiro[1H-isobenzofuran-3, T-cyclopentane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[0273] 5.5-dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 1);

[0274] 5,5-dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 2); 3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0275] 3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0276] (5R)-3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0277] (5R)-3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0278] (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0279] (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0280] (5R)-5-ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0281] (5R)-5-ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0282] (5R)-5-ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0283] (5R)-5-ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0284] (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0285] (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0286] (5R)-5-ethyl-5-methyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[0287] (5R)-5-ethyl-5-methyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclopentane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[0288] (5R)-5-ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0289] (5R)-5-ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0290] (5R)-3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0291] (5R)-3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0292] (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0293] (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0294] (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0295] (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0296] (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0297] (5R)-5-ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0298] (5R)-5-ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0299] (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[0300] (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[0301] (5R)-5-ethyl-5-methyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0302] (5R)-5-ethyl-5-methyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0303] (5R)-5-ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0304] (5R)-5-ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0305] (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0306] (5R)-3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0307] 3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0308] 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1); 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[0309] 5,5-dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 1);

[0310] 5.5-dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 2);

[0311] 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 1);

[0312] 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 2);

[0313] 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[0314] 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[0315] 5.5-dimethyl-3-(6-spiro[1H-isobenzofuran-3, T-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0316] 5.5-dimethyl-3-(6-spiro[1H-isobenzofuran-3, T-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0317] 5.5-dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 1);

[0318] 5,5-dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 2);

[0319] 3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0320] 3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-5-methyl-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0321] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0322] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0323] (5R)-5-ethyl-5-methyl-3-(5-methyl-6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0324] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0325] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2); 5,5-dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)imidazolidine-2, 4-dione (enantiomer 1);

[0326] 5,5-dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)imidazolidine-2, 4-dione (enantiomer 2);

[0327] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione;

[0328] (5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0329] (5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0330] (5R)-5-ethyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[0331] (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione;

[0332] (5R)-5-ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[0333] (5R)-5-ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[0334] (5R)-5-ethyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[0335] (5R)-3-{4-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]phenyl}-5-ethyl-5-methyl- 2,4-imidazolidinedione; and

[0336] (5R)-3-[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione; or a pharmaceutically acceptable salt and / or solvate thereof.

[0337] Most suitably, the Kv3 modulator is:

[0338] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[0339]

[0340] or a pharmaceutically acceptable salt and / or solvate thereof.

[0341] Such Kv3 modulators are disclosed in PCT publication number W02012168710 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular a Kv3 modulator may be a compound described in any one of claims 1 to 41 of W02012168710 ora pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 81 of W02012168710 or a pharmaceutically acceptable salt and / or solvate thereof.

[0342] Alternatively, the Kv3 modulator is compound of formula (IV):

[0343]

[0344] wherein:

[0345] W is group (Wa), group (Wb) or group (Wc):

[0346]

[0347] (Wc);

[0348] wherein:

[0349] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[0350] R2is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[0351] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0352] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0353] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0354] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[0355] X is CH or N;

[0356] Y is CR15 or N;

[0357] R15 is H or Ci-4alkyl;

[0358] R22 is H, Cl, F, Ci-4alkyl;

[0359] R23 is H, Ci-4alkyl, Cl, CF3, O-Ci-4alkyl, OCF3or N(CH3)2;

[0360] R24 is H, Cl, F, Ci-4alkyl, O-Ci-4alkyl, CN, OCF3 or CF3;

[0361] R25 is H, Cl, F, O-Ci-4alkyl or Ci-4alkyl; and

[0362] R26 is H or Ci-4alkyl;

[0363] wherein for R22 to R26, Ci-4alkyl may be substituted by O-methyl; with the provisos that:

[0364] not all of R22 to R26 may be H;

[0365] when R4 is H, then R23 is methyl or CF3 and R22, R24, R25 and R26 are all H;

[0366] when one of R22, R24, R25 or R26 is F, then at least one of R22 to R26 cannot be H or F; and

[0367] when R24 is not H, at least one of R22 or R23 is not H

[0368] R4 is H or C1-4 alkyl;

[0369] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom.

[0370] Or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. More suitably, the Kv3 modulator is selected from the following compounds (‘List D’): 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0371] 4-{6-[(3,3-diethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0372] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 1);

[0373] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 2);

[0374] 5-methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 1);

[0375] 5-methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 2);

[0376] 5-methyl-4-[6-(3H-spiro[2-benzofuran-1, T-cyclobutan]-6-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0377] 5-methyl-4-[6-(3H-spiro[2-benzofuran-1, T-cyclopentan]-6-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0378] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-4-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0379] 5-methyl-4-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0380] 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-methylpyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0381] 5-methyl-4-[5-methyl-6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-{5-methyl-6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0382] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3,1'-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0383] 5-methyl-4-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)pyridin-3-yl]-2,4-dihydro- 3H-1,2,4-triazol-3-one; and

[0384] 5-methyl-4-{2-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyrimidin-5-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0385] 5-methyl-4-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0386] 5-methyl-4-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0387] 4-{4-[(2,6-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[4-chloro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0388] 4-(4-{[4-fluoro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0389] 4-{4-[(3-chlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0390] 4-{4-[(3,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-chloro-2-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[3-chloro-5-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0391] 5-methyl-4-[4-({3-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0392] 4-{4-[(3-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0393] 5-methyl-4-(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0394] 4-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0395] 4-{4-[(3,4-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-{4-[(2-methylphenyl)oxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0396] 5-methyl-4-(4-{[3-(1-methylethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[3-(dimethylamino)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0397] 4-{4-[(2-fluoro-6-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(4-{[2-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one;

[0398] 4-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-methylphenyl)oxy]phenyl}-2,4-dihydro-3H1,2,4-triazol-3-one;

[0399] 4-(4-{[3-trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0400] 4-[4-[4-fluoro-3-(trifluoromethoxy)phenoxy]phenyl]-3-methyl-1H-1,2,4-triazol-5-one; 5-methyl-4-(5-methyl-6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0401] 4-(6-{[3-(ethyloxy)phenyl]oxy}-5-methyl-3-pyridinyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0402] 4-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5methly-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0403] 4-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; and

[0404] 5-methyl-4-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[0405] or a pharmaceutically acceptable salt and / or solvate thereof.

[0406] Most suitably, the Kv3 modulator is:

[0407] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[0408]

[0409] or a pharmaceutically acceptable salt and / or solvate thereof.

[0410] Such Kv3 modulators are disclosed in PCT publication number WO2013175215 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 47 of WO2013175215 ora pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 54 of WO2013175215 or a pharmaceutically acceptable salt and / or solvate thereof.

[0411] Alternatively, the Kv3 modulator is compound of formula (V):

[0412]

[0413] wherein:

[0414] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[0415] R2is H, Ci-5alkyl, C3-5 spiro carbocyclyl, haloCi-5alkyl or halo;

[0416] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0417] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0418] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0419] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[0420] X is CH or N;

[0421] Y is CR15 or N;

[0422] R15 is H or Ci-4alkyl;

[0423] R4 is C1-4 alkyl;

[0424] R5 is H, Deuterium, C1-4 alkyl;

[0425] or R4 and Rs can be fused to form C3-4 spiro carbocyclyl;

[0426] wherein R2 and R3 may be attached to the same or a different ring atom; wherein R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0427] or a pharmaceutically acceptable salt and / or solvate thereof.

[0428] Such Kv3 modulators are disclosed in PCT publication number WO2013083994 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 41 of WO2013083994 ora pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 10 of WO2013083994 or a pharmaceutically acceptable salt and / or solvate thereof.

[0429] Alternatively, the Kv3 modulator is compound of formula (VI):

[0430]

[0431] wherein:

[0432] W is group (Wa), group (Wb) or group (Wc):

[0433]

[0434] wherein:

[0435] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[0436] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[0437] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0438] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0439] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0440] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[0441] R16 is halo, C1-4 alkyl, C1-4 alkoxy, halo-Ci-4alkyl, halo-Ci-4alkoxy, or CN;

[0442] R17 is H, halo, cyano, C1-4 alkyl or C1-4 alkoxy; with the proviso that when R17 is H, R16 is not in the para position;

[0443] R4 is C1-4 alkyl;

[0444] Rs is H or C1-4 alkyl;

[0445] or R4 and Rs can be fused to form C3-4 spiro carbocyclyl;

[0446] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0447] or a pharmaceutically acceptable salt and / or solvate thereof.

[0448] More suitably, the Kv3 modulator is selected from the following compounds (‘List F’): (5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-2-pyridyl]imidazolidine-2, 4-dione

[0449]

[0450] (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[0451]

[0452] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-2-pyridyl]imidazolidine-2, 4-dione

[0453]

[0454] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[0455]

[0456] 5,5-dimethyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-2-pyridyl)imidazolidine-2, 4-dione

[0457]

[0458] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-2-pyridyl)imidazolidine-2, 4-dione

[0459]

[0460] or a pharmaceutically acceptable salt and / or solvate thereof.

[0461] Most suitably, the Kv3 modulator is:

[0462] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[0463]

[0464] or a pharmaceutically acceptable salt and / or solvate thereof.

[0465] Such Kv3 modulators are disclosed in PCT publication number WO2017103604 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 60 of WO2017103604 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 6 of WO2017103604 or a pharmaceutically acceptable salt and / or solvate thereof.

[0466] Alternatively, the Kv3 modulator is compound of formula (VII):

[0467]

[0468] wherein:

[0469] X is H or CH3;

[0470] Y is H or CH3;

[0471] wherein at least one of X and Y is H;

[0472] W is group (Wa), group (Wb) or group (Wc):

[0473] wherein group (Wa) and group (Wb) are:

[0474]

[0475] wherein:

[0476] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy or haloCi-4alkoxy;

[0477] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[0478] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0479] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0480] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0481] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[0482] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0483] wherein group (Wc) is:

[0484]

[0485] wherein:

[0486] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy or CN;

[0487] R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[0488] R18 is H, halo, CN, Ci-4alkyl or Ci-4alkoxy;

[0489] Z is group (Za) or (Zb):

[0490] wherein group (Za) is:

[0491]

[0492] (Za); wherein:

[0493] R4 is H or C1-4 alkyl;

[0494] R5 is H or C1-4 alkyl; or

[0495] R4 and R5 can be fused to form a C3-5 spiro carbocyclyl or a C2-5 spiro heterocyclyl; and wherein group (Zb) is:

[0496]

[0497] wherein:

[0498] R19 is C1-4 alkyl;

[0499] or a pharmaceutically acceptable salt and / or solvate thereof.

[0500] More suitably, the Kv3 modulator is selected from the following compounds (‘List G’): syn-5,5-dimethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[0501] syn-5,5-dimethyl-3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0502] syn-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-isopropyl-benzonitrile; ant / -5,5-dimethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy] cyclobutyl]imidazolidine-2, 4-dione;

[0503] ant / -5,5-dimethyl-3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0504] ant / -4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-isopropyl-benzonitrile; syn-5,5-dimethyl-3-[3-[3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione; ant / -5,5-dimethyl-3-[3-[3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione; syn-3-[3-(2-tert-butylphenoxy)cyclobutyl]-5,5-dimethyl-imidazolidine-2,4-dione; ant / -3-[3-(2-tert-butylphenoxy)cyclobutyl]-5,5-dimethyl-imidazolidine-2,4-dione; syn-3-tert-butyl-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]benzonitrile; ant / -3-tert-butyl-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]benzonitrile; syn-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-(trifluoromethoxy)benzonitrile;

[0505] ant / -4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-(trifluoromethoxy)benzonitrile;

[0506] ant / -5,5-dimethyl-3-(3-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxycyclobutyl)imidazolidine-2, 4-dione; syn-5,5-dimethyl-3-(3-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxycyclobutyl)imidazolidine-2, 4-dione;

[0507] syn-(5R)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0508] ant / -(5R)-5-ethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[0509] ant / -(5R)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0510] syn-(5S)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0511] ant / -(5S)-5-ethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[0512] ant / -(5S)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0513] syn-3-methyl-4-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-1 H-1,2,4-triazol-5-one;

[0514] ant / -3-methyl-4-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-1 H-1,2,4-triazol-5-one;

[0515] 4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]spiro[2H-benzofuran-3, T-cyclopropane]-7-carbonitrile;

[0516] 6-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-2-oxa-6,8-diazaspiro[3.4]octane-5, 7-dione;

[0517] 3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclo butyl]imidazolidine-2, 4-dione;

[0518] (5S)-5-methyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione; and

[0519] (5R)-5-methyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[0520] or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. Such Kv3 modulators are disclosed in PCT publication number WO2018020263 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 90 of WO2018020263 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 29 of WO2018020263 or a pharmaceutically acceptable salt and / or solvate thereof. Alternatively, the Kv3 modulator is compound of formula (VIII):

[0521]

[0522] wherein:

[0523] Ri is H or methyl;

[0524] R2 and R3 are both methyl, or R2 and R3, together with the carbon atom to which they are attached, are a spirocyclopropyl ring;

[0525] R4 is methyl or ethyl;

[0526] R5 is H or methyl;

[0527] or R4 and R5, together with the carbon atom to which they are attached, form a C3-C4 spiro carbocyclyl;

[0528] or a salt and / or solvate and / or derivative thereof.

[0529] More suitably, the Kv3 modulator is selected from the following compounds (‘List H’): 5.5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[0530] 3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0531] (5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione;

[0532] 5.5-dimethyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione;

[0533] (5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[0534] (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[0535] 5.5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;

[0536] (5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2, 4-dione;

[0537] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[0538] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione; (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;

[0539] (5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2, 4-dione;

[0540] 7-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6, 8-dione;

[0541] 6-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5, 7-dione; and

[0542] (5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[0543] or a pharmaceutically acceptable salt and / or solvate thereof.

[0544] Most suitably, the Kv3 modulator is:

[0545] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[0546]

[0547] or a salt and / or solvate thereof and / or derivative thereof.

[0548] Most suitably, the Kv3 modulator is:

[0549] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[0550]

[0551] or a salt and / or solvate thereof and / or derivative thereof.

[0552] Most suitably, the Kv3 modulator is:

[0553] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[0554]

[0555] or a salt and / or solvate thereof and / or derivative thereof. Such Kv3 modulators are disclosed in PCT publication number W02020079422 and PCT publication number WO2021156584 which are incorporated by reference in their entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 34 of W02020079422 or a pharmaceutically acceptable salt and / solvate thereof, or any one of claims 1 to 41 of WO2021156584 or a pharmaceutically acceptable salt and / solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 15 of W02020079422 or a pharmaceutically acceptable salt and / solvate thereof, or any one of Examples 1 to 15 of WO2021156584 or a pharmaceutically acceptable salt and / solvate thereof.

[0556] Alternatively, the Kv3 modulator is compound of formula (X):

[0557]

[0558] wherein:

[0559] V is group (Va), group (Vb) or group (Vc);

[0560] wherein group (Va) and group (Vb) are:

[0561]

[0562] wherein:

[0563] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[0564] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[0565] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0566] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0567] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0568] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl; wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0569] wherein group (Vc) is:

[0570]

[0571] (Vc);

[0572] wherein:

[0573] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy or CN;

[0574] R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[0575] R18 is H, halo, CN, Ci-4alkyl or Ci-4alkoxy;

[0576] W is N or CH;

[0577] X is N or CH;

[0578] Y is N or CH;

[0579] wherein at least one of W, X and Y is CH, and when one of X and Y is N, the other is CH;

[0580] Z is a 5-membered heteroaryl comprising one or two nitrogen atoms, and wherein one of the nitrogen atoms and one of the carbon atoms may be independently optionally substituted by methyl; or Z is a 6-membered heteroaryl comprising one or two nitrogen atoms, wherein one of the carbon atoms may be optionally substituted by methyl; and

[0581] provided that Z is not

[0582]

[0583] or a pharmaceutically acceptable salt and / or solvate thereof.

[0584] More suitably, the Kv3 modulator is selected from the following compounds (‘List J’): 3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[0585] 7-methyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[0586] 3-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[0587] 3-[6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one; 7-methyl-3-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[0588] 3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-2-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[0589] 3-[6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[0590] 3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one;

[0591] 3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0592] 3-[5-[3-(trifluoromethoxy)phenoxy]pyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0593] 3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0594] 3-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one; 3-(2-{2H-spiro[1-benzofuran-3, T-cyclopropane]oxy}pyrimidin-5-yl)-1H,2H,3H-imidazo[4,5-b]pyridin-2-one;

[0595] 4-[[5-(2-oxo-1H-imidazo[4,5-b]pyridin-3-yl)-2-pyridyl]oxy]-2- (trifluoromethoxy)benzonitrile;

[0596] 7-methyl-3-(2-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-one;

[0597] 3-[2-(3-methoxyphenoxy)pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0598] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one; 2-methyl-6-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-4H-imidazo[4,5-c]pyrazol-5-one;

[0599] 2-methyl-6-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-4H-imidazo[4,5-c]pyrazol-5-one;

[0600] 6-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-2-methyl-4H-imidazo[4,5-c]pyrazol-5-one;

[0601] 2-methyl-6-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)-4H-imidazo[4,5-c]pyrazol-5-one;

[0602] 2-methyl-6-(2-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrimidin-5-yl)-4H-imidazo[4,5-c]pyrazol-5-one;

[0603] 3-[2-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-c]pyridin-2-one;

[0604] 2-methyl-9-[6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-7H-purin-8-one;

[0605] 2-methyl-9-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-7H-purin-8-one; 2-methyl-9-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one;

[0606] 2-methyl-9-[6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-7H-purin-8-one;

[0607] 9-[6-(3-methoxyphenoxy)-3-pyridyl]-2-methyl-7H-purin-8-one;

[0608] 9-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-7H-purin-8-one;

[0609] 9-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-2-methyl-7H-purin-8-one;

[0610] 3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0611] 3-[2-[4-methyl-3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0612] 3-[2-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0613] 6-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-one;

[0614] 3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-c]pyridin-2-one;

[0615] 1-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-3H-imidazo[4,5-b]pyridin-2-one;

[0616] 5-methyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one;

[0617] 6-methyl-3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one; and

[0618] 3-[2-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[0619] or a salt and / or solvate thereof and / or derivative thereof.

[0620] Most suitably, the Kv3 modulator is:

[0621] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[0622]

[0623] or a pharmaceutically acceptable salt and / or solvate thereof

[0624] Such Kv3 modulators are disclosed in PCT publication number WO2023017263 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to

[0625]

[0626] a Kv3 modulator may be any one of Examples 1 to 39 of WO2023017263 or a pharmaceutically acceptable salt and / or solvate thereof.

[0627] Alternatively, the Kv3 modulator is compound of formula (XI):

[0628]

[0629] wherein

[0630] W is group (Wa), group (Wb) or group (Wc):

[0631] wherein group (Wa) and group (Wb) are:

[0632]

[0633] wherein:

[0634] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy or haloCi-4alkoxy;

[0635] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[0636] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0637] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0638] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[0639] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl; wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[0640] wherein group (Wc) is:

[0641]

[0642] wherein:

[0643] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy or CN; R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[0644] R18 is H, halo, CN, C1-4alkyl or C1-4alkoxy;

[0645] Z is group (Za):

[0646]

[0647] wherein:

[0648] R4 is H or C1-4 alkyl;

[0649] R5 is H or C1-4 alkyl; or

[0650] R4 and Rs can be fused to form a C3-5 spiro carbocyclyl;

[0651] or a pharmaceutically acceptable salt and / or solvate thereof.

[0652] More suitably, the Kv3 modulator is selected from the following compounds (‘List K’): 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[0653] (5R)-3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5-ethyl-imidazolidine-2, 4-dione;

[0654] 3-(2-amino-6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-5,5-dimethyl-imidazolidine-2, 4-dione;

[0655] (5R)-3-(2-amino-6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-5-ethyl-imidazolidine-2, 4-dione;

[0656] 3-[2-amino-6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[0657] 3-[2-amino-6-(3-methoxyphenoxy)-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione; 3-[2-amino-6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[0658] (5R)-3-[2-amino-6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5-ethyl-imidazolidine-2, 4-dione;

[0659] 3-[2-amino-6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione;

[0660] 4-[[6-amino-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-pyridyl]oxy]-2- (trifluoromethoxy)benzonitrile;

[0661] 4-[[6-amino-5-[(4R)-4-ethyl-2,5-dioxo-imidazolidin-1-yl]-2-pyridyl]oxy]-2- (trifluoromethoxy)benzonitrile; 4-[[6-amino-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1 -yl)-2-pyridyl]oxy]-2-isopropyl-benzonitrile;

[0662] 4-[[6-amino-5-[(4R)-4-ethyl-2,5-dioxo-imidazolidin-1-yl]-2-pyridyl]oxy]-2-isopropyl-benzonitrile; and

[0663] 3-[2-amino-6-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[0664] or a pharmaceutically acceptable salt and / or solvate thereof.

[0665] Such Kv3 modulators are disclosed in PCT application number PCT / GB2023 / 053142 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 41 of PCT / GB2023 / 053142 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[0666] Alternatively, the Kv3 modulator is a compound as disclosed in PCT publication number WO2019222816 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 14 of WO2019222816 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 93 of WO2019222816 or a pharmaceutically acceptable salt and / or solvate thereof.

[0667] Alternatively, the Kv3 modulator is a compound as disclosed PCT publication number W02020000065 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 18 of W02020000065 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 77 of W02020000065 or a pharmaceutically acceptable salt and / or solvate thereof.

[0668] Alternatively, the Kv3 modulator is a compound as disclosed in US publication number US20200131156 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 20 of US20200131156 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 118 of US20200131156 or a pharmaceutically acceptable salt and / or solvate thereof.

[0669] Alternatively, the Kv3 modulator is a compound as disclosed in PCT publication number W02021214090 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 38 of W02021214090 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 53 of W02021214090 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Alternatively, the Kv3 modulator is a compound as disclosed PCT publication number WO2024086061 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein. In particular, a Kv3 modulator may be a compound described in any one of claims 1 to 17 of WO2024086061 or a pharmaceutically acceptable salt and / or solvate thereof. In particular, a Kv3 modulator may be any one of Examples 1 to 3 of WO2024086061 or a pharmaceutically acceptable salt and / or solvate thereof.

[0670] In one embodiment, the Kv3 modulator is:

[0671] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[0672]

[0673] In another embodiment, the Kv3 modulator a salt and / or solvate of:

[0674] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[0675]

[0676] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0677] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[0678]

[0679] In one embodiment, the Kv3 modulator is:

[0680] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[0681]

[0682] In another embodiment, the Kv3 modulator is the salt and / or solvate of: (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[0683]

[0684] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0685] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[0686]

[0687] In one embodiment, the Kv3 modulator is:

[0688] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[0689]

[0690] In another embodiment, the Kv3 modulator is a salt and / or solvate of:

[0691] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[0692]

[0693] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0694] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[0695]

[0696] In one embodiment, the Kv3 modulator is:

[0697] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[0698]

[0699] In another embodiment, the Kv3 modulator is a salt and / or solvate of:

[0700] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[0701]

[0702] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0703] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[0704]

[0705] In one embodiment, the Kv3 modulator is:

[0706] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[0707]

[0708] In another embodiment, the Kv3 modulator is a salt and / or solvate of:

[0709] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[0710]

[0711] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0712] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[0713]

[0714] In one embodiment, the Kv3 modulator is:

[0715] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[0716]

[0717] In another embodiment, the Kv3 modulator is a salt and / or solvate of:

[0718] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[0719]

[0720] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[0721] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[0722]

[0723] In another embodiment, the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of (a) 2-methyl-9-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one or (b) 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione. More suitably (a) 2-methyl-9-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one or (b) 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione. The Kv3 modulator may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).

[0724] Unless defined for as part of a formula or compound structure, the Kv3 modulator encompasses all isomers of the Kv3 modulators disclosed herein including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0725] The Kv3 modulator encompasses all isotopic forms of the Kv3 modulators provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0726] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. In one embodiment, the Kv3 modulator is provided in a natural isotopic form. In one embodiment, the Kv3 modulator is provided in an unnatural variant isotopic form. In one embodiment, the Kv3 modulator is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the Kv3 modulator is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0727] Depending on the nature of the specific Kv3 modulator, the Kv3 modulator may be provided in the form of a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate. In some embodiments the Kv3 modulator is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate (i.e. a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). In other embodiments the Kv3 modulator is provided in the form of a pharmaceutically acceptable salt. In further embodiments the Kv3 modulator is provided in the form of a pharmaceutically acceptable solvate. In some embodiments the Kv3 modulator is provided in free form (i.e. not a salt or solvate).

[0728] Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Pharmaceutically acceptable salts may also be formed with metal ions such as metal salts, such as sodium or potassium salts, and organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.

[0729] The Kv3 modulator may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0730] A plurality of Kv3 modulators may be utilized in combination (for administration separately, sequentially or together). Kv3 modulators (one or more) may also be utilised in combination with other medicaments of use in the treatment or prophylaxis of ALS (for administration separately, sequentially or together).

[0731] Therapeutic Uses, Prophylactic Uses and Applications

[0732] The invention is directed to the treatment or prophylaxis of ALS in a subject. The ALS may be familial ALS or sporadic ALS. One of the known genetic risk factors for familial ALS is mutation of the SOD1 gene. The ALS may be classical ALS, primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA). The ALS may be diagnosed by, for example, genetic testing (particularly for familial ALS), physical examination, medical history review, neurologic examination (e.g. testing reflexes and muscle strength), electromyography (EMG), blood tests, urine tests, spinal tap, muscle biopsy or by establishing total Kv3 channel activity as discussed above.

[0733] In one embodiment the subject has a mutation in any one or more of the SOD1, fus, C9orf72, TDP43 or SQSTM1 genes. Suitably the subject has a mutation in the SOD1 gene (e.g. wherein the mutation is SOD1G93A). Suitably the Kv3 channel type is selected from the list consisting of one or more of Kv3.1, Kv3.2, Kv3.3 and Kv3.4 (such as Kv3.1, Kv3.3 and Kv3.4, such as Kv3.1 and / or Kv3.4. In one embodiment the Kv3 channel type is Kv3.1. In one embodiment the Kv3 channel type is Kv3.4. The invention may be of particular utility in the treatment or prophylaxis of ALS in a subject having reduced total Kv3 channel activity, such as reduced Kv3 channel expression, e.g. in a muscle sample, or such as reduced Kv3 channel function, relative to a comparable, normal (healthy) control sample.

[0734] In some embodiments, the total Kv3 channel activity is quantified. Quantification of total Kv3 channel activity (e.g. Kv3 channel function or Kv3 channel expression) may be for the purpose of diagnosing ALS, establishing risk of developing ALS, monitoring ALS progression, or monitoring the effect of treatment. Direct quantification can be achieved by, for example analysis of a sample from a subject. Indirect quantification can be achieved by, for example, analysis of brain activity.

[0735] A sample, as used herein, will be understood to be an appropriate sample for the intended analysis methodology i.e. a sample which allows the determination of reduced total Kv3 channel activity. For example, the sample may be a biopsy containing tissue such as muscle. Samples may be obtained or provided by any suitable method known in the art.

[0736] Brain activity of a subject (suitably, motor cortex hyperexcitability, e.g. relative to a healthy control) as an indirect indicator of suitability for treatment, response to treatment, or total Kv3 channel activity level may be established, for example, using transcranial magnetic stimulation (“TMS”) (such as the ppTMS short interval intracortical inhibition (SICI) protocol), see Vucic et al. 2018) or functional magnetic resonance imaging (“fMRI”) (see Bakker et al. 2015). Motor cortex hyperexcitability may be indicated specifically by reduction or absence of SICI and / or an increase in intracortical facilitation (ICF) and / or reduction in resting motor threshold (RMT), e.g. relative to a healthy control.

[0737] Methods for determining reduced total Kv3 channel activity (e.g. reduced Kv3 channel expression) include:

[0738] (i) methods which detect RNA changes, including analysis of a suitable sample of RNA, such as acquired from muscle, circulating cells or cell free exosomes, using a suitable technique for the detection of Kv3 channel RNA such as RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR or in situ hybridization;

[0739] (ii) methods which detect epigenetic changes, including (a) analysis of DNA obtained from muscle, circulating cells or cell free DNA, using a suitable technique for the detection of epigenic changes likely to result in reduced Kv3 channel expression, including DNA methylation analysis or characterisation of histone modification or (b) analysis of a suitable sample of RNA, such as acquired from muscle, circulating cells or cell free exosomes, and analysed by RNA sequencing, gene expression array, real-time quantitative PCR, digital droplet PCR or in situ hybridization; and / or (iii) methods which detect protein changes, including analysis of muscle or circulating cells using a suitable technique for the detection of Kv3 channel proteins such as immunohistochemistry, Western blot; flow cytometry or mass cytometry.

[0740] It will be appreciated that a plurality of analysis techniques may be applied in combination.

[0741] Suitably, the step of identifying that the ALS may be susceptible to treatment or prophylaxis by increasing total Kv3 channel activity comprises (i) applying a suitable method for determining reduced total Kv3 channel activity, (ii) analysis of data produced by the method, and (iii) interpretation of the data produced by the method to determine the likelihood of reduced total Kv3 channel activity.

[0742] In one embodiment it is identified that the ALS may be susceptible to treatment or prophylaxis by increasing total Kv3 channel activity by testing the sample for decreased total Kv3 channel activity relative to normal total Kv3 channel activity. Suitably the sample is a tissue sample from the subject. Suitably the tissue sample is a sample of muscle or cells.

[0743] In one embodiment it is identified that the ALS may be susceptible to treatment or prophylaxis by increasing total Kv3 channel activity by testing the brain activity of the subject relative to normal brain activity. Suitably brain activity is established using TMS (such as ppTMS). Suitably brain activity is established using fMRI.

[0744] In some embodiments, for prophylaxis of ALS, the subject is at significant risk of developing ALS. A subject is at significant risk of developing ALS if the subject has a higher risk of developing ALS than average, e.g. due to the subject having genetic risk factors or based on analysis of a sample from the subject.

[0745] Administration

[0746] The invention is typically intended for use with mammalian subjects, in particular human subjects. The Kv3 modulator will typically be administered to a subject in need thereof, in particular a mammalian subject in need thereof, in particular a human subject in need thereof. Ideally the Kv3 modulator is administered in a safe and effective amount.

[0747] The Kv3 modulator may be administered by any suitable route, which may depend on the nature of the specific agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration. Conveniently, the Kv3 modulator is administered orally.

[0748] The Kv3 modulator may be provided in the form of a pharmaceutical composition comprising the Kv3 modulator and a pharmaceutically acceptable carrier or excipient.

[0749] If delivered orally, the Kv3 modulator may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution). A liquid formulation will generally consist of a suspension or solution of the Kv3 modulator in a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine, or a nonaqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent.

[0750] A tablet formulation can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0751] Suitably, the pharmaceutical composition is in unit dose form, such as a tablet, capsule or ampoule. Suitably the unit dose form is for oral delivery.

[0752] The pharmaceutical composition may for example contain from 0.1% to 99.99% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The pharmaceutical composition may contain from 0.01% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The pharmaceutical composition may contain from 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, depending on the method of administration. The pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example from 100 mg to 400 mg, depending on the method of administration.

[0753] The dose of the compound used will vary in the usual way with the seriousness of the cancer, the weight of the sufferer, and other similar factors. However, as a general guide, suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer. A plurality of unit does, such as a plurality of tablets, may be taken together.

[0754] Suitably, the Kv3 modulator is administered orally, such as administered orally in a solid pharmaceutical composition.

[0755] The dose provided to a subject will typically be a safe and effective dose, i.e. an amount providing an acceptable balance of desired benefits and undesired side effects. A “safe and effective amount" is intended to include an amount of a compound that is effective to achieve a desirable effect in treatment of a disease-state. A desirable effect is typically clinically significant and / or measurable, for instance in the context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and / or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms. The safe and effective amount is one that is sufficient to achieve the desirable effect when the Kv3 modulator is administered.

[0756] For avoidance of doubt, a “safe and effective amount” as recited herein can be achieved by any suitable dosage regimen. Hence, for example, references herein to administering a safe and effective amount of a compound, such as by a particular administration route, include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route. For instance, orally administering a safe and effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective amount is thereby achieved by oral administration.

[0757] Administration of a Kv3 modulator may typically be once or twice per day. Suitable daily doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg.

[0758] Combinations with Further Agents

[0759] Treatment with the Kv3 modulator may be combined with one or more further pharmaceutically acceptable active ingredients, such as riluzole, edaravone, a combination of sodium phenylbutyrate and ursodoxicoltaurine (taurursodiol) or tofersen.

[0760] The Kv3 modulator and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing. If administered simultaneously, the Kv3 modulator may be e.g. (a) formulated separately from the further pharmaceutically acceptable active ingredient, or (b) if appropriate, formulated together with the further pharmaceutically acceptable active ingredient.

[0761] The invention is further exemplified by the following non-limiting examples. EXAMPLES

[0762] Example 1: Potassium channel expression reduction in a mouse model of ALS Potassium channel expression in a mouse model of ALS was investigated. Experimental animals were male and female transgenic mice expressing mutated human SOD1G93A(strain: B6SJL-Tg(SOD1G93A)1Gur / J; The Jackson Laboratory Stock Number: 002726) and wild-type (WT) littermates. This mutation is known to be associated with ALS, producing in mice a progressive phenotype of reduced motor function. Multiple experiments were performed using this model wherein mice were sacrificed at 40, 63, 85 and 120 days of age. These time points correspond to the presymptomatic, onset, and advanced stages of motor dysfunction, respectively. Muscle samples were analysed. Groups of mice were organised as follows. Each group consisted of 20 mice, with a subgroup of 8 mice from each group used for immunohistochemistry studies detailed below.

[0763]

[0764] The Kv3 modulator administered in the examples was (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione (see WO2012076877, example 62). To test the positive modulator properties of this compound, Kv3.1 channels were expressed in human embryo kidney (HEK) 293T cells, and the cells were treated with two concentrations of compound, i.e., 0.02 μM and 0.2 μM. Using whole-cell patch clamp, Kv3.1 currents were evoked by depolarizing the membrane from a holding potential of -90 mV to test potentials from -100 mV to +30 mV in 10 mV increments. Treatment significantly increased Kv3.1 currents, especially at voltages close to the threshold for Kv3 channel activation (-40 to 0 mV). When the normalised conductance was plotted as a function of membrane voltage, there was a leftward shift in the voltage dependence of activation upon compound treatment. Thus, this compound modulates the voltage-dependence of activation of Kv3.1 channels and lowers the voltage at which the channels are activated, thus facilitating channel opening at more hyperpolarised potentials. Using an lonworks™ automated patch-clamp assay, the compound increased Kv3.1, Kv3.2, and Kv3.4 currents measured at -15mV in a concentration-dependent manner with pEC50 values of 6.15 ± 0.04, 6.52 ± 0.05, and 5.6 ± 0.04, respectively. RNA isolation and real time qPCR

[0765] RNA isolation and real time qPCR was carried out. Total RNA was extracted from snap-frozen muscles with TRIzol (Thermo Fisher Scientific, Walthman, MA, USA) and RNA was reverse-transcribed using the SuperScript™ III Reverse Transcriptase (18080093 invitrogen) following the manufacturer’s instructions. Gene expression was measured by RT-qPCR using the SsoAdvanced Universal Sybr green supermix (1725274, Bio-Rad) and the QuantStudio™ 5 Real-Time PCR System (Thermo Fisher Scientific). The results are shown in Figs. 1-4.

[0766] In Figs. 1 and 2 it can be seen that SOD1G93Amice showed a progressive downregulation of Kv3.1 and Kv3.4 mRNA expression in the fast-twitch EDL and TA muscles during disease progression. Meanwhile, the expression of Kv3.1 and Kv3.4 was stable in slow-twitch soleus muscle. Fig. 3 demonstrates that Kv3.1, Kv3.3 and Kv3.4 mRNA expression was downregulated in SOD1G93Acompared to WT mice at the end stage (120 days) of the disease in fast-twitch tibialis anterior (“TA”, also referred to herein as “anterios tibialis”). The same downregulation was also observed in other fast-twitch muscles (quadriceps). Fig. 4 demonstrates that Kv3.1, Kv3.3 and Kv3.4 mRNA expression was downregulated in SOD1G93Acompared to WT mice at the end stage (120 days) of the disease in the spinal cord. By contrast Kv3.1, Kv3.3, Kv3.4 mRNA expression was not downregulated in the motor cortex of SOD1G93Acompared to WT mice (120 days).

[0767] Expression of Kv3 channels in different muscle fiber subtypes was also investigated. Contiguous transversal sections of TA muscles from 2-month-old wild type mice were processed for immunofluorescence analysis of specific fiber subtypes, i.e., myosin heavy chain (MyHC) 2a, MyHC 2x, and MyHC 2b, coupled with NADH staining to merge information with fiber metabolism (oxidative vs glycolytic). It was found that Kv3.1 and Kv3.4 are mainly expressed in type 2a and 2x fibers (Fig. 13).

[0768] Micro-RNA retro-transcription and q-PCR

[0769] Micro RNAs (miRNAs) are known to be modulators of transcript levels. For miRNA quantification, total RNA (10 ng) was reverse-transcribed with a stem-loop primer specific for each mature miRNA using a TaqMan MicroRNA Reverse Transcription Kit. A PCR mixture was prepared using TaqMan Universal PCR Master Mix and premixed TaqMan probe and primer pairs specific for each miRNA included in the TaqMan MicroRNA Assays. For quantification of mRNAs and pri-miRNAs, total RNA (500 ng) was reverse-transcribed using iScript select cDNA Synthesis Kit (Bio-Rad Laboratories, Hercules, CA) with a random primer. Micro-RNA expression was measured by RT-qPCR using the SsoAdvanced Universal Sybr green supermix (1725274, Bio-Rad) and the QuantStudio™ 5 Real-Time PCR System (Thermo Fisher Scientific). The results are shown in Fig. 5. The expression of members of the miR-17-92 complex, namely miR19a and miR19b, which target Kv3.4 transcripts were found to be upregulated in the end stage (120 days) of disease in SOD1G93ATA muscles thereby matching downregulation of Kv3.4 mRNA expression. miR669c (a member of the C2MC complex) was also downregulated in the end stage (120 days) of disease in SOD1G93A.

[0770] Motor neuron count

[0771] Motor neuron counts were investigated for healthy and model animals and model animals treated with Kv3 modulator. Ventral horn motor neurons from lumbar samples were counted via immunofluorescence using NeuroTrace (Nissl stain, Thermo fisher). Lumbar-1 samples were sectioned with a thickness of 20 pm. Three slices per lumbar-1 were mounted on a microscope slide. Each slide was washed in PBS solution and permeabilized with 0.1% Triton X-100 in PBS for 10 min at room temperature. The NeuroTrace was subjected to 1:300 dilution and allowed to stand at room temperature for 20 min. After washing the sample with PBS, it was completely dried and mounted with a mounting solution containing DAPI. The motor neuron-stained images were visualized using the Olympus’s Immunofluorescence microscope (Olympus, BZ21). The number of motor neurons in the ventral horn of the lumbar region of the spinal cord were counted. Only the cells of sizes of 750 pixels or larger were counted using the Image J software.

[0772] The results are shown in Fig. 6, wherein G1 to G4 refers to Group 1 to Group 4 and TG refers to treatment group. Nissl positive motor neuron count in lumbar-1 region of the spinal cord of Group 2 (SOD1G93Aand vehicle) was significantly lower compared to Group 1. Treatment with Kv3 modulator led to significant and dose dependent increases in Nissl positive motor neuron count compared to Group 2.

[0773] GFAP / lba1 staining

[0774] Immunofluorescence analysis of the ventral horn of the spinal cord motor neurons was performed using GFAP (Cell signaling technology) for astrogliosis, and Iba1 (WAKO) for microgliosis. Lumbar samples of the spinal cord were sectioned with a thickness of 20 μm. Three slices per lumbar region were mounted on a microscope slide. The slide was washed in PBS solution and blocked in a solution containing PBS, 5% normal goat serum and 0.3% Triton X-100 for 1 hr at RT. The sections were incubated overnight at 4°C with the appropriate primary antibody. The sections were washed in PBS solution, and incubated in secondary antibody for 1 hr at RT. Finally, the sections were washed in PBS solution and completely dried and mounted with a mounting solution containing DAPI. The astrogliosis and microgliosis stained images were visualized using the Olympus’s Immunofluorescence microscope (Olympus, BZ21). The intensity of fluorescence in the ventral horn of the lumbar was analyzed using the Image J software. The results are shown in Fig. 7. Astrogliosis in lumbar-1 region of the spinal cord was quantified by mean intensity of GFAP staining. Intensity of Group 2 (SOD1G93Aand vehicle) was significantly higher than that of Group 1. Intensity of Group 3 was significantly higher than Group 1, but also significantly lower than Group 2. Intensity of Group 4 showed a similar trend to that of Group 3. Microgliosis in lumbar-1 region of the spinal cord was quantified by mean intensity of Iba1 staining. Intensity of Group 2 (SOD1G93Aand vehicle) was significantly higher than that of Group 1. Intensity of the treatment groups were significantly higher than Group 1, but also significantly lower than Group 2.

[0775] Neurofilament light chain (Nf-L) measurement in plasma

[0776] Neurofilament light chain (Nf-L) measurement in plasma is used as a biomarker of neurodegeneration in ALS and other neurodegenerative disorders. It is an indicator of neuronal damage (elevated Nf-L levels reflect neurodegeneration, which is central to the pathology of ALS) and of disease progression (Higher Nf-L levels correlate with more advanced disease stages and faster progression).

[0777] Nf-L level in plasma was very low in Group 1, and significantly higher in the SOD1G93Agroups. Nf-L of Group 3 (treatment group with Kv3 modulator compound, low dose) was significantly lower compared to Group 2 (SOD1G93Aand vehicle). Nf-L of Group 4 (treatment group with Kv3 modulator compound, high dose) was lower compared to Group 2.

[0778] Kv3 channel expression and acute damage of motor units

[0779] It was investigated whether damage to the motor unit affects the expression of all Kv3 family members. Three experiments were employed: i) sciatic nerve resection to cause structural denervation, ii) botulinum neurotoxin (BoTN) injection to cause functional denervation without dismantling the NMJs, and iii) barium chloride (BaCl2) injection to directly induce extensive myofiber degeneration (Tierney and Sacco, 2016). Muscle pathology was analysed at various time points. By hematoxylin / eosin staining of transversal sections of quadriceps muscle, it was found that nerve cut and BoTN injection caused atrophy, whereas BaCl2injection caused massive damage followed by progressive formation of centronucleated fibers, which is a sign of muscle regeneration (Fig. 15). To validate the effects of this experimental approach, expression levels of genes associated with muscle denervation were analysed such as acetylcholine receptor (Chrn), myogenin (Myog), and Runt-related transcription factor 1 (Runxl), and muscle regeneration such as myosin heavy chain type 3 (Myhc3) and myosin heavy chain type 8 (Myhc8) (Fig. 14, left panels Chm to Myhc8). Nerve resection and BoTN injection resulted in the upregulation of denervation and regeneration markers, whereas BaCl2injection resulted in the upregulation of mainly muscle regeneration markers. Next, levels of expression of the genes coding for Kv3 channels were assessed (Fig. 14, right panels Kcnd to Kcnc4). Kcnc1 transcripts were downregulated after structural and functional denervation as well as muscle damage, indicating that the expression of Kv3.1 channels is sensitive to the integrity of the motor unit. Kcncl transcripts were downregulated after structural and functional denervation as well as muscle damage, indicating that the expression of Kv3.1 channels is sensitive to the integrity of the motor unit. Kcnc3 transcript levels were downregulated specifically upon muscle damage, whereas Kcnc4 transcripts were decreased after nerve resection and BaCl2injection, but not after injection of BoNT, indicating that the expression of this channel is modified upon structural denervation and muscle damage. Interestingly, the expression of these genes gradually returned to normal along with the myofiber regeneration process. These results indicate that the transcription of the genes coding for Kv3.1, Kv3.3, and Kv3.4 is affected by acute damage to the motor unit.

[0780] Example 2: Potassium channel expression reduction in human subjects with ALS Potassium channel expression in muscle samples from human subjects with ALS was investigated essentially as set out in Example 1, “RNA isolation and real time qPCR”.

[0781] It was shown that Kv3.4 mRNA expression was significantly downregulated in sporadic ALS in Vastus Lateralis (VL) muscle of human subjects with ALS compared to the controls (see Figs. 10A and 10B).

[0782] Example 3: Localisation studies in muscle samples

[0783] In order to understand the possible role of Kv3 channels in muscle and the contribution of their reduced expression to the pathological process in ALS, Kv3.1 and Kv3.4 localisation in muscle samples was investigated by microscopy. Muscles were isolated from 2 month old mice of the same genotype as those of Example 1 and immediately fixed in 4% paraformaldehyde (PFA) for 15 min at RT. Skeletal muscles were further dissected into muscle bundles of approximately 20 myofibers each. The samples were quenched in 50 mM NH4CI for 30 min at RT and then saturated for 2 h in blocking solution [15% vol / vol goat serum, 2% wt / vol bovine serum albumin (BSA), 0.25% wt / vol gelatin, and 0.2% wt / vol glycine in phosphate-buffered saline (PBS) containing 0.5% Triton X-100], Incubation with primary antibodies against Kv3.1, Kv3.4, and DHPR was carried out for at least 48 h in blocking solution. The muscles were then thoroughly washed and incubated with a secondary antibody conjugated with Alexa-555 or Alexa-488 diluted in blocking solution. Images were collected with a Leica SP5 confocal microscope (Leica Microsystems, Wetzlar, Germany). Images are provided in Fig. 11.

[0784] Triads are composed of invaginations of the sarcolemma, forming transverse tubules (t-tubules) that interact with the sarcoplasmic reticulum (SR). Dihydropyridine receptors (DHPR) are located in the junctional SR (J-SR), which is the area of the terminal SR cisternae facing the t-tubules within triads, positioned between the longitudinal SR (L-SR). By confocal microscopy and assessments of the fluorescence intensity profile of Kv3.1 or Kv3.4 and DHPR, it was found that in TA myofibers, Kv3.1 is localized to both the sarcolemma and the triads, while Kv3.4 has a regular doublet pattern overlapping with that of DHPR, indicating that Kv3.4 is enriched in the triads.

[0785] Skeletal muscle contraction starts with action potentials in the motor neuron (MN), a process known as excitation-contraction coupling (ECC). This mechanism connects the electrical events in the sarcolemma with myofiber contraction and force generation via specialized structures called triads. Triads are composed of invaginations of the sarcolemma, forming transverse tubules (t-tubules) that interact with the sarcoplasmic reticulum (SR). Dihydropyridine receptors (DHPR) are located in the junctional SR (J-SR), which is the area of the terminal SR cisternae facing the t-tubules within triads, positioned between the longitudinal SR (L-SR).

[0786] By using this confocal microscopy approach and assessing the fluorescence intensity profile of Kv3.1 or Kv3.4 and DHPR, it was found that in TA myofibers, Kv3.1 is localized to both the sarcolemma and the triads, while Kv3.4 has a regular doublet pattern overlapping with that of DHPR, indicating that Kv3.4 is enriched in the triads (see Fig. 11 and Fig. 12). Together, these observations indicate that the Kv3.1 and Kv3.4 channels localise in the muscle triad, suggesting a role in the muscle contraction process. Kv3 channel opening in this location may help to prevent prolonged activation and excessive calcium entry which would lead to muscle cell damage. Loss of Kv3 channels in muscle may therefore lead to increased vulnerability of the muscle cells to degeneration in ALS and increasing total Kv3 activity could therefore help to protect muscle cells from damage and loss

[0787] In addition to the findings above, Kv3.4 channels are known to act as oxygen sensors. For example, in carotid body cells that monitor blood oxygenation, Kv3.4 channels act as sensors to provide a protective mechanism in the case of hypoxia (Vega-Saenz & Rudy, 1992; Kaab et al. 2005). Kv3.4 channels might play a similar role in striated muscle cells, with loss of Kv3.4 channels in muscle leading to reduced resilience and increased sensitivity to oxidative stress.

[0788] Kv3 channels are also expressed on motoneurons and so may be implicated in neuronal aspects of the pathophysiology of ALS. The role of Kv3 channels in neurons has been studied extensively (Rudy & McBain, 2001; Kaczmarek & Zhang, 2017). The channels ensure rapid repolarisation of neurons during an action potential. Neurons that express Kv3, such as parvalbumin-positive interneurons in midbrain and cortex, or projection neurons in the auditory brainstem, show a fast-firing phenotype. The channels are also expressed by specific populations of pyramidal neurons, including layer V projection neurons in motor cortex (Soares et al., 2017). Increased excitability of these neurons is observed as early as the 2-3rd week of life in the SOD1G93Amouse, preceding neuronal loss (Fogarty et al. 2015). Reduced expression of Kv3.1 could contribute to this hyperexcitability. In ALS patients, as well as in SOD1G93Amice, cortical hyperexcitability occurs early in the course of disease and can be detected using non-invasive techniques such as TMS (e.g. Vucic and Rutkove 2018). Neuronal hyperexcitability may be the cause of early symptoms of ALS, such as muscle fasciculations.

[0789] Conclusion

[0790] In conclusion, it has been established that Kv3 channels, in particular Kv3.1, and Kv3.4, are expressed on striated muscle fibres that are central to the pathophysiology of human genetic and sporadic forms of ALS. Downregulation of Kv3 channels appears to occur early in the course of disease in relevant mouse models and could contribute to the disease process. Administration of a selective Kv3 modulator, in a mouse model of ALS ameliorates the phenotype. Kv3.4 mRNA expression was significantly downregulated in sporadic ALS in vastus lateralis (VL) muscle of human subjects.

[0791] The new findings presented herein, particularly when combined with existing information on Kv3 channels also outlined above, indicate that increasing Kv3 function or expression in muscle and / or specific neurons in the central and peripheral nervous systems could prevent or slow the progression of ALS.

[0792] Potentiation Assay (Measurement of Kv3 Channel Modulation)

[0793] The ability of agents to modulate the voltage-gated potassium channel subtypes Kv3.4 / Kv3.3 / Kv3.2 / Kv3.1 may be determined using the following assay. Analogous methods may be used to investigate the ability of the compounds of the invention to modulate other channel subtypes.

[0794] Cell biology

[0795] To assess compound effects on human Kv3.3 channels (hKv3.3), a stable cell line expressing human Kv3.3 channels is created by transfecting Chinese Hamster Ovary (CHO)-K1 cells with a pBacMire_KCNC-3 vector. Cells are cultured in DMEM / F12 (Gibco) supplemented with 10% Foetal Bovine Serum (Gibco), 1X non-essential amino acids (Invitrogen) and geneticin (G418) 400 microg / mL. Cells are grown and maintained at 37 °C in a humidified environment containing 5% CO2 in air.

[0796] To assess compound effects on human Kv3.2 channels (hKv3.2), a stable cell line expressing human Kv3.2 channels (hKv3.2) is created by transfecting CHO-K1 cells with a pCIH5-hKv3.2 vector. Cells are cultured in DMEM / F12 medium supplemented by 10% Foetal Bovine Serum, 1X non-essential amino acids (Invitrogen) and 500ug / ml of Hygromycin-B (Invitrogen). Cells are grown and maintained at 37 °C in a humidified environment containing 5% CO2 in air.

[0797] To assess compound effects on human Kv3.1 channels (hKv3.1): Human embryonic kidney (HEK)-hKv3.1 cell line is generated by transfecting HEK-293 cells with an expression vector with human Kv3.1 (NM_004976.4). Cells are cultured with MEM supplemented with 10% Heat- Inactivated FBS, 2 mM L-glutamine, 1% Penicillin-Streptomycin, and 0.6 mg / ml of Geneticin (G418). HEK-hKv3.1b cells were amplified in T175 cm2 flask at 37°C with 5% CO2, using MEM amplification medium, containing the G418 selection antibiotic (0.6mg / ml). Cells were detached every 3-4 days, using DPBS to wash twice the flask, then TrypLE to dislodge the cells, and re-plated at a density of 2-4x106cells / flask.

[0798] To assess compound effects on human Kv3.4 channels (hKv3.4):

[0799] Human embryonic kidney (HEK)-hKv3.4 cell line is generated by transfecting HEK-293 cells with an expression vector with human Kv3.4 (NM_004978). Cells are cultured with MEM supplemented with 10% Heat- Inactivated FBS, 2 mM L-glutamine, 1% Penicillin-Streptomycin, and 0.6 mg / ml of Geneticin (G418). HEK-hKv3.4 cells were amplified in T175 cm2 flask at 37oC with 5% CO2, using MEM amplification medium, containing the G418 selection antibiotic (0.6mg / ml). Cells were detached every 3-4 days, using DPBS to wash twice the flask, then TrypLE to dislodge the cells, and re-plated at a density of 4-8x106cells / flask.

[0800] Cell preparation for IonWorks Quattro™ experiments

[0801] The day of the experiment, cells are removed from the incubator and the culture medium removed. Cells are washed with 5 ml of Dulbecco’s PBS (DPBS) calcium and magnesium free and detached by the addition of 3 ml Versene (Invitrogen, Italy) followed by a brief incubation at 37 °C for 5 minutes. The flask is tapped to dislodge cells and 10 ml of DPBS containing calcium and magnesium is added to prepare a cell suspension. The cell suspension is then placed into a 15 ml centrifuge tube and centrifuged for 2 min at 1200 rpm. After centrifugation, the supernatant is removed and the cell pellet re-suspended in 4 ml of DPBS containing calcium and magnesium using a 5 ml pipette to break up the pellet. Cell suspension volume is then corrected to give a cell concentration for the assay of approximately 3 million cells per ml.

[0802] All the solutions added to the cells are pre-warmed to 37 °C.

[0803] Electrophysiology

[0804] Experiments are conducted at r.t. using IonWorks Quattro™ planar array electrophysiology technology (Molecular Devices Corp.) with PatchPlate™ PPC. Stimulation protocols and data acquisition are carried out using a microcomputer (Dell Pentium 4). Planar electrode hole resistances (Rp) are determined by applying a 10 mV voltage step across each well. These measurements are performed before cell addition. After cell addition and seal formation, a seal test is performed by applying a voltage step from -80 mV to -70 mV for 160 ms. Following this, amphotericin-B solution is added to the intracellular face of the electrode to achieve intracellular access. Cells are held at -70 mV. Leak subtraction is conducted in all experiments by applying 50 ms hyperpolarizing (10 mV) prepulses to evoke leak currents followed by a 20 ms period at the holding potential before test pulses.

[0805] For hKv3.2 and hKv3.1, assays from the holding potential of -70 mV, a first test pulse at -15 mV was applied for 100 ms and after 100 ms at -70 mV a second pulse at +40 mV was applied for 50 ms. Cells were then maintained for 100 ms at -100 mV and another pulse from -70mV to +40 mV (duration 50 ms) was applied to clamp later the voltage at -40 mV during 200ms For hKv3.3 assays, from the holding potential of -70 mV, a first test pulse to 0 mV is applied for 500 ms and following a further 100 ms at -70 mV, a second pulse to 40 mV is applied for 200 ms. These longer test pulses are used to study inactivation of hKv3.3 channels. Test pulses protocol may be performed in the absence (pre-read) and presence (post-read) of the test compound. Pre- and post-reads may be separated by the compound addition followed by a 3 minute incubation.

[0806] For hKv3.4, assays from the holding potential of -70 mV, a first test pulse at -15 mV was applied for 100 ms and after 200 ms at -70 mV a second pulse was applied at 0 mV for 100 ms then after 200 ms at -70 mV a third pulse was applied at +40 mV during 200 ms.

[0807] Solutions and drugs

[0808] The intracellular solution contains the following (in mM): K-gluconate 100, KCI 54, MgCl23.2, HEPES 5, adjusted to pH 7.3 with KOH. Amphotericin-B solution is prepared as 50mg / ml stock solution in DMSO and diluted to a final working concentration of 0.1 mg / ml in intracellular solution. The external solution is Dulbecco’s Phosphate Buffered Saline (DPBS) and contained the following (in mM): CaCl20.90, KCI 2.67, KH2PO41.47, MgCl.6H2O 0.493, NaCI 136.9, Na2PO48.06, with a pH of 7.4.

[0809] Kv3 modulator (or reference compounds such as / \ / -cyclohexyl- / \ / -[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]- / \ / '-phenylurea) is dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 pL) is transferred to another compound plate and external solution containing 0.05% pluronic acid (66 pL) is added. 3.5 pL from each plate containing a compound of the invention is added and incubated with the cells during the IonWorks Quattro™ experiment. The final assay dilution is 200 and the final compound concentrations are in the range 50 pM to 50 nM.

[0810] Data analysis

[0811] The recordings are analysed and filtered using both seal resistance (>20 MQ) and peak current amplitude (>500 pA at the voltage step of 40 mV) in the absence of compound to eliminate unsuitable cells from further analysis. For hKv3.2 and hKv3.1 assays, paired comparisons of evoked currents between pre- and post-drug additions measured for the -15 mV voltage step are used to determine the positive modulation effect of each compound. Kv3 channel-mediated outward currents are measured determined from the mean amplitude of the current over the final 10 ms of the -15 mV voltage pulse minus the mean baseline current at -70 mV over a 10 ms period just prior to the -15 mV step. These Kv3 channel currents following addition of the test modulator are then compared with the currents recorded prior to modulator addition. Data are normalised to the maximum effect of the reference compound (50microM of / V-cyclohexyl- / V-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]- / \ / '-phenylurea) and to the effect of a vehicle control (0.5% DMSO). The normalised data are analysed using ActivityBase or Excel software. The concentration of modulator required to increase currents by 50% of the maximum increase produced by the reference compound (EC50) is determined by fitting of the concentration-response data using a four parameter logistic function in ActivityBase. For hKv3.3 assays, paired comparisons of evoked currents between pre- and post-drug additions are measured for the OmV step, considering the peak current and the decay (inactivation) of the current over the duration of the Omv test pulse (500 ms).

[0812] / \ / -cyclohexyl- / \ / -[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]- / \ / '-phenylurea is obtained from ASINEX (Registry Number: 552311-06-5).

[0813] Compounds described herein as particular Kv3 modulators have been described in the prior art as demonstrating an ability to potentiate one of more of Kv3 channels and are therefore expected to have utility in the methods of the invention.

[0814] Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0815] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow.

[0816] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. Clauses of the invention:

[0817] A series of clauses setting out embodiments of the invention is as follows.

[0818] Clause 1. A method for the treatment of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing total Kv3 channel activity in the subject.

[0819] Clause 2. A method for the treatment of ALS in a subject, the method comprising the steps of:

[0820] i) diagnosing the subject with ALS; and

[0821] ii) increasing total Kv3 channel activity in the subject.

[0822] Clause 3. A method for the treatment of ALS in a subject who may be susceptible to treatment by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0823] i) identifying that the ALS may be susceptible to treatment by increasing total Kv3 channel activity in the subject; and

[0824] ii) increasing total Kv3 channel activity in the subject.

[0825] Clause 4. A method for the treatment of ALS in a subject, the method comprising the steps of:

[0826] i) providing a sample from the subject;

[0827] ii) using the sample to diagnose the subject with ALS; and iii) increasing total Kv3 channel activity in the subject.

[0828] Clause 5. A method for the treatment of ALS in a subject who may be susceptible to treatment by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0829] i) providing a sample from the subject;

[0830] ii) using the sample to identify that the ALS may be susceptible to treatment by increasing total Kv3 channel activity; and

[0831] iii) increasing total Kv3 channel activity in the subject.

[0832] Clause 6. A method for the prophylaxis of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing total Kv3 channel activity in the subject.

[0833] Clause 7. A method for the prophylaxis of ALS in a subject, the method comprising the steps of:

[0834] i) establishing that the subject is at significant risk of developing ALS; and ii) increasing total Kv3 channel activity in the subject.

[0835] Clause 8. A method for the prophylaxis of ALS in a subject at significant risk of developing ALS who may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0836] i) identifying that the ALS may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject; and ii) increasing total Kv3 channel activity in the subject.

[0837] Clause 9. A method for the prophylaxis of ALS in a subject, the method comprising the steps of:

[0838] i) providing a sample from the subject;

[0839] ii) using the sample establish that the subject is at significant risk of developing ALS; and

[0840] iii) increasing total Kv3 channel activity in the subject.

[0841] Clause 10. A method for the prophylaxis of ALS in a subject at significant risk of developing ALS who may be susceptible to prophylaxis by increasing total Kv3 channel activity in the subject, the method comprising the steps of:

[0842] i) providing a sample from the subject;

[0843] ii) using the sample to identify that the ALS may be susceptible to prophylaxis by increasing total Kv3 channel activity; and

[0844] iii) increasing total Kv3 channel activity in the subject.

[0845] Clause 11. The method of any one of clauses 4, 5, 9 or 10 wherein it is identified that the ALS may be susceptible to treatment or prophylaxis by increasing total Kv3 channel activity by testing the sample for decreased total Kv3 channel activity.

[0846] Clause 12. The method of clause 11 wherein the total Kv3 channel activity is decreased relative to normal Kv3 channel activity.

[0847] Clause 13. The method of any one of clauses 4, 5, 9 or 10 to 12, wherein the sample is a tissue sample from the subject.

[0848] Clause 14. The method of clause 13, wherein the tissue sample is a sample of muscle. Clause 15. The method of clause 13, wherein the tissue sample is a sample of muscle fiber.

[0849] Clause 16. The method of clause 13, wherein the sample is a sample of cerebrospinal fluid (CSF).

[0850] Clause 17. The method of any one of clauses 4, 5, 9 or 10 to 12, wherein it is identified that the ALS may be susceptible to treatment or prophylaxis by increasing total Kv3 channel activity by testing the brain activity of the subject.

[0851] Clause 18. The method of clause 17, wherein the brain activity is motor cortex hyperexcitability (e.g. relative to a healthy control).

[0852] Clause 19. The method of clause 18, wherein motor cortex hyperexcitability is indicated by reduction or absence of SICI and / or an increase in intracortical facilitation (ICF) and / or reduction in resting motor threshold (RMT).

[0853] Clause 20. The method of any one of clauses 17 to 19, wherein the brain activity is established using TMS (e.g. paired-pulse TMS). Clause 21. The method of any one of clauses 17 to 19, wherein the brain activity is established using functional magnetic resonance imaging (fMRI).

[0854] Clause 22. The method of any one of clauses 11 to 21, wherein the decreased total Kv3 channel activity is due to decreased function of Kv3 channels.

[0855] Clause 23. The method of clause 22, wherein the decreased total Kv3 channel activity is due to decreased expression of Kv3 channels.

[0856] Clause 24. The method of any one of clauses 1 to 23, wherein total Kv3 channel activity is increased by increasing the function of Kv3 channels in the subject.

[0857] Clause 25. The method of any one of clauses 1 to 24, wherein total Kv3 channel activity is increased by increasing the expression of Kv3 channels in the subject.

[0858] Clause 26. The method of clause 25, wherein after treatment the expression of Kv3 channels is increased in muscle or the brain.

[0859] Clause 27. The method of clause 26, wherein after treatment the expression of Kv3 channels is increased in muscle.

[0860] Clause 28. The method of clause 25, wherein after treatment the expression of Kv3 channels is increased in a specific tissue type.

[0861] Clause 29. The method of clause 28, wherein the specific tissue type is muscle fibers. Clause 30. The method of clause 25, wherein the expression of Kv3 channels is increased in the plasma membrane of a specific cell type.

[0862] Clause 31. The method of clause 30, wherein specific cell type is muscle fiber cells.

[0863] Clause 32. The method of any one of clauses 1 to 31, wherein expression of Kv3 channels is increased after treatment by increasing the quantity of relevant transcription activation factors, increasing the number of copies of relevant genes, or other epigenetic modifications to histone (e.g. acetylation, methylation), chromatin or nucleic acids (e.g. methylation); or by gene therapy, for example using DNA or RNA or using a vector such as a viral vector, which encodes and is capable of resulting in the expression of Kv3 channels.

[0864] Clause 33. The method of any one of clauses 1 to 32, wherein expression of Kv3 channels is increased by regulating gene expression in the subject.

[0865] Clause 34. The method of any one of clauses 1 to 33, wherein an agent is delivered to the subject (such as a small molecule) which targets an miRNA which is an anti-Kv3 channelencoding mRNA miRNA.

[0866] Clause 35. The method of clause 34, wherein the miRNA is selected from one or more of the members of the miR-17-92 complex, such as miR19a, miR19b or miR669c.

[0867] Clause 36. The method of any one of clauses 1 to 35, wherein the level of Kv3 channel expression is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 300%, at least 400% or at least 500% relative to the level of Kv3 channel expression before treatment.

[0868] Clause 37. The method of any one of clauses 1 to 13, wherein the level of Kv3 channel expression is increased after treatment by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% relative to the level of Kv3 channel expression in a control; and / or the level of Kv3 channel expression is increased after treatment to at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300% or at least 400% of the level of Kv3 channel expression in a control.

[0869] Clause 38. The method of clause 37, wherein the control is a sample of healthy tissue or a healthy cell which has not received treatment.

[0870] Clause 39. The method of any one of clauses 1 to 38, wherein the level of Kv3 channel expression after treatment does not substantially exceed the level of Kv3 channel expression in a control, such as the level of Kv3 channel expression exceeds the level of Kv3 channel expression in a control by no more than 1%, such as 5%, such as 10%.

[0871] Clause 40. The method of any one of clauses 1 to 39, wherein the quantity of Kv3 channels was declining and after treatment, the rate of decline has reduced or the quantity of Kv3 channels has substantially stabilised (e.g. in line with that of a healthy control).

[0872] Clause 41. The method of clause 40, wherein the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150% or at least 200% relative to the rate of decline before treatment. Clause 42. The method of either clause 40 or 41, wherein the rate of decline of Kv3 channels is achieved wherein the rate of decline has reduced, compared to a healthy control. Clause 43. The method of any one of clauses 40 to 42, wherein the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150% or at least 200% relative to the rate of decline in a healthy control.

[0873] Clause 44. The method of any one of clauses 1 to 43, wherein the level of Kv3 channel expression is quantified by RNA isolation from the subject and real time qPCR e.g. to establish the level of Kv3 channel mRNA.

[0874] Clause 45. The method of clause 44, wherein the level of Kv3 channel expression is quantified as set out in Example 1 “RNA isolation and real time qPCR”.

[0875] Clause 46. The method of any one of clauses 1 to 43, wherein the level of Kv3 channel expression is quantified by micro-RNA retro-transcription and q-PCR e.g. to establish the level of micro RNAs targeting Kv3 channel transcripts (e.g. members of the miR-17-92 complex, such as miR19a, miR19b, or miR669c).

[0876] Clause 47. The method of clause 46, wherein the level of Kv3 channel expression is quantified as set out in Example 1 “Micro-RNA retro-transcription and q-PCR”.

[0877] Clause 48. The method of any one of clauses 1 to 47, wherein the function of Kv3 channels is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190% or at least 200% relative to the function of Kv3 channels before treatment.

[0878] Clause 49. The method of any one of clauses 1 to 48, wherein the level of Kv3 channel function is increased after treatment by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% relative to the level of Kv3 channel function in a control.

[0879] Clause 50. The method of any one of clauses 1 to 49, wherein the level of Kv3 channel function is increased after treatment to at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% of the level of Kv3 channel function in a control.

[0880] Clause 51. The method of either clause 49 or 50, wherein the control is a sample of healthy tissue or a healthy cell which has not received treatment.

[0881] Clause 52. The method of any one of clauses 1 to 51, wherein the level of Kv3 channel function after treatment does not substantially exceed the level of Kv3 channel function in a control, such as the level of Kv3 channel function exceeds the level of Kv3 channel function in a control by no more than 1%, such as 5%, such as 10%.

[0882] Clause 53. The method of any one of clauses 1 to 52, wherein the rate of decline of Kv3 channel function is reduced where, before treatment, the function of Kv3 channels was declining and after treatment, the rate of decline has reduced or the function of Kv3 channels has substantially stabilised (e.g. in line with that of a healthy control).

[0883] Clause 54. The method of clause 53, wherein the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140% or at least 150% relative to the rate of decline before treatment.

[0884] Clause 55. The method of either clause 53 or 54, wherein the rate of decline is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140% or at least 150% relative to the rate of decline in a healthy control.

[0885] Clause 56. The method of any one of clauses 1 to 55, wherein total Kv3 channel activity is increased by administering a Kv3 modulator to the subject.

[0886] Clause 57. A Kv3 modulator for use in the treatment of ALS in a subject. Clause 58. A pharmaceutical composition comprising a Kv3 modulator for use in the treatment of ALS in a subject.

[0887] Clause 59. A pharmaceutical composition comprising a Kv3 modulator and a pharmaceutically acceptable excipient or carrier for use in the treatment of ALS in a subject. Clause 60. Use of a Kv3 modulator in the manufacture of a medicament for the treatment of ALS in a subject.

[0888] Clause 61. A Kv3 modulator for use in the prophylaxis of ALS in a subject.

[0889] Clause 62. A pharmaceutical composition comprising a Kv3 modulator for use in the prophylaxis of ALS in a subject.

[0890] Clause 63. A pharmaceutical composition comprising a Kv3 modulator and a pharmaceutically acceptable excipient or carrier for use in the prophylaxis of ALS in a subject. Clause 64. Use of a Kv3 modulator in the manufacture of a medicament for the prophylaxis of ALS in a subject.

[0891] Clause 65. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 64, wherein the ALS is selected from the group consisting of classical ALS, primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA).

[0892] Clause 66. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 65, wherein the ALS is selected from the group consisting of familial ALS or sporadic ALS.

[0893] Clause 67. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 66, wherein the ALS is familial ALS.

[0894] Clause 68. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 67, wherein the subject has a mutation in any one or more of the SOD1, fus, C9orf72, TDP43 or SQSTM1 genes.

[0895] Clause 69. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 68, wherein the subject has a mutation in the SOD1 gene.

[0896] Clause 70. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 69, wherein the mutation is SOD1G93A.

[0897] Clause 71. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 70, wherein the Kv3 channel type is selected from the list consisting of one or more of Kv3.1, Kv3.2, Kv3.3 and Kv3.4.

[0898] Clause 72. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 71, wherein the Kv3 channel type is selected from the list consisting of one or more of Kv3.1, Kv3.3 and Kv3.4.

[0899] Clause 73. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 72, wherein the Kv3 channel type is Kv3.1 and / or Kv3.4. Clause 74. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 73, wherein the Kv3 channel type is Kv3.1.

[0900] Clause 75. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 73, wherein the Kv3 channel type is Kv3.4.

[0901] Clause 76. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 75, wherein the Kv3 modulator is selected from the list consisting of one or more of a modulator of Kv3.1, Kv3.2, Kv3.3 and Kv3.4.

[0902] Clause 77. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 76, wherein the Kv3 modulator is a modulator of Kv3.1.

[0903] Clause 78. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 76, wherein the Kv3 modulator is a modulator of Kv3.2.

[0904] Clause 79. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 76, wherein the Kv3 modulator is a modulator of Kv3.3.

[0905] Clause 80. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 76, wherein the Kv3 modulator is a modulator of Kv3.4.

[0906] Clause 81. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 80, wherein the Kv3 modulator is an agent which is capable of producing at least 10% potentiation, and more suitably at least 20% potentiation of whole-cell currents mediated by Kv3 channels.

[0907] Clause 82. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 81, wherein the Kv3 modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by Kv3.1 channels. Clause 83. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 82, wherein the pEC50of the modulator is in the range of 4-8 (such as 5-7.5) or the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0908] Clause 84. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 81, wherein the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by Kv3.2 channels. Clause 85. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 84, wherein the pEC50of the modulator is in the range of 4-8 (such as 5-7.5) or the pEC50of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0909] Clause 86. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 81, wherein the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by Kv3.3 channels. Clause 87. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 86, wherein the pEC₅₀ of the modulator is in the range of 4-8 (such as 5-7.5) or the pEC₅₀ of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0910] Clause 88. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 81, wherein the modulator is capable of producing at least 10% potentiation, suitably at least 20%, suitably at least 30%, suitably at least 50%, suitably at least 100%, suitably at least 200% potentiation of whole-cell currents mediated by Kv3.4 channels. Clause 89. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 82 to 88, wherein the pEC₅₀ of the modulator is in the range of 5-7.5.

[0911] Clause 90. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 82 to 88, wherein the pEC₅₀ of the modulator is greater than 4, suitably greater than 5, suitably greater than 6, suitably greater than 7.

[0912] Clause 91. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 90, wherein the pEC₅₀ of the modulator is greater than 7.

[0913] Clause 92. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 91, wherein the Kv3 channels are human Kv3 channels. Clause 93. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 81 to 92, wherein the channels are recombinantly expressed in mammalian cells.

[0914] Clause 94. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 81 to 93, wherein the percentage potentiation of whole-cell currents is established in the assay set out below under ‘Potentiation Assay (Measurement of Kv3 Channel Modulation)’.

[0915] Clause 95. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound of formula (I):

[0916]

[0917] wherein:

[0918] R1is halo, C1-4 alkyl, C1-4 alkoxy, halo-Ci-4 alkyl, halo-C1-4alkoxy, or cyano; R2is H, halo, cyano, C1-4 alkyl or C1-4 alkoxy; with the proviso that when R2is H, R1 is not in the para position;

[0919] X is C or N;

[0920] Y is C or N;

[0921] R3is C1-4 alkyl;

[0922] R4is H, deuterium, or C1-4 alkyl; or R3and R4can be fused to form a C3-4 spiro carbocyclyl group;

[0923] or a pharmaceutically acceptable salt and / or solvate thereof.

[0924] Clause 96. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List A’):

[0925] (5R)-5-methyl-3-{4-[(3-methylphenyl)oxy]phenyl}-2,4-imidazolidinedione;

[0926] (5R)-5-methyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0927] (5R)-3-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-imidazolidinedione;

[0928] (5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0929] (5R)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0930] (5S)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[0931] (5R)-5-methyl-3-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; (5R)-5-methyl-3-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0932] (5R)-3-{6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0933] (5R)-3-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0934] (5R)-3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[0935] (5R)-3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione; (5R)-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0936] (5R)-5-methyl-3-(6-{[2-methyl-5-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0937] (5R)-5-methyl-3-(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0938] (5R)-5-ethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0939] (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0940] (5S)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0941] (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; 5.5-dimethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0942] 3-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0943] 3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0944] 3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[0945] (5R)-5-(1-methylethyl)-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

[0946] (5R)-5-methyl-3-(2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione; (5R)-5-ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

[0947] (5R)-5-(1, 1 -dimethylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0948] (5R)-5-ethyl-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0949] 7-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-5,7-diazaspiro[3.4]octane-6,8-dione;

[0950] 6-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-4,6-diazaspiro[2.4]heptane-5,7-dione;

[0951] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(1-methylethyl)benzonitrile;

[0952] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(trifluoromethyl)oxy]benzonitrile;

[0953] 3-{6-[(4-fluoro-3-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione; 3-{6-[(4-fluoro-2-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione; 5.5-dimethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione; (5R)-5-(1-methylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[0954] 3-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione; 3-(2-{[2-(1,1-dimethylethyl)phenyl]oxy}-5-pyrimidinyl)-5,5-dimethyl-2,4-imidazolidinedione;

[0955] (5R)-5-ethyl-5-methyl-3-(2-{[4-methyl-3-(methyloxy)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

[0956] (5R)-5-ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-5-methyl-2,4-imidazolidinedione;

[0957] 5.5-dimethyl-3-[6-({3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0958] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-ethylbenzonitrile; 2-chloro-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile; 5.5-dimethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0959] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(methyloxy)benzonitrile;

[0960] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-methylbenzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(trifluoromethyl)benzonitrile;

[0961] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-ethylbenzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-2-ethylbenzonitrile; 3-cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0962] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(1,1-dimethylethyl)benzonitrile;

[0963] 2-[(cyclopropylmethyl)oxy]-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0964] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(ethyloxy)benzonitrile; 2-cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

[0965] 5.5-dimethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4-imidazolidinedione;

[0966] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-3-(1,1-dimethylethyl)benzonitrile;

[0967] 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(1-methylethyl)oxy]benzonitrile; 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1-methylethyl)oxy]benzonitrile;

[0968] 3-cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0969] 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitrile;

[0970] 2-cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0971] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione;

[0972] 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile;

[0973] 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0974] 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(methyloxy)benzonitrile; 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(ethyloxy)benzonitrile; 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(ethyloxy)benzonitrile; 3-cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0975] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2- (methyloxy)benzonitrile;

[0976] 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(methyloxy)benzonitrile; 2-[(cyclopropylmethyl)oxy]-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile;

[0977] (5R)-5-ethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

[0978] 2-cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0979] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0980] (5R)-5-ethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4-imidazolidinedione;

[0981] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1-methylethyl)oxy]benzonitrile;

[0982] 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-3-methylbenzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1 -imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitrile;

[0983] 3-ethyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)-3-methylbenzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)benzonitrile; and

[0984] 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl)benzonitrile;

[0985] or a pharmaceutically acceptable salt and / or solvate thereof.

[0986] Clause 97. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[0987] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[0988]

[0989] or a pharmaceutically acceptable salt and / or solvate thereof.

[0990] Clause 98. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 8 of WO2011069951 or a pharmaceutically acceptable salt and / or solvate thereof.

[0991] Clause 99. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Example 1 to 86 of WO2011069951 or a pharmaceutically acceptable salt and / or solvate thereof.

[0992] Clause 100. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (II):

[0993]

[0994] wherein:

[0995] Ri is H, or Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, haloCi-4alkoxy;

[0996] R2is H, Ci-4alkyl, C3-4 spiro carbocyclyl, haloCi-4alkyl or halo;

[0997] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[0998] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[0999] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group to form a tricycle when considered together with the phenyl;

[1000] X is C or N;

[1001] Y is C or N;

[1002] R4 is C1-4 alkyl;

[1003] R5 is H, Deuterium, C1-4 alkyl;

[1004] or R4 and Rs can be fused to form C3-4 spiro carbocyclyl;

[1005] wherein R2 and R3 may be attached to the same or a different ring atom; and wherein R2 may be attached to a fused ring atom;

[1006] or a pharmaceutically acceptable salt and / or solvate thereof.

[1007] Clause 101. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List B’):

[1008] (5R)-3-[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione; (5R)-5-methyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2,4-imidazolidinedione;

[1009] (5R)-3-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[1010] 5,5-dimethyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2,4-imidazolidinedione; (5R)-5-ethyl-3-{6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

[1011] (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

[1012] (5R)-3-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione;

[1013] (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinedione;

[1014] (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-2,4-imidazolidinedione;

[1015] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-2,4-imidazolidinedione; 7-{6-[(3,3-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)oxy]-3-pyridinyl}-5,7-diazaspiro[3.4]octane-6, 8-dione;

[1016] 6-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-4,6-diazaspiro[2.4]heptane-5, 7-dione;

[1017] 3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[1018] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-(1,1-dimethylethyl)-2,4-imidazolidinedione;

[1019] (5R)-5-ethyl-3-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[1020] 5.5-dimethyl-3-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[1021] (5R)-5-ethyl-5-methyl-3-[6-(spiro[1 -benzofuran-3, 1 '-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[1022] (5R)-5-ethyl-3-(6-{[(3S / R)-3-methyl-1,3-dihydro-2-benzofuran-4-yl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (diastereoisomeric mixture);

[1023] (5R)-5-ethyl-3-{6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2);

[1024] (5R)-5-ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (distereoisomeric mixture);

[1025] (5R)-5-ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2);

[1026] 5.5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (racemate mixture);

[1027] 5.5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (enantiomers 1 and enantiomer 2);

[1028] 5.5-dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

[1029] 5,5-dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (enantiomer 1 and enantiomer 2);

[1030] (5R)-5-ethyl-5-methyl-3-[6-(1 / 7-spiro[2-benzopyran-4,1'-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[1031] 3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5,5-dimethyl-2,4-imidazolidinedione;

[1032] (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-(1-methylethyl)-2,4-imidazolidinedione; (5R)-3-{6-[(2,2-dimethyl-2,3-dihydro-1 -benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-2,4-imidazolidinedione;

[1033] 5.5-dimethyl-3-[6-(1 / 7-spiro[2-benzopyran-4, T-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4-imidazolidinedione;

[1034] (5R)-3-[2-(2,3-dihydrospiro[chromene-4, T-cyclopropan]-5-yloxy)-5-pyrimidinyl]-5-ethyl-5-methyl-2,4-imidazolidinedione;

[1035] 5.5-dimethyl-3-{6-[(4-methyl-3,4-dihydro-2 / 7-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (racemate mixture, enantiomer 1, enantiomer 2);

[1036] (5R)-5-ethyl-5-methyl-3-{6-[(3-methyl-3,4-dihydro-2 / 7-chromen-5-yl)oxy]-3-pyridinyl}- 2.4-imidazolidinedione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[1037] (5R)-5-ethyl-5-methyl-3-[6-(1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridinyl]-2,4-imidazolidinedione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[1038] 3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinedione (racemate mixture, enantiomer 1, enantiomer 2);

[1039] (5R)-5-ethyl-5-methyl-3-[2-(4-methylchroman-5-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

[1040] (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[1041] (5R)-3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1042] (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[1043] (5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;

[1044] (5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione;

[1045] (5R)-3-{2-[(2,2-difluoro-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione;

[1046] (5R)-5-ethyl-5-methyl-3-{2-[(2,4,4-trimethyl-4H-3,1-benzoxazin-5-yl)oxy]-5-pyrimidinyl}- 2.4-imidazolidinedione;

[1047] 5.5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[1048] 3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1049] 5.5-dimethyl-3-[2-(7-methylspiro[1 H-isobenzofuran-3, T-cyclobutane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione; (5R)-5-ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione;

[1050] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[1051] (5R)-5-ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

[1052] (5R)-5-ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione;

[1053] (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[1054] (5R)-3-[6-(3,3-dimethylisochroman-5-yl)oxy-3-pyridyl]-5-ethyl-5-methyl-imidazolidine- 2, 4-dione;

[1055] (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-4-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1056] (5R)-5-ethyl-5-methyl-3-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]imidazolidine-2, 4-dione;

[1057] (5R)-3-{6-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione; and

[1058] 5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione;

[1059] or a pharmaceutically acceptable salt and / or solvate thereof.

[1060] Clause 102. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1061] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2, 4-dione

[1062]

[1063] or a pharmaceutically acceptable salt and / or solvate thereof.

[1064] Clause 103. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1065] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[1066]

[1067] or a pharmaceutically acceptable salt and / or solvate thereof.

[1068] Clause 104. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 561 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 41 of W02012007877 or a pharmaceutically acceptable salt and / or solvate thereof.

[1069] Clause 105. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 70 of W02012007877 or a pharmaceutically acceptable salt and / or solvate thereof.

[1070] Clause 106. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (HI):

[1071]

[1072] wherein:

[1073] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[1074] R2is H, Ci-5alkyl, C3-5 spiro carbocyclyl, haloCi-5alkyl or halo;

[1075] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1076] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1077] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1078] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1079] X is CH or N;

[1080] Y is CR15 or N;

[1081] R15 is H or Ci-4alkyl; R4 is C1-4 alkyl;

[1082] R5 is H, Deuterium, C1-4 alkyl;

[1083] or R4 and Rs can be fused to form C3-4 spiro carbocyclyl;

[1084] wherein R2 and R3 may be attached to the same or a different ring atom; wherein R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1085] or a pharmaceutically acceptable salt and / or solvate thereof.

[1086] Clause 107. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List C’):

[1087] 3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[1088] 3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1089] 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[1090] 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[1091] 5,5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 1);

[1092] 5.5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 2);

[1093] 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[1094] 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[1095] 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[1096] 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[1097] 5.5-dimethyl-3-(2-spiro[1H-isobenzofuran-3, T-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[1098] 5.5-dimethyl-3-(2-spiro[1H-isobenzofuran-3, T-cyclopentane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[1099] 5.5-dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 1); 5,5-dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (enantiomer 2);

[1100] 3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl-imidazolidine- 2, 4-dione;

[1101] 3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1102] (5R)-3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1103] (5R)-3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1104] (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1105] (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1106] (5R)-5-ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1107] (5R)-5-ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1108] (5R)-5-ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1109] (5R)-5-ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1110] (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1111] (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1112] (5R)-5-ethyl-5-methyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[1113] (5R)-5-ethyl-5-methyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclopentane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[1114] (5R)-5-ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1115] (5R)-5-ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1116] (5R)-3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione; (5R)-3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1117] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1118] (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1119] (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1120] (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1121] (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1122] (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1123] (5R)-5-ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1124] (5R)-5-ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1125] (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 1);

[1126] (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione (diastereoisomer 2);

[1127] (5R)-5-ethyl-5-methyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1128] (5R)-5-ethyl-5-methyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1129] (5R)-5-ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1130] (5R)-5-ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1131] (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1132] (5R)-3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1133] 3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione; 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[1134] 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[1135] 5,5-dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 1);

[1136] 5.5-dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 2);

[1137] 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 1);

[1138] 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 2);

[1139] 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 1);

[1140] 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione (enantiomer 2);

[1141] 5.5-dimethyl-3-(6-spiro[1H-isobenzofuran-3, T-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1142] 5.5-dimethyl-3-(6-spiro[1H-isobenzofuran-3, T-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1143] 5.5-dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 1);

[1144] 5,5-dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (enantiomer 2);

[1145] 3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1146] 3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-5-methyl-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1147] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1148] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1149] (5R)-5-ethyl-5-methyl-3-(5-methyl-6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1150] (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1); (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1151] 5,5-dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)imidazolidine-2, 4-dione (enantiomer 1);

[1152] 5,5-dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)imidazolidine-2, 4-dione (enantiomer 2);

[1153] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione;

[1154] (5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1155] (5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1156] (5R)-5-ethyl-3-(6-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2, 4-dione;

[1157] (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione;

[1158] (5R)-5-ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 1);

[1159] (5R)-5-ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine-2, 4-dione (diastereoisomer 2);

[1160] (5R)-5-ethyl-3-(2-spiro[1 H-isobenzofuran-3, 1 '-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2, 4-dione;

[1161] (5R)-3-{4-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]phenyl}-5-ethyl-5-methyl- 2,4-imidazolidinedione; and

[1162] (5R)-3-[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione; or a pharmaceutically acceptable salt and / or solvate thereof.

[1163] Clause 108. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1164] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[1165]

[1166] or a pharmaceutically acceptable salt and / or solvate thereof. Clause 109. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator may be a compound described in any one of claims 1 to 41 of W02012168710 or a pharmaceutically acceptable salt and / or solvate thereof.

[1167] Clause 110. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 81 of W02012168710 or a pharmaceutically acceptable salt and / or solvate thereof.

[1168] Clause 111. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (IV):

[1169]

[1170] wherein:

[1171] W is group (Wa), group (Wb) or group (Wc):

[1172]

[1173] (Wc);

[1174] wherein:

[1175] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[1176] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[1177] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1178] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1179] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1180] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1181] X is CH or N;

[1182] Y is CR15 or N; R15 is H or Ci-4alkyl;

[1183] R22 is H, Cl, F, Ci-4alkyl;

[1184] R23 is H, Ci-4alkyl, Cl, CF3, O-Ci-4alkyl, OCF3or N(CH3)2;

[1185] R24 is H, Cl, F, Ci-4alkyl, O-Ci-4alkyl, CN, OCF3 or CF3;

[1186] R25 is H, Cl, F, O-Ci-4alkyl or Ci-4alkyl; and

[1187] R26 is H or Ci-4alkyl;

[1188] wherein for R22 to R26, Ci-4alkyl may be substituted by O-methyl; with the provisos that:

[1189] not all of R22 to R26 may be H;

[1190] when R4 is H, then R23 is methyl or CF3 and R22, R24, R25 and R26 are all H;

[1191] when one of R22, R24, R25 or R26 is F, then at least one of R22 to R26 cannot be H or F; and

[1192] when R24 is not H, at least one of R22 or R23 is not H

[1193] R4 is H or C1-4 alkyl;

[1194] wherein R2and R3 may be attached to the same or a different ring atom; R2may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom.

[1195] Or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. Clause 112. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List D’):

[1196] 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1197] 4-{6-[(3,3-diethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1198] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 1);

[1199] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 2);

[1200] 5-methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 1);

[1201] 5-methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 2);

[1202] 5-methyl-4-[6-(3H-spiro[2-benzofuran-1, T-cyclobutan]-6-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-[6-(3H-spiro[2-benzofuran-1, T-cyclopentan]-6-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1203] 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-4-yl)oxy]pyridin-3-yl}-5-methyl-2,4-dihydro- 3H-1,2,4-triazol-3-one

[1204] 5-methyl-4-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1205] 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-methylpyridin-3-yl}-5-methyl- 2.4-dihydro-3H-1,2,4-triazol-3-one;

[1206] 5-methyl-4-[5-methyl-6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1207] 5-methyl-4-{5-methyl-6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin- 3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1208] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1209] 5-methyl-4-[6-(spiro[1-benzofuran-3, T-cyclopropan]-4-yloxy)pyridin-3-yl]-2,4-dihydro- 3H-1,2,4-triazol-3-one; and

[1210] 5-methyl-4-{2-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyrimidin-5-yl}- 2.4-dihydro-3H-1,2,4-triazol-3-one.

[1211] 5-methyl-4-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1212] 5-methyl-4-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1213] 4-{4-[(2,6-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[4-chloro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1214] 4-(4-{[4-fluoro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1215] 4-{4-[(3-chlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1216] 4-{4-[(3,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-chloro-2-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[3-chloro-5-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1217] 5-methyl-4-[4-({3-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol- 3-one;

[1218] 4-{4-[(3-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1219] 4-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol- 3-one;

[1220] 4-{4-[(3,4-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(2,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-{4-[(2-methylphenyl)oxy]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1221] 4-{4-[(2-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1222] 5-methyl-4-(4-{[3-(1-methylethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(4-{[3-(dimethylamino)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1223] 4-{4-[(2-fluoro-6-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(4-{[2-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1224] 4-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{4-[(3-methylphenyl)oxy]phenyl}-2,4-dihydro-3H1,2,4-triazol-3-one;

[1225] 4-(4-{[3-trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1226] 4-[4-[4-fluoro-3-(trifluoromethoxy)phenoxy]phenyl]-3-methyl-1H-1,2,4-triazol-5-one; 5-methyl-4-(5-methyl-6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1227] 4-(6-{[3-(ethyloxy)phenyl]oxy}-5-methyl-3-pyridinyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1228] 4-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5methly-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-methyl-4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1229] 4-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; and

[1230] 5-methyl-4-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one;

[1231] or a pharmaceutically acceptable salt and / or solvate thereof.

[1232] Clause 113. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein Kv3 modulator is: 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[1233]

[1234] or a pharmaceutically acceptable salt and / or solvate thereof.

[1235] Clause 114. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 47 of WO2013175215 or a pharmaceutically acceptable salt and / or solvate thereof.

[1236] Clause 115. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 54 of WO2013175215 or a pharmaceutically acceptable salt and / or solvate thereof.

[1237] Clause 116. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (V):

[1238]

[1239] wherein:

[1240] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[1241] R2is H, Ci-5alkyl, C3-5 spiro carbocyclyl, haloCi-5alkyl or halo;

[1242] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1243] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1244] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1245] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1246] X is CH or N; Y is CR15 or N;

[1247] R15 is H or Ci-4alkyl;

[1248] R4 is C1-4 alkyl;

[1249] R5 is H, Deuterium, C1-4 alkyl;

[1250] or R4 and R5 can be fused to form C3-4 spiro carbocyclyl;

[1251] wherein R2 and R3 may be attached to the same or a different ring atom; wherein R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1252] or a pharmaceutically acceptable salt and / or solvate thereof.

[1253] Clause 117. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 41 of WO2013083994 or a pharmaceutically acceptable salt and / or solvate thereof.

[1254] Clause 118. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator may be any one of Examples 1 to 10 of WO2013083994 or a pharmaceutically acceptable salt and / or solvate thereof.

[1255] Clause 119. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (VI):

[1256]

[1257] wherein:

[1258] W is group (Wa), group (Wb) or group (Wc):

[1259]

[1260] wherein:

[1261] R1 is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[1262] R2is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[1263] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1264] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent; R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1265] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1266] R16 is halo, C1-4 alkyl, C1-4 alkoxy, halo-Ci-4alkyl, halo-Ci-4alkoxy, or CN;

[1267] R17 is H, halo, cyano, C1-4 alkyl or C1-4 alkoxy; with the proviso that when R17 is H, R16 is not in the para position;

[1268] R4 is C1-4 alkyl;

[1269] Rs is H or C1-4 alkyl;

[1270] or R4 and R5 can be fused to form C3-4 spiro carbocyclyl;

[1271] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1272] or a pharmaceutically acceptable salt and / or solvate thereof.

[1273] Clause 120. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List F’):

[1274] (5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-2-pyridyl]imidazolidine-2, 4-dione

[1275]

[1276] (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[1277]

[1278] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-2-pyridyl]imidazolidine-2, 4-dione

[1279]

[1280] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1281]

[1282] 5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl)imidazolidine-2, 4-dione

[1283]

[1284] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl)imidazolidine-2, 4-dione

[1285]

[1286] or a pharmaceutically acceptable salt and / or solvate thereof.

[1287] Clause 121. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1288] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1289]

[1290] or a pharmaceutically acceptable salt and / or solvate thereof. Clause 122. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt of:

[1291] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1292]

[1293] Clause 123. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1294] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1295]

[1296] Clause 124. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 60 of WO2017103604 or a pharmaceutically acceptable salt and / or solvate thereof.

[1297] Clause 125. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 6 of WO2017103604 or a pharmaceutically acceptable salt and / or solvate thereof.

[1298] Clause 126. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (VII):

[1299]

[1300] wherein:

[1301] X is H orCH3;

[1302] Y is H orCH3;

[1303] wherein at least one of X and Y is H; W is group (Wa), group (Wb) or group (Wc):

[1304] wherein group (Wa) and group (Wb) are:

[1305]

[1306] wherein:

[1307] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy or haloCi-4alkoxy;

[1308] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[1309] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1310] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1311] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1312] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1313] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1314] wherein group (Wc) is:

[1315]

[1316] wherein:

[1317] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy or CN;

[1318] R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[1319] R18 is H, halo, CN, Ci-4alkyl or Ci-4alkoxy;

[1320] Z is group (Za) or (Zb):

[1321] wherein group (Za) is:

[1322]

[1323] wherein:

[1324] R4 is H or C1-4 alkyl;

[1325] R5 is H or C1-4 alkyl; or

[1326] R4 and R5 can be fused to form a C3-5 spiro carbocyclyl or a C2-5 spiro heterocyclyl; and wherein group (Zb) is:

[1327]

[1328] wherein:

[1329] R19 is C1-4 alkyl;

[1330] or a pharmaceutically acceptable salt and / or solvate thereof.

[1331] Clause 127. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List G’):

[1332] syn-5,5-dimethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[1333] syn-5,5-dimethyl-3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1334] syn-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-isopropyl-benzonitrile; ant / -5,5-dimethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy] cyclobutyl]imidazolidine-2, 4-dione;

[1335] ant / -5,5-dimethyl-3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1336] ant / -4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-isopropyl-benzonitrile; syn-5,5-dimethyl-3-[3-[3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione; ant / -5,5-dimethyl-3-[3-[3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione; syn-3-[3-(2-tert-butylphenoxy)cyclobutyl]-5,5-dimethyl-imidazolidine-2,4-dione; ant / -3-[3-(2-tert-butylphenoxy)cyclobutyl]-5,5-dimethyl-imidazolidine-2,4-dione; syn-3-tert-butyl-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]benzonitrile; ant / -3-terf-butyl-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1 -yl)cyclobutoxy]benzonitrile; syn-4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-(trifluoromethoxy)benzonitrile;

[1337] ant / -4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]-2-(trifluoromethoxy)benzonitrile;

[1338] ant / -5,5-dimethyl-3-(3-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxycyclobutyl)imidazolidine-2, 4-dione;

[1339] syn-5,5-dimethyl-3-(3-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxycyclobutyl)imidazolidine-2, 4-dione;

[1340] syn-(5R)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1341] ant / -(5R)-5-ethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[1342] ant / -(5R)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1343] syn-(5S)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1344] ant / -(5S)-5-ethyl-3-[3-[4-methyl-3-(trifluoromethoxy)phenoxy]cyclobutyl]imidazolidine-2,4-dione;

[1345] ant / -(5S)-5-ethyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1346] syn-3-methyl-4-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-1 H-1,2,4-triazol-5-one;

[1347] ant / -3-methyl-4-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-1 H-1,2,4-triazol-5-one;

[1348] 4-[3-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)cyclobutoxy]spiro[2H-benzofuran-3, T-cyclopropane]-7-carbonitrile;

[1349] 6-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclobutyl]-2-oxa-6,8-diazaspiro[3.4]octane-5, 7-dione;

[1350] 3-[3-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxycyclo butyl]imidazolidine-2, 4-dione;

[1351] (5S)-5-methyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione; and

[1352] (5R)-5-methyl-3-[3-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxycyclobutyl]imidazolidine-2, 4-dione;

[1353] or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. Clause 128. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 90 of WO2018020263 or a pharmaceutically acceptable salt and / or solvate thereof.

[1354] Clause 129. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 29 of WO2018020263 or a pharmaceutically acceptable salt and / or solvate thereof.

[1355] Clause 130. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound of formula (VIII):

[1356]

[1357] wherein:

[1358] Ri is H or methyl;

[1359] R2 and R3 are both methyl, or R2 and R3, together with the carbon atom to which they are attached, are a spirocyclopropyl ring;

[1360] R4 is methyl or ethyl;

[1361] R5 is H or methyl;

[1362] or R4 and R5, together with the carbon atom to which they are attached, form a C3-C4 spiro carbocyclyl;

[1363] or a salt and / or solvate and / or derivative thereof.

[1364] Clause 131. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List H’):

[1365] 5.5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[1366] 3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1367] (5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione;

[1368] 5.5-dimethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione; (5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[1369] (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione;

[1370] 5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;

[1371] (5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2, 4-dione;

[1372] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[1373] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione;

[1374] (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;

[1375] (5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine- 2, 4-dione;

[1376] 7-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6, 8-dione;

[1377] 6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5, 7-dione; and

[1378] (5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione;

[1379] or a pharmaceutically acceptable salt and / or solvate thereof.

[1380] Clause 132. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1381] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1382]

[1383] or a salt and / or solvate thereof and / or derivative thereof.

[1384] Clause 133. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1385] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1386]

[1387] or a salt and / or solvate thereof and / or derivative thereof.

[1388] Clause 134. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1389] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[1390]

[1391] or a salt and / or solvate thereof and / or derivative thereof.

[1392] Clause 135. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 34 of W02020079422 or a pharmaceutically acceptable salt and / solvate thereof, or any one of claims 1 to 41 of WO2021156584 or a pharmaceutically acceptable salt and / solvate thereof.

[1393] Clause 136. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator may be any one of Examples 1 to 15 of W02020079422 or a pharmaceutically acceptable salt and / solvate thereof, or any one of Examples 1 to 15 of WO2021156584 or a pharmaceutically acceptable salt and / solvate thereof.

[1394] Clause 137. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is compound of formula (X):

[1395]

[1396] wherein:

[1397] V is group (Va), group (Vb) or group (Vc);

[1398] wherein group (Va) and group (Vb) are:

[1399]

[1400] wherein:

[1401] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy, or haloCi-4alkoxy;

[1402] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[1403] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1404] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1405] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1406] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl;

[1407] wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1408] wherein group (Vc) is:

[1409]

[1410] wherein:

[1411] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy orCN;

[1412] R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[1413] R18 is H, halo, CN, C1-4alkyl or C1-4alkoxy;

[1414] Wis N or CH;

[1415] X is N or CH;

[1416] Y is N or CH;

[1417] wherein at least one of W, X and Y is CH, and when one of X and Y is N, the other is CH;

[1418] Z is a 5-membered heteroaryl comprising one or two nitrogen atoms, and wherein one of the nitrogen atoms and one of the carbon atoms may be independently optionally substituted by methyl; or Z is a 6-membered heteroaryl comprising one or two nitrogen atoms, wherein one of the carbon atoms may be optionally substituted by methyl; and

[1419] provided that Z is not

[1420]

[1421] or a pharmaceutically acceptable salt and / or solvate thereof.

[1422] Clause 138. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List J’):

[1423] 3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[1424] 7-methyl-3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[1425] 3-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[1426] 3-[6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one; 7-methyl-3-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[1427] 3-(5-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-2-pyridyl)-1H-imidazo[4,5-b]pyridin-2-one;

[1428] 3-[6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one;

[1429] 3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one;

[1430] 3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1431] 3-[5-[3-(trifluoromethoxy)phenoxy]pyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1432] 3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1433] 3-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-1H-imidazo[4,5-b]pyridin-2-one; 3-(2-{2H-spiro[1-benzofuran-3, T-cyclopropane]oxy}pyrimidin-5-yl)-1H,2H,3H-imidazo[4,5-b]pyridin-2-one;

[1434] 4-[[5-(2-oxo-1H-imidazo[4,5-b]pyridin-3-yl)-2-pyridyl]oxy]-2- (trifluoromethoxy)benzonitrile;

[1435] 7-methyl-3-(2-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-one; 3-[2-(3-methoxyphenoxy)pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1436] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1437] 2-methyl-6-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-4H-imidazo[4,5-c]pyrazol-5-one;

[1438] 2-methyl-6-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-4H-imidazo[4,5-c]pyrazol-5-one;

[1439] 6-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-2-methyl-4H-imidazo[4,5-c]pyrazol-5-one;

[1440] 2-methyl-6-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)-4H-imidazo[4,5-c]pyrazol-5-one;

[1441] 2-methyl-6-(2-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxypyrimidin-5-yl)-4H-imidazo[4,5-c]pyrazol-5-one;

[1442] 3-[2-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-c]pyridin-2-one;

[1443] 2-methyl-9-[6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-7H-purin-8-one;

[1444] 2-methyl-9-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-7H-purin-8-one;

[1445] 2-methyl-9-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one;

[1446] 2-methyl-9-[6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-7H-purin-8-one;

[1447] 9-[6-(3-methoxyphenoxy)-3-pyridyl]-2-methyl-7H-purin-8-one;

[1448] 9-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-7H-purin-8-one;

[1449] 9-[6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-2-methyl-7H-purin-8-one;

[1450] 3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1451] 3-[2-[4-methyl-3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1452] 3-[2-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1453] 6-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-2,4-dihydroimidazo[4,5-c]pyrazol-5-one;

[1454] 3-[6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-1H-imidazo[4,5-c]pyridin-2-one;

[1455] 1-(6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-3H-imidazo[4,5-b]pyridin-2-one; 5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one;

[1456] 6-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)-1H-imidazo[4,5-b]pyridin-2-one; and

[1457] 3-[2-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one;

[1458] or a salt and / or solvate thereof and / or derivative thereof.

[1459] Clause 139. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1460] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[1461]

[1462] or a pharmaceutically acceptable salt and / or solvate thereof

[1463] Clause 140. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 41 of WO2023017263 or a pharmaceutically acceptable salt and / or solvate thereof.

[1464] Clause 141. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 39 of WO2023017263 or a pharmaceutically acceptable salt and / or solvate thereof.

[1465] Clause 142. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound of formula (XI):

[1466]

[1467] wherein

[1468] W is group (Wa), group (Wb) or group (Wc):

[1469] wherein group (Wa) and group (Wb) are:

[1470]

[1471] wherein:

[1472] Ri is H, Ci-4alkyl, halo, haloCi-4alkyl, CN, Ci-4alkoxy or haloCi-4alkoxy;

[1473] R2 is H, Ci-4alkyl, C3-5 spiro carbocyclyl, haloCi-4alkyl or halo;

[1474] R3 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R3 is absent;

[1475] R13 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R13 is absent;

[1476] R14 is H, Ci-4alkyl, haloCi-4alkyl, halo; or R14 is absent;

[1477] A is a 5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group to form a tricycle when considered together with the phenyl; wherein R2 and R3 may be attached to the same or a different ring atom; R2 may be attached to a fused ring atom; and wherein R13 and R14 may be attached to the same or a different ring atom;

[1478] wherein group (Wc) is:

[1479]

[1480] wherein:

[1481] R16 is halo, Ci-4alkyl, Ci-4alkoxy, haloCi-4alkyl, haloCi-4alkoxy or CN;

[1482] R17 is H, halo, CN, Ci-4alkyl, Ci-4alkoxy or haloCi-4alkoxy;

[1483] R18 is H, halo, CN, C1-4alkyl or C1-4alkoxy;

[1484] Z is group (Za):

[1485]

[1486] wherein:

[1487] R4 is H or C1-4 alkyl;

[1488] R5 is H or C1-4 alkyl; or R4 and Rs can be fused to form a C3-5 spiro carbocyclyl;

[1489] or a pharmaceutically acceptable salt and / or solvate thereof.

[1490] Clause 143. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is selected from the following compounds (‘List K’):

[1491] 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[1492] (5R)-3-[2-amino-6-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxy-3-pyridyl]-5-ethyl-imidazolidine-2, 4-dione;

[1493] 3-(2-amino-6-spiro[2H-benzofuran-3, T-cyclopropane]-4-yloxy-3-pyridyl)-5,5-dimethyl-imidazolidine-2, 4-dione;

[1494] (5R)-3-(2-amino-6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-5-ethyl-imidazolidine-2, 4-dione;

[1495] 3-[2-amino-6-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[1496] 3-[2-amino-6-(3-methoxyphenoxy)-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione; 3-[2-amino-6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[1497] (5R)-3-[2-amino-6-[4-methyl-3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5-ethyl-imidazolidine-2, 4-dione;

[1498] 3-[2-amino-6-[3-(trifluoromethoxy)phenoxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione;

[1499] 4-[[6-amino-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-pyridyl]oxy]-2-(trifluoromethoxy)benzonitrile;

[1500] 4-[[6-amino-5-[(4R)-4-ethyl-2,5-dioxo-imidazolidin-1-yl]-2-pyridyl]oxy]-2-(trifluoromethoxy)benzonitrile;

[1501] 4-[[6-amino-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-pyridyl]oxy]-2-isopropyl-benzonitrile;

[1502] 4-[[6-amino-5-[(4R)-4-ethyl-2,5-dioxo-imidazolidin-1-yl]-2-pyridyl]oxy]-2-isopropyl-benzonitrile; and

[1503] 3-[2-amino-6-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione;

[1504] or a pharmaceutically acceptable salt and / or solvate thereof.

[1505] Clause 144. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 41 of PCT / GB2023 / 053142 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 145. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound as disclosed in PCT publication number WO2019222816 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein.

[1506] Clause 146. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 14 of WO2019222816 or a pharmaceutically acceptable salt and / or solvate thereof.

[1507] Clause 147. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 93 of WO2019222816 or a pharmaceutically acceptable salt and / or solvate thereof.

[1508] Clause 148. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 18 of W02020000065 or a pharmaceutically acceptable salt and / or solvate thereof.

[1509] Clause 149. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 77 of W02020000065 or a pharmaceutically acceptable salt and / or solvate thereof.

[1510] Clause 150. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound as disclosed in US publication number US20200131156 which is incorporated by reference in its entirety for the purpose of the Kv3 modulators disclosed therein.

[1511] Clause 151. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 20 of US20200131156 or a pharmaceutically acceptable salt and / or solvate thereof.

[1512] Clause 152. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 118 of US20200131156 or a pharmaceutically acceptable salt and / or solvate thereof.

[1513] Clause 153. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 38 of W02021214090 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof.

[1514] Clause 154. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 53 of W02021214090 or a pharmaceutically acceptable salt and / or pharmaceutically acceptable solvate thereof. Clause 155. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a compound described in any one of claims 1 to 17 of WO2024086061 or a pharmaceutically acceptable salt and / or solvate thereof.

[1515] Clause 156. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is any one of Examples 1 to 3 of WO2024086061 or a pharmaceutically acceptable salt and / or solvate thereof.

[1516] Clause 157. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1517] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[1518]

[1519] Clause 158. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1520] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[1521]

[1522] Clause 159. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1523] (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione

[1524]

[1525] Clause 160. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1526] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[1527]

[1528] Clause 161. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1529] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[1530]

[1531] Clause 162. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1532] (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione

[1533]

[1534] Clause 163. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1535] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[1536]

[1537] Clause 164. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1538] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[1539]

[1540] Clause 165. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1541] 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5-yl]imidazolidine-2, 4-dione

[1542]

[1543] Clause 166. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1544] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[1545]

[1546] Clause 167. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1547] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[1548]

[1549] Clause 168. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1550] (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2, 4-dione

[1551]

[1552] Clause 169. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1553] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[1554]

[1555] Clause 170. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1556] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[1557]

[1558] Clause 171. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1559] 5-methyl-4-{6-[(7-methylspiro[1-benzofuran-3, T-cyclopropan]-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

[1560]

[1561] Clause 172. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1562] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1563]

[1564] Clause 173. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1565] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1566]

[1567] Clause 174. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1568] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-2-pyridyl]imidazolidine-2, 4-dione

[1569]

[1570] Clause 175. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1571] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1572]

[1573] Clause 176. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1574] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1575]

[1576] Clause 177. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1577] 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1578]

[1579] Clause 178. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1580] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1581]

[1582] Clause 179. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1583]

[1584] Clause 180. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1585] (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione

[1586]

[1587] Clause 181. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1588] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[1589]

[1590] Clause 182. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1591] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[1592]

[1593] Clause 183. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1594] (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione

[1595]

[1596] Clause 184. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is:

[1597] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[1598]

[1599] Clause 185. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a salt and / or solvate of:

[1600] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[1601]

[1602] Clause 186. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of:

[1603] 3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one

[1604]

[1605] Clause 187. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 56 to 94, wherein the Kv3 modulator is a pharmaceutically acceptable salt and / or solvate of (a) 2-methyl-9-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one or (b) 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione.

[1606] Clause 188. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 187, wherein the Kv3 modulator is (a) 2-methyl-9-(6-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxy-3-pyridyl)-7H-purin-8-one or (b) 3-[2-amino-6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazolidine-2, 4-dione.

[1607] Clause 189. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 188, wherein the subject is a mammal.

[1608] Clause 190. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 189, wherein the subject is a human.

[1609] Clause 191. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 190, wherein the Kv3 modulator is administered orally. Clause 192. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 191, wherein the Kv3 modulator is administered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge).

[1610] Clause 193. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to clause 191, wherein the Kv3 modulator is administered in a liquid pharmaceutical composition (such as a suspension, emulsion or solution).

[1611] Clause 194. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 193, wherein the Kv3 modulator is administered in a safe and effective amount.

[1612] Clause 195. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 194, wherein the Kv3 modulator is administered to a subject in need thereof.

[1613] Clause 196. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 195, wherein the Kv3 modulator is administered at a unit dose of 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg.

[1614] Clause 197. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 196, wherein the Kv3 modulator is administered more than once or twice a day e.g. two or three times a day.

[1615] Clause 198. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 197, wherein the Kv3 modulator is administered continuously e.g. at least daily for a period of multiple weeks.

[1616] Clause 199. The method, Kv3 modulator for use, pharmaceutical composition for use or use according to any one of clauses 1 to 198, wherein the Kv3 modulator is administered in combination with one or more further pharmaceutically acceptable active ingredients of use in the treatment or prophylaxis of ALS.

[1617] Clause 200. The method, Kv3 modulator for use, pharmaceutical composition for use or use according clause 199, wherein the one or more further pharmaceutically acceptable active ingredients selected from the group consisting of: riluzole, edaravone, a combination of sodium phenylbutyrate and ursodoxicoltaurine (taurursodiol) or tofersen. REFERENCES

[1618] Bakker, Arnold, et al. "Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance." NeuroImage: Clinical 7 (2015): 688-698.

[1619] Fogarty MJ, Noakes PG, Bellingham MC. Motor cortex layer V pyramidal neurons exhibit dendritic regression, spine loss, and increased synaptic excitation in the presymptomatic hSOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Neurosci. 2015;35(2):643-7

[1620] Kääb S, Miguel-Velado E, López-López JR, Pérez-García MT. Down regulation of Kv3.4 channels by chronic hypoxia increases acute oxygen sensitivity in rabbit carotid body. J Physiol. 2005 Jul 15;566(Pt 2):395-408

[1621] Kaczmarek LK, Zhang Y. Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance. Physiol Rev. 2017;97(4):1431-1468

[1622] Rudy B, McBain CJ. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 2001;24(9):517-26.

[1623] Soares D, Goldrick I, Lemon RN, Kraskov A, Greensmith L, Kalmar B. Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque. J Comp Neurol. 2017;525(9):2164-2174 Tierney, Matthew T., and Alessandra Sacco. "Satellite cell heterogeneity in skeletal muscle homeostasis." Trends in cell biology 26.6 (2016): 434-444.

[1624] Vega-Saenz de Miera E, Rudy B. Modulation of K+ channels by hydrogen peroxide. Biochem Biophys Res Commun. 1992; 186(3): 1681 -7

[1625] Vucic, Steve, and Seward B. Rutkove. "Neurophysiological biomarkers in amyotrophic lateral sclerosis." Current opinion in neurology 31.5 (2018): 640-647.

[1626] US20200131156

[1627] WO2011069951

[1628] WO2012007877

[1629] WO2012168710

[1630] WO2013083994

[1631] WO2013175215

[1632] WO2017103604

[1633] WO2018020263

[1634] WO2019222816

[1635] WO2020000065

[1636] WO2020079422

[1637] WO2021156584

[1638] WO2021214090 WO2023017263 WO2024086061

Claims

1. Claims1. A method for the treatment or prophylaxis of ALS in a subject, the method comprising increasing total Kv3 channel activity in the subject.

2. The method of claim 1, wherein total Kv3 channel activity is increased by administering a Kv3 modulator to the subject.

3. A Kv3 modulator for use in the treatment or prophylaxis of ALS in a subject.

4. The method of either claim 1 or 2, wherein total Kv3 channel activity is increased by increasing the function of Kv3 channels in the subject.

5. The method of either claim 1 or 2, wherein total Kv3 channel activity is increased by increasing the expression of Kv3 channels in the subject.

6. The method or Kv3 modulator for use of either claim 2 or 3, wherein the Kv3 modulator increases total Kv3 channel activity by increasing the function of Kv3 channels in the subject.

7. The method or Kv3 modulator for use of any one of claims 1 to 6, wherein the subject is a mammal.

8. The method or Kv3 modulator for use of any one of claims 1 to 7, wherein the ALS is familial ALS.

9. The method or Kv3 modulator for use of any one of claims 1 to 8, wherein the subject has a mutation in the SOD1 gene.

10. The method or Kv3 modulator for use of claim 9, wherein the mutation is SOD1G93A.

11. The method or Kv3 modulator for use of any one of claims 1 to 10, wherein the Kv3 channel type is Kv3.1.

12. The method or Kv3 modulator for use of any one of claims 1 to 10, wherein the Kv3 channel type is Kv3.4.

13. The method or Kv3 modulator for use of any one of claims 1 to 12, wherein the Kv3 modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.1 channels recombinantly expressed in mammalian cells and wherein the pEC50 of the modulator is in the range of 4-8.

14. The method or Kv3 modulator for use of any one of claims 1 to 12, wherein the Kv3 modulator is capable of producing at least 20% potentiation of whole-cell currents mediated by human Kv3.4 channels recombinantly expressed in mammalian cells and wherein the pEC50 of the modulator is in the range of 4-8.

15. The method or Kv3 modulator for use of any one of claims 1 to 14, wherein the Kv3 modulator is selected from:16.(a)17.(5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]- 2,4-imidazolidinedione19. 21.or a pharmaceutically acceptable salt and / or solvate thereof,22.(b)23.(5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3 pyridyl]imidazolidine-2, 4-dione25. 27.or a pharmaceutically acceptable salt and / or solvate thereof,28.(c)29.5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3, T-cyclopropane]-4-yl)oxypyrimidin-5- yl]imidazolidine-2, 4-dione31. 33.or a pharmaceutically acceptable salt and / or solvate thereof, (d)34.(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyrazin-2-yl]imidazolidine-2, 4-dione36. 38.or a pharmaceutically acceptable salt and / or solvate thereof,39.(e)40.(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2, 4-dione42. 44.or a pharmaceutically acceptable salt and / or solvate thereof,45.(f)46.3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one48. 50.or a pharmaceutically acceptable salt and / or solvate thereof, or51.(g)52.3-[2-[3-(trifluoromethoxy)phenoxy]pyrimidin-5-yl]-1H-imidazo[4,5-b]pyridin-2-one54. 56.or a pharmaceutically acceptable salt and / or solvate thereof.

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