WO2013182851A1

WO2013182851A1 - Prophylaxis or treatment of diseases where a modulator of kv3.3 channels is required

Info

Publication number: WO2013182851A1
Application number: PCT/GB2013/051488
Authority: WO
Inventors: Charles Large
Original assignee: Autifony Therapeutics Limited
Priority date: 2012-06-06
Filing date: 2013-06-06
Publication date: 2013-12-12

Abstract

The present invention relates to the prophylaxis or treatment of diseases and disorders wherein a modulator of Kv3.3 channels is required, including spinocerebellar ataxia, by administering a compound of formula (I):

Description

PROPHYLAXIS OR TREATMENT OF DISEASES WHERE A MODULATOR OF KV3.3 CHANNELS IS

REQUIRED

Technical field

This invention relates to compounds and pharmaceutical compositions containing such compounds for use in the prophylaxis or treatment of diseases and disorders wherein a modulator of Kv3.3 channels is required, including spinocerebellar ataxia.

Background to the invention

The Kv3 voltage-gated potassium channel family includes four members, Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Genes for each of these subtypes can generate multiple isoforms by alternative splicing, producing versions with different C-terminal domains. Thirteen isoforms have been identified in mammals to date, but the currents expressed by these variants appear similar (Rudy and McBain, 2001, Trends in Neurosciences 24, 517-526). Kv3 channels are activated by depolarisation of the plasma membrane to voltages more positive than -20mV; furthermore, the channels deactivate rapidly upon repolarisation of the membrane. These biophysical properties ensure that the channels open towards the peak of the depolarising phase of the neuronal action potential to initiate repolarisation. Rapid termination of the action potential mediated by Kv3 channels allows the neuron to recover more quickly to reach sub-threshold membrane potentials from which further action potentials can be triggered. As a result, the presence of Kv3 channels in certain neurons contributes to their ability to fire at high frequencies (Rudy and McBain, 2001, Trends in Neurosci. 24, 517-526). Kv3.1-3 subtypes are predominant in the CNS, whereas Kv3.4 channels are found predominantly in skeletal muscle and sympathetic neurons (Weiser et al., 1994, J. Neurosci. 14, 949-972). Kv3.1-3 channel subtypes are differentially expressed by sub-classes of interneurons in cortical and hippocampal brain areas (e.g. Chow et al., 1999, J. Neurosci. 19, 9332-9345; Martina et al., 1998, J. Neurosci. 18, 8111-8125; McDonald and Mascagni, 2006, Neurosci. 138, 537-547, Chang et al., 2007, J. Comp. Neurol. 502, 953-972), in the thalamus (e.g. Kasten et al., 2007, J.Physiol. 584, 565-582), cerebellum (Sacco et al., 2006, Mol. Cell. Neurosci. 33, 170-179; Puente et al., 2010, Histochem. Cell Biol. 134, 403-409), and auditory brain stem nuclei (Li et al., 2001, J. Comp. Neurol. 437, 196-218).

Kv3 channels are important determinants of the function of the cerebellum, a region of the brain important for motor control (Joho and Hurlock, 2009, Cerebellum 8, 323-333). Characterisation of mice in which specific Kv3 subtypes have been deleted shows that the absence of Kv3.3 channels gives rise to a phenotype characterised by mild ataxia and motor deficits (McMahon et al., 2004, Eur.

J. Neurosci. 19, 3317-3327). Likely underlying these behavioural deficits, Purkinje neurons in the cerebellum show increased excitability in the Kv3.3 knockout mice (Zagha et al., 2010, J.Neurophysiol. 103, 3516-25). Double deletion of Kv3.3 and Kv3.1 channels gives rise to a severe phenotype characterised by spontaneous seizures, ataxia, and an increased sensitivity to the effects of ethanol on motor coordination (Espinosa et al., 2001, J. Neurosci. 21, 6657-6665; Espinosa et al., 2008, J. Neurosci. 28, 5570-5581).

Spinocerebellar ataxia type 13 (SCA13) is a human autosomal dominant disease caused by mutations in the KCNC3 gene that encodes the Kv3.3 channel. SCA13 is either a neurodevelopmental disorder that is evident in infancy or a progressive neurodegenerative disease that emerges during adulthood (Figueroa et al., 2010, Hum Mutat. 31, 191-196). The known mutations in the KCNC3 gene have been shown to cause a reduction in function of the channels in some cases (Waters et al., 2006, Nat. Genet. 38, 447-451; Minassian et al., 2012, J Physiol. 590.7, 1599-1614), and a gain of function in other cases (Figueroa et al., 2011, PLoS ONE 6, el7811). For example, an F448L mutation alters channel gating and causes early-onset SCA13, whereas R420H and R423H mutations are associated with reduced Kv3 current amplitude by a dominant negative mechanism (Figueroa et al., 2010, Hum Mutat. 31, 191- 196; Minassian et al., 2012, J Physiol. 590.7, 1599-1614). R420H leads to an adult form of SCA13, whereas R423H is associated with an early-onset ataxia. Early onset forms of SCA13 may be associated with deficits in the development of the cerebellum (Issa et al., 2012, Dis Model Mech. 5, 921-929), which are secondary to loss of Kv3.3 function.

Small molecule modulators of Kv3.3, which are able to correct the deficits observed in the mutant channels, might be beneficial in the treatment of spinocerebellar ataxia, in particular SCA13.

Hearing loss represents an epidemic that affects approximately 16% of the population in Europe and the US (Goldman and Holme, 2010, Drug Discovery Today 15, 253-255), with a prevalence estimated at 250 million people worldwide (B. Shield, 2006, Evaluation of the social and economic costs of hearing impairment. A report for Hear-lt AISBL: www.hear- it.org/multimedia/Hear_lt_Report_October_2006.pdf). Kv3.3 channels are expressed at high levels in auditory brainstem nuclei (Li et al., 2001, J. Comp. Neurol. 437, 196-218), where they contribute to the activity of neurons that transmit auditory information from the brainstem to higher brain regions. Phosphorylation of Kv3.3 channels in auditory brainstem neurons is suggested to contribute to the physiological adaptation to sound (Desai et al., 2008, J.Biol. Chem. 283, 22283-22294). Furthermore, a loss of Kv3 channel function, which likely includes a loss of Kv3.3 channel function, has been shown to be associated with noise-trauma induced hearing loss (Pilati et al., 2012, Hear Res. 283, 98-106). These data support the hypothesis that modulation of Kv3.3 channels in auditory brainstem nuclei could have a therapeutic benefit in patients suffering from hearing loss.

Patent applications WO2011/069951, WO2012/076877 and WO2012/168710 (application number PCT/GB2012/051278) disclose compounds which are modulators of Kv3.1 and Kv3.2. Further, the value of such compounds is demonstrated in animal models of seizure, hyperactivity, sleep disorders, psychosis, hearing disorders and bipolar disorders. There remains a need for the identification of alternative modulators of Kv3 channels, in particular modulators of the Kv3.3 channel, which may demonstrate high in vivo potency, channel selectivity or desirable pharmacokinetic parameters that reduce the dose required for therapeutic effect in vivo. For certain therapeutic indications, there is also a need to identify compounds with a different modulatory effect on Kv3 channels, for example, compounds that alter the kinetics of channel gating or channel inactivation, and which may behave in vivo as negative modulators of the channels.

Summary of the invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, for use in the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required:

wherein:

W is group (Wa), group (Wb) or group (Wc):

wherein:

Ri is H, Ci_₄alkyl, halo, haloCi_₄alkyl, CN, Ci_₄alkoxy, or haloCi_₄alkoxy;

R₂ is H, Ci_₄alkyl, C₃.₅ spiro carbocyclyl, haloCi_₄alkyl or halo;

R₃ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or R₃ is absent;

Ri3 is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or Ri₃ is absent;

Ri₄ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or ₁₄ is absent;

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;

X is CH or N;

Y is CR₁₅ or N;

Ri₅ is H or Ci_₄alkyl;

Ri6 is halo, Ci_₄ alkyl, Ci_₄ alkoxy, halo-Ci_₄alkyl, halo-Ci_₄alkoxy, or CN;

Ri₇ is H, halo, cyano, Ci_ alkyl or Ci_₄ alkoxy; with the proviso that when Ri₇ is H, Ri₆ is not in the para position;

R₄ is Ci_-4 alkyl;

R₅ is H or Ci_-4 alkyl;

or R₄ and R₅ can be fused to form C₃.₄ spiro carbocyclyl;

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 R_u may be attached to the same or a different ring atom.

Also provided is a method of prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required, by administering to a subject a compound of formula (I) or a

pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, as defined above. Further provided is the use of compounds of formula (I) as defined above in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required.

A disorder where a modulator of Kv3.3 channels is required is spinocerebellar ataxia, such as spinocerebellar ataxia type 13.

Detailed description of the invention

wherein:

W is group (Wa), group (Wb) or group (Wc):

wherein: i is H, Ci_₄alkyl, halo, haloCi_₄alkyl, CN, Ci_₄alkoxy, or haloCi_₄alkoxy;

R₂ is H, Ci_₄alkyl, C₃.₅ spiro carbocyclyl, haloCi_₄alkyl or halo;

R₃ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or R₃ is absent;

Ri3 is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or Ri₃ is absent;

Ri₄ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or ₁₄ is absent;

X is CH or N;

Y is CR₁₅ or N;

Ri₅ is H or Ci_₄alkyl;

Ri6 is halo, Ci_ alkyl, Ci_₄ alkoxy, halo-Ci_₄alkyl, halo-Ci_₄alkoxy or CN;

Ri₇ is H, halo, cyano, Ci_₄ alkyl or Ci_₄ alkoxy; with the proviso that when Ri₇ is H, Ri₆ is not in the para position;

R₄ is Ci_-4 alkyl; R₅ is H or Ci_4 alkyl;

or R₄ and R₅ can be fused to form C₃.₄ spiro carbocyclyl;

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 Ri₃ and R_u may be attached to the same or a different ring atom.

The present invention also provides a method of prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required, by administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required.

Suitably, Ri is H, Ci_₄alkyl, halo or haloCi_₄alkyl. In another embodiment of the invention Ri is H or methyl. In one embodiment of the invention Ri is H. In another embodiment of the invention Ri is Ci_ ₄alkyl, in particular methyl. When W is group (Wa), suitably Ri is H. When W is group (Wb), suitably Ri is H or methyl.

When W is group (Wb), suitably Ri is positioned at the para position of the phenyl ring, as illustrated below:

Suitably R₂ is H, Ci_₄alkyl, C₃.₅spiro carbocyclyl, or haloCi_₄alkyl. In one embodiment of the invention R₂ is Ci_₄alkyl, in particular methyl, ethyl, isopropyl, tert-butyl or cyclopropyl, especially methyl, ethyl, isopropyl or tert-butyl. In one embodiment of the invention R₂ is C₃.₅spiro carbocyclyl. In one embodiment of the invention R₂ is C₃spiro carbocyclyl. In another embodiment of the invention R₂ is C₄ spiro carbocyclyl. In a further embodiment of the invention R₂ is C₅spiro carbocyclyl. In one embodiment of the invention R₂ is haloCi_₄alkyl, in particular trifluoromethyl or 2,2,2-trifluoroethyl. In one embodiment of the invention R₂ is halo, in particular fluoro. In another embodiment of the invention R₂ is H.

In one embodiment of the invention R₃ is H, Ci_₄alkyl, haloCi_₄alkyl or halo. Alternatively, R₃ is H, Ci_₄alkyl, or haloCi_₄alkyl. Suitably R₃ is H or Ci_₄alkyl. In one embodiment of the invention R₃ is H. In one embodiment of the invention R₃ is Ci_₄alkyl, in particular methyl, ethyl, isopropyl, tert-butyl or cyclopropyl, especially methyl, ethyl, isopropyl or tert-butyl, such as methyl or ethyl. In one embodiment of the invention, R₃ is haloCi_₄alkyl, in particular trifluoromethyl or 2,2,2-trifluoroethyl. In one embodiment of the invention R₃ is halo, in particular fluoro. The skilled person will appreciate that, depending on the size, presence of heteroatoms and the degree of unsaturation of the A ring, R₃ may be absent. Consequently, in another embodiment of the invention R₃ is absent. Suitably R₃ is H, methyl or trifluoromethyl.

In one embodiment of the invention R₂ may be H, Ci_₄alkyl, haloCi_₄alkyl or C₃.₅spiro carbocycyl and R₃ may be H, Ci_₄alkyl, or haloCi_₄alkyl. In a particular embodiment of the invention, R₂ may be methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, C₃.₅spiro carbocyclyl, trifluoromethyl or 2,2,2-trifluoroethyl and R₃ may be H, methyl, ethyl or trifluoromethyl. In certain embodiments of the invention R₃ is H and R₂ is H, methyl, ethyl, isopropyl or C₃.₄ spiro carbocyclyl. In further embodiments of the invention R₃ and R₂ are both fluoro (such as attached to the same ring carbon atom). In one embodiment of the invention R₂ is Ci_₄alkyl and R₃ is H, for example R₂ is methyl, ethyl, tert-butyl or cyclopropyl. In one embodiment of the invention R₂ is Ci_₄alkyl and R₃ is Ci_₄alkyl, for example R₂ is methyl and R₃ is methyl, R₂ is ethyl and R₃ is ethyl or R₂ is methyl and R₃ is ethyl. In another embodiment of the invention R₂ is trifluoromethyl and R₃ is methyl.

In one embodiment of the invention R₂ and R₃ are attached to the same ring atom. In an alternative embodiment of the invention R₂ and R₃ are attached to different ring atoms. In one embodiment of the invention R₁₃ is H, F or methyl. In one embodiment of the invention R₁₃ is H. In another embodiment of the invention R₁₃ is Ci_₄alkyl, in particular methyl. In a further embodiment of the invention R₁₃ is halo, in particular fluoro. In an additional embodiment of the invention R₁₃ is haloCi. ₄alkyl, such as trifluoromethyl. The skilled person will appreciate that, depending on the size, presence of heteroatoms and the degree of unsaturation of the A ring, R₁₃ may be absent. Consequently, in another embodiment of the invention R₁₃ is absent.

In one embodiment of the invention ₁₄ is H, F or methyl. In one embodiment of the invention R_u is H. in another embodiment of the invention R_u is Ci_₄alkyl, in particular methyl. In a further embodiment of the invention R_u is halo, in particular fluoro. In an additional embodiment of the invention R₁₃ is haloCi. ₄alkyl, such as trifluoromethyl. The skilled person will appreciate that, depending on the size, presence of heteroatoms and the degree of unsaturation of the A ring, R_u may be absent. Consequently, in another embodiment of the invention R_u is absent.

In one embodiment of the invention R₁₃ and R_u are attached to the same ring atom. In an alternative embodiment of the invention R₁₃ and R_u are attached to different ring atoms.

In certain embodiments of the invention R₂, R₃, R₁₃ and R_u are each independently selected from H, Ci_ ₄alkyl, haloCi_₄alkyl and halo, such as H, Ci_₄alkyl and haloCi_₄alkyl. Suitably R₂, R₃, R₁₃ and R₁₄ are each independently selected from H, F, methyl and trifluoromethyl.

Suitably, 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. In one embodiment of the invention A is a 5 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group to form a tricycle when considered together with the phenyl. In another embodiment of the invention A is a 6 membered saturated or unsaturated heterocycle, with at least one O atom; which heterocycle is optionally fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group to form a tricycle when considered together with the phenyl. In one embodiment of the invention A is a 5 membered saturated or unsaturated heterocycle with at least one O atom, which heterocycle is fused with a cyclopropyl group to form a tricycle when considered together with the phenyl. In another embodiment of the invention A is a 6 membered saturated or unsaturated heterocycle with at least one O atom, which heterocycle is fused with a cyclopropyl group to form a tricycle when considered together with the phenyl. In one embodiment of the invention A is a 5 membered saturated or unsaturated heterocycle with at least one O atom. In one embodiment of the invention A is a 6 membered saturated or unsaturated heterocycle with at least one O atom.

In certain embodiments of the invention the ring A contains one heteroatom. In other embodiments of the invention the ring A contains two heteroatoms (e.g. two oxygen atoms, one oxygen atom and one nitrogen atom, or one oxygen atom and one sulphur atom), in particular two oxygen atoms or one oxygen atom and one nitrogen atom.

Suitably, A is dihydrofuran, isoxazole, dihydropyran, 1,3-dioxolane, 1,3-oxazine or dihydropyran fused with a cyclopropyl group. In one embodiment of the invention A is dihydrofuran. In one embodiment of the invention A is dihydropyran. In another embodiment of the invention A is dihydrofuran fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group. In another embodiment of the invention A is dihydropyran fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group. In a further embodiment the invention A is dihydrofuran fused with a cyclopropyl group. In still further embodiment the invention A is dihydropyran fused with a cyclopropyl group.

In one embodiment of the invention A is fused with a cyclopropyl group. In another embodiment A is fused with a cyclobutyl group. In a further embodiment of the invention A is fused with a cyclopentyl group. In one embodiment of the invention A is not fused with a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.

In one embodiment of the invention W is group (Wa):

In one embodiment of the invention W is group (Wb):

(Wb). In one embodiment of the invention A is dihydrofuran, dihydropyran, furan, pyran, oxazole, isoxazole, oxazine, dioxine or 1,3-dioxalane. In another embodiment A is dihydrofuran, dihydropyran or 1,3- dioxalane.

In one embodiment of the invention A is:

denotes a portion of the phenyl ring to which ring A is fused.

In another embodiment of the invention A is:

wherein

denotes a portion of the phenyl ring to which ring A is fused.

In a further embodiment of the invention A is: wherein

denotes a portion of the phenyl ring to which ring A is fused.

When A contains a 5 membered heterocycle containing one oxygen atom, suitably the heterocycle is dihydrofuran. When A is a 5 membered heterocycle containing one oxygen atom, suitably the oxygen atom is located at the benzylic position relative to the phenyl ring.

When W is group (Wa), suitably A is a 5 membered heterocycle containing one heteroatom, wherein the oxygen atom is located at the benzylic or para position relative to the phenyl ring.

When W is group (Wb), suitably A is a 5 membered heterocycle containing one heteroatom, wherein the oxygen atom is located at the benzylic or meta position relative to the phenyl ring.

When W is group (Wa), in one embodiment of the invention, group (Wa) is:

When W is group (Wa), in another embodiment or the invention, group (Wa) is:

When W is group (Wb), in one embodiment of the invention, group (Wb) is:

When W is group (Wb), in another embodiment of the invention, (Wb) is:

When W is group (Wb) in a further embodiment of the invention, group (Wb) is:

When A contains a 6 membered heterocycle containing one oxygen atom, suitably the heterocycle is dihydropyran.

When W is group (Wa), suitably A is a 6 membered heterocycle containing one oxygen atom, wherein the oxygen atom is located at the para position relative to the phenyl ring.

When W is group (Wb), suitably A contains a 6 membered heterocycle containing one oxygen atom, wherein the oxygen atom is located at the meta position relative to the phenyl ring. When W is group (Wa), in one embodiment of the invention, group (Wa) is:

When W is group (Wa), in another embodiment of the invention, group (Wa) is:

When W is group (Wb), in one embodiment of the invention, group (Wb) is:

When W is group (Wb), in one embodiment of the invention, group (Wb) is:

When W is group (Wb), in one embodiment of the invention, group (Wb) is:

When W is group (Wa), in one embodiment of the invention, A is:

wherein m and p denote the meta and para positions, respectively, of ring A relative to the phenyl ring.

When W is group (Wa), in a further embodiment of the invention, A is selected from the group consisting of:

wherein m and p denote the meta and para positions, respectively, of ring A relative to the phenyl ring. When W is group (Wb), in one embodiment of the invention, A is:

When W is group (Wb), in one embodiment of the invention, A is:

When W is group (Wb), in one embodiment of the invention, A is:

When W is group (Wb), in another embodiment of the invention, A

In one embodiment W is the group Wc.

When W is group (Wc), in one embodiment of the invention i₆ is Ci_₄alkoxy. In another embodiment of the invention i₆ is methoxy. In one embodiment of the invention i₆ is Ci_₄alkyl. In another embodiment of the invention i₆ is methyl. In a further embodiment of the invention Ri₆ is ethyl. In a yet further embodiment of the invention i₆ is propyl. In a yet further embodiment of the invention i₆ is butyl. In one embodiment of the invention Ri₆ is halo. In another embodiment of the invention Ri₆ is chloro. In a further embodiment of the invention Ri₆ is fluoro. In one embodiment of the invention Ri₆ is halo-Ci_₄alkoxy. In another embodiment of the invention Ri₆ is trifluoromethoxy. In one embodiment of the invention Ri₆ is halo-Ci_₄alkyl. In another embodiment of the invention Ri₆ is trifluoromethyl. In one embodiment of the invention Ri₆ is cyano.

In one embodiment of the invention, Ri₇ is H. In one embodiment of the invention Ri₇ is Ci_₄alkyl. In another embodiment of the invention Ri₇ is methyl. In one embodiment of the invention Ri₇ is halo. In another embodiment of the invention, R₁₇ is chloro. In a further embodiment of the invention R₁₇ is fluoro. In one embodiment of the invention R₁₇ is Ci_₄alkyl. In one embodiment of the invention R₁₇ is cyano.

In one embodiment of the invention Ri₆ is Ci_₄alkyl, Ci_₄alkoxy, or halo-Ci_₄alkoxy; R₁₇ is H, cyano or alkyl; X is N, Y is N or CRi₅, R₄ is Ci_₄alkyl, and R₅ is Ci_₄alkyl or H. In one embodiment of the invention Ri₆ is propyl, butyl, methoxy, propoxy, or trifluoromethoxy; R₁₇ is H, cyano or methyl; X is N, Y is N or CRi₅, R₄ is ethyl, and R₅ is methyl or H.

In one embodiment, one of Ri₆ and R₁₇ is in the para position and the remaining Ri₆ or R₁₇ is in the meta position. In one embodiment, one of Ri₆ and R₁₇ is in the para position and the remaining Ri₆ or R₁₇ is in the ortho position.

In one embodiment of the invention Ri₆ is Ci_₄alkoxy and R₁₇ is Ci_₄alkyl. In one embodiment of the invention Ri₆ is methoxy and R₁₇ is methyl. In one embodiment of the invention Ri₆ is Ci_₄alkoxy in the meta position and R₁₇ is Ci_₄alkyl in the para position. In a further embodiment of the invention Ri₆ is methoxy in the meta position, R₁₇ is methyl in the para position, R₄ is Ci_₄alkyl, R₅ is H, R₄ is in the R configuration. In a yet further embodiment of the invention Ri₆ is methoxy in the meta position, R₁₇ is methyl in the para position, X is N, Y is C, R₄ is Ci_₄alkyl, R₅ is H and the absolute configuration of the stereogenic centre is R. In a still further embodiment of the invention Ri₆ is methoxy in the meta position, R₁₇ is methyl in the para position, X is N, Y is C, R₄ is ethyl, R₅ is H and the absolute

configuration of the stereogenic centre is R.

Suitably, R₄ is methyl, ethyl, isopropyl or t-butyl. In one embodiment of the invention R₄ is methyl. In another embodiment of the invention R₄ is ethyl. In a further embodiment of the invention R₄ is propyl, such is isopropyl. In a yet further embodiment of the invention R₄ is butyl, such as t-butyl. Suitably, R₅ is H or methyl. In one embodiment of the invention R₅ is H. In a second embodiment of the invention R₅ is Ci_₄alkyl, in particular R₅ is methyl.

In one embodiment of the invention R₄ and R₅ together form a C₃ spiro carbocycle. In a second embodiment of the invention R₄ and R₅ together form a C₄ spiro carbocycle. In a further embodiment of the invention R₄ is methyl and R₅ is methyl. In an embodiment of particular interest, R₄ is ethyl and R₅ is methyl. In another embodiment, R₄ is ethyl and R₅ is ethyl. In an additional embodiment, R₄ is ethyl and R₅ is H.

Suitably, R₄ and R₅ have the stereochemical arrangement:

In one embodiment of the invention X is CH. In another embodiment of the invention X is N.

In one embodiment of the invention Y is CRi₅. In another embodiment of the invention Y is N. In a further embodiment of the invention Y is CRi₅, wherein Ri₅ is H. In a still further embodiment of the invention Y is CRi₅, wherein Ri₅ is Ci_₄alkyl, in particular methyl.

In one embodiment of the invention X is CH and Y is CRi₅, wherein Ri₅ is H. In another embodiment of the invention X is N and Y is CRi₅, wherein Ri₅ is H. In a further embodiment of the invention X is N and Y is CRi₅, wherein Ri₅ is methyl. In a further embodiment of the invention X is CH and Y is CRi₅, wherein Ri₅ is methyl. In a still further embodiment of the invention X is N and Y is N.

When W is group (Wc), suitably the compound of formula (I) is selected from:

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

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

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

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

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

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

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

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

(5 ?)-5-methyl-3-(6-{[3-(l-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

(5 ?)-5-methyl-3-[6-({3-[(l-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidinedione;

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

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

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

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

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

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

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

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

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

(5 ?)-5-ethyl-3-(6 [3-(l-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

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

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

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

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

(5 ?)-5-(l-methylethyl)-3-(4 [4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinedione;

(5 ?)-5-methyl-3-(2 [3-(l-methylethyl)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

(5 ?)-5-ethyl-3-(2 [3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-2,4-imidazolidinedione;

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

(5 ?)-5-ethyl-5-methyl-3-(6 [4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidined 7-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-5,7-diazaspiro[3.4]octane-6,8-dione;

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-l-imidazolidinyl)-2-pyridinyl]oxy}-2-(l-methylethyl)benzonitrile 4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-2-[(trifluoromethyl)oxy]benzonitr

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-(l-methylethyl)-3-(6 [4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidined^

3-(6 [2-(l,l-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione;

3-(2 [2-(l,l-dimethylethyl)phenyl]oxy}-5-pyrimidinyl)-5,5-dimethyl-2,4-imidazolidined

(5R)-5-ethyl-5-methyl-3-(2 [4-methyl-3-(methyloxy)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazoli

(5R)-5-ethyl-3-(2 [3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-5-methyl-2,4-imidazolidin

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

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-3-ethylbenzonitrile;

2- chloro-4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

5,5-dimethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidi 4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-2-(methyloxy)benzonitrile;

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-3-methylbenzonitrile;

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-3-(trifluoromethyl)benzonitri 4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-2-ethylbenzonitrile;

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyrimidinyl]oxy}-2-ethylbenzonitrile;

3- cyclopropyl-4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridin^^

2-[(cyclopropylmethyl)oxy]-4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}benzoni

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-2-(ethyloxy)benzonitrile;

2-cyclopropyl-4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}benzonitrile;

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

4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyrimidinyl]oxy}-3-(1 -dimethylethyl)ben 4 [5-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)-2-pyridinyl]oxy}-2-[(l-methylethyl)o

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

3- cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)benzonitri

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

2- cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo

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

3- (14-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-l-imidazolidinyl]-2- pyrimidinyl}oxy)benzonitrile;

3- (14-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-l-imidazolidinyl]-2- pyridinyl}oxy)benzonitrile;

4- {[4-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)phenyl]oxy}-2-(methyloxy)benzonitrile;

4-{[4-(4,4-dimethyl-2,5-dioxo-l-imidazolidinyl)phenyl]oxy}-2-(ethyloxy)benzonitrile;

4-({4-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]phenyl}oxy)-2-(ethyloxy)benzonitrile;

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

3- (1 -dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)benzonit

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

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

2-[(cyclopropylmethyl)oxy]-4-({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)benzonitr (5R)-5-ethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl]-2,4-imidazolidin

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

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

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

4-({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)-2-[(l-methylethyl)oxy]benzonitri 4-({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)-3-methylbenzonitrile;

4-({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)-2-[(trifluoromethyl)oxy]benzonitri

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

4- ({5-[(4R)-4-ethyl-2,5-dioxo-l-imidazolidinyl]-2-pyrimidinyl}oxy)-3-methylbenzonitrile;

3- (1 -dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo and

4- ({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-l-imidazolidinyl]-2-pyridinyl}oxy)-2-(l-methylethyl)benzonitri or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

When W is group (Wb), suitably the compound of formula (I) is selected from:

(5R)-3-[4-(l,3-dihydro-2-benzofuran-4-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione;

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

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

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

(5R)-5-ethyl-3-{6-[(3-ethyl-l,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione;

(5R)-5-ethyl-3-(6-{[3-(l-methylethyl)-l,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)-2,4-imidazolidinedione;

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

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

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

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

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

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

(5R)-3 2-[(3 -dimethyl-2 -dihydro-l-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5-(14-dimethylethyl)-2,^ imidazolidinedione;

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

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

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

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

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

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

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);

5,5-dimethyl-3-{6-[(la-methyl-l,la,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4- imidazolidinedione;

5,5-dimethyl-3-{6-[(la-methyl-l,la,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}-2,4- imidazolidinedione (enantiomer 1 and enantiomer 2);

(5R)-5-ethyl-5-methyl-3-[6-(lH-spiro[2-benzopyran-4,l'-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4- imidazolidinedione;

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

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

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

5,5-dimethyl-3-[6-(lH-spiro[2-benzopyran-4,l'-cyclopropan]-5-yloxy)-3-pyridinyl]-2,4- imidazolidinedione;

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

5,5-dimethyl-3-{6-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione (racemate mixture, enantiomer 1, enantiomer 2); (5R)-5-ethyl-5-methyl-3 6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4- imidazolidinedione (diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

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

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

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

(diastereoisomeric mixture, diastereoisomer 1, diastereoisomer 2);

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

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

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

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

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

(5R)-3-{2-[(2,2-difluoro-l,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,l-benzoxazin-5-yl)oxy]-5-pyrimidinyl}-2,4- imidazolidinedione;

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

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

5,5-dimethyl-3-[2-(7-methylspiro[lH-isobenzofuran-3,l'-cyclobutane]-4-yl)oxypyrimidin-5- yl]imidazolidine-2,4-dione;

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

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

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

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

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

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

(5R)-3-[6-[(3,3-diethyl-lH-isobenzofuran-4-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-[6-[(2,4,4-trimethyl-3,l-benzoxazin-5-yl)oxy]-3-pyridyl]imidazolidine-2,4-dione; (5R)-3-{6-[(3,3-dimethyl-l,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5-ethyl-5-methyl-2,4- imidazolidinedione;

5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine- 2,4-dione; or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

When W is group (Wa), suitably the compound of formula (I) is selected from:

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

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

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

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

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

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

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

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

5,5-dimethyl-3-(2-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxypyrimidin-5-yl)imidazolidine-2,4- dione;

5,5-dimethyl-3-(2-spiro[lH-isobenzofuran-3,l'-cyclopentane]-5-yloxypyrimidin-5-yl)imidazolidine-2,4- dione;

5,5-dimethyl-3-[2-[[3-(trifluoromethyl)-l,3-dihydroisobenzofuran-5-yl]oxy]pyrimidin-5-yl]imidazolidine

2.4- dione (enantiomer 1);

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

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

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

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

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

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

(5R)-5-ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]pyrimidin-5- yl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-3-[2-[(3-ethyl-l,3-dihydroisobenzofuran-5-yl)oxy]pyrim^

2,4-dione (diastereoisomer 1);

(5R)-5-ethyl-3-[2-[(3-ethyl-l,3-dihydroisobenzofuran-5-yl)oxy]pyrim^

2,4-dione (diastereoisomer 2);

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

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

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

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

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

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

(5R)-3-[2-[(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-dion (5R)-3-[6-[(3 -dimethyl-lH-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4- dione;

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

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

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

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

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

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

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

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

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

(5R)-5-ethyl-5-methyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine- 2,4-dione; (5 )-5-ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-l,3-dihydroisobenzofuran-5-yl]oxy]-3- pyridyl]imidazolidine-2,4-dione (diastereoisomer 1);

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

(5R)-3-[6-[(3 -dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-d (5R)-3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5-ethyl^

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

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

3-[6-[(3-tert-butyl-1 -dihydroisobenzofuran-5-yl)oxy]-3-pyri^

(enantiomer 2);

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

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

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

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

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

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

5,5-dimethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2,4-dione; 5,5-dimethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclopentane]-5-yloxy-3-pyridyl)imidazolidine-2,4-dione; 5,5-dimethyl-3-[6-[[3-(trifluoromethyl)-l,3-dihydroisobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2,4- dione (enantiomer 1);

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

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

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

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

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

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

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

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

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

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

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

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

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

(5R)-5-ethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione;

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

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

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

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

(5R)-3-[4-(l,3-dihydro-2-benzofuran-5-yloxy)phenyl]-5-methyl-2,4-imidazolidinedione;

or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

Suitably, the compound of formula (I) contains a (Wa) group corresponding to one of the following phenol groups:

Suitably, the compound of formula (I) contains a (Wb) group corresponding to one of the followin phenol groups:

Alternatively, when the compound of formula (I) contains a (Wb) group corresponding to one of owing phenol groups:

For the avoidance of doubt, the embodiments of any one feature of the compounds of the invention may be combined with any embodiment of another feature of compounds of the invention to create a further embodiment.

The term 'halo' or 'halogen' as used herein, refers to a fluorine, chlorine, bromine or iodine atom. Particular examples of halo are fluorine and chlorine, especially fluorine. When the compound contains a Ci_₄alkyl group, whether alone or forming part of a larger group, e.g. Ci_ ₄alkoxy, the alkyl group may be straight chain, branched, cyclic, or a combination thereof. Examples of Ci_₄alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl and cyclobutyl. A particular group of exemplary Ci_₄alkyl groups are methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl. An example of Ci_₄alkoxy is methoxy. The term 'haloCi_₄alkyl' as used herein, includes straight chain, branched chain or cyclic alkyl groups containing 1 to 4 carbon atoms substituted by one or more halo atoms, for example fluoromethyl, difluoromethyl and trifluoromethyl. A particular group of exemplary haloCi_₄ alkyl include methyl and ethyl groups substituted with one to three halo atoms, in particular one to three fluoro atoms, such as trifluoromethyl or 2,2,2-trifluoroethyl. The term 'haloCi_₄alkoxy' as used herein, includes straight chain, branched chain or cyclic alkoxy groups containing 1 to 4 carbon atoms substituted by one or more halo atoms, for example fluoromethoxy, difluoromethoxy and trifluoromethoxy. A particular group of exemplary haloCi_₄ alkyl include methoxy and ethoxy groups substituted with one to three halo atoms, in particular one to three fluoro atoms.

The term '5 or 6 membered saturated or unsaturated heterocycle, with at least one O atom' includes for example dihydrofuran, dihydropyran, furan, pyran, oxazole, isoxazole, oxazine, dioxine, morpholine or 1,3-dioxalane.

It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J. Pharm. Sci. (1977) 66, pp 1-19. 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. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non- stoichiometric forms.

The compounds of formula (I) 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). It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) for use the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required, for use in a method of preventing or treating a disease or disorder where a modulator of Kv3.3 channels is required, and for use in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required. As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable prodrug such as an ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

Suitably, a pharmaceutically acceptable prodrug is formed by functionalising the secondary nitrogen of the hydantoin, for example with a group "L" as illustrated below:

A compound of formula (I) may be functionalised via the secondary nitrogen of the hydantoin with a group L, wherein L is selected from: a) ^■PO(OH)0^" ·Μ⁺, wherein M⁺ is a pharmaceutically acceptable monovalent counterion, b) ^■PO(0^~)₂ ·2Μ⁺,

c) ^■PO(0^~)₂ »D²⁺, wherein D²⁺ is a pharmaceutically acceptable divalent counterion,

d) ^■CH( ^x)-PO(OH)0^" ·Μ⁺, wherein R^x is hydrogen or alkyl,

e) ^■CH(R^x)-PO(0^")₂ ·2Μ⁺,

f) -CH(R^x)-PO(0^~)₂ »D²⁺

g) -S0₃-.M⁺,

h) -CH(R^x)-S0₃ ^"»M⁺, and

i) -CO-CH₂CH₂-C0₂»M⁺. All isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures) are contemplated for the uses and method of the invention. Where additional chiral centres are present in compounds of formula (I), 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.

Isotopically-labelled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature, or in which the proportion of an atom having an atomic mass or mass number found less commonly in nature has been increased (the latter concept being referred to as "isotopic enrichment") are also contemplated for the uses and method of the invention. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as ²H (deuterium), ³H, C, ¹³C, ¹⁴C, ¹⁸F, ¹²³l or ¹²⁵l, which may be naturally occurring or non-naturally occurring isotopes. Compounds of formula (I) and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are contemplated for use for the uses and method of the present invention. Isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H or ¹⁴C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. ³H, and carbon-14, i.e. ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography).

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof. Compounds of formula (I), and salts and solvates thereof wherein W is group (Wc) may be prepared by the general methods outlined in WO2011/069951.

Compounds of formula (I), and salts and solvates thereof wherein W is group (Wb) may be prepared by the general methods outlined in WO2012/076877. Compounds of formula (I), and salts and solvates thereof wherein W is group (Wa) may be prepared by the general methods outlined in WO2012/168710.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates may be of use for the treatment or prophylaxis of a disease or disorder where a modulator of the Kv3.3 channel is required. As used herein, a modulator of Kv3.3 is a compound which alters the properties of this channel, either positively or negatively. Compounds of the invention may be tested in the assay of Biological Example 1 to determine their modulatory properties.

As described in Biological Example 1, the following compounds of formula (I) wherein W is group (Wc) were investigated as Kv3.3 channel modulators in a recombinant cell assay:

5,5-dimethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4- imidazolidinedione (Example 57 of WO2011/069951);

(5 )-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4- imidazolidinedione (Example 64 of WO2011/069951);

(5R)-5-ethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinyl]-2,4- imidazolidinedione (Example 79 of WO2011/069951). As described in Biological Example 1, the following compounds of formula (I) wherein W is group (Wb) were investigated as Kv3.3 channel modulators in a recombinant cell assay:

(5R)-5-ethyl-3-[6-(spiro[l-benzofuran-3,l'-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4- imidazolidinedione (Example 15 of WO2012/076877);

5,5-dimethyl-3-[6-(spiro[l-benzofuran-3,l'-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4- imidazolidinedione (Example 16 of WO2012/076877);

5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxypyrimidin-5- yl]imidazolidine-2,4-dione (Example 58 of WO2012/076877);

5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxy-3- pyridyl]imidazolidine-2,4-dione (Example 70 of WO2012/076877). As described in Biological Example 1, the following compounds of formula (I) wherein W is group (Wa) were investigated as Kv3.3 channel modulators in a recombinant cell assay:

5,5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]pyrimidin-5- yl]imidazolidine-2,4-dione (enantiomer 1) (Example 5 of WO2012/168710);

5,5-dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]pyrimidin-5- yl]imidazolidine-2,4-dione (enantiomer 2) (Example 6 of WO2012/168710);

(5R)-3-[6-[(3,3-dimethyl-lH-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5-methyl-imidazolidine-

2.4- dione (Example 33 of WO2012/168710);

5.5- dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]-3- pyridyl]imidazolidine-2,4-dione (enantiomer 1) (Example 52 of WO2012/168710); 5,5-dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]-3- pyridyl]imidazolidine-2,4-dione (enantiomer 2) (Example 53 of WO2012/168710);

5,5-dimethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2,4- dione (Example 58 of WO2012/168710);

(5 )-3-[6-[(3,3-dimethyl-lH-isobenzofuran-5-yl)oxy]-5-methyl-3-pyridyl]-5-ethyl-5-methyl- imidazolidine-2,4-dione (Example 64 of WO2012/168710);

(5R)-3-[6-[(3,3-dimethyl-lH-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-imidazolidine-2,4-dione (Example 72 of WO2012/168710);

(5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]-3- pyridyl]imidazolidine-2,4-dione (diastereoisomer 1) (Example 73 of WO2012/168710);

(5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]-3- pyridyl]imidazolidine-2,4-dione (diastereoisomer 2) (Example 74 of WO2012/168710);

(5R)-5-ethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2,4- dione (Example 75 of WO2012/168710);

3-[6-[(3-tert-butyl-l,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4- dione (enantiomer 1) (Example 50 of WO2012/168710);

3-[6-[(3-tert-butyl-l,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4- dione (Example 51 of WO2012/168710).

In certain disorders it may be of benefit to utilise a modulator of Kv3.3 or Kv3.1 which demonstrates a particular selectivity profile between the two channels. For example a compound may be selective for modulation of Kv3.3 channels over modulation of Kv3.1 channels demonstrating, for example, at least a 2 fold, 5 fold or 10 fold activity for Kv3.3 channels than for Kv3.1 channels. Alternatively, a compound may be selective for modulation of Kv3.3 channels over modulation of Kv3.2 channels demonstrating, for example, at least a 2 fold, 5 fold or 10 fold activity for Kv3.3 channels than for Kv3.2 channels. In other cases a compound may demonstrate comparable activity between modulation of Kv3.3 and Kv3.1 channels, for example the activity for each channel is less than 2 fold that for the other channel, such as less than 1.5 fold or less than 1.2 fold. In other cases a compound may demonstrate comparable activity between modulation of Kv3.3 and Kv3.2 channels, for example the activity for each channel is less than 2 fold that for the other channel, such as less than 1.5 fold or less than 1.2 fold. In other cases a compound may demonstrate comparable activity between modulation of Kv3.3, Kv3.2 and Kv3.1 channels, for example the activity for each channel is less than 2 fold that for any other channel, such as less than 1.5 fold or less than 1.2 fold. The activity of a compound is suitably quantified by its potency as indicated by an EC₅₀ value.

Diseases or conditions that may be mediated by modulation of Kv3.3 channels may be selected from: - ataxia, in particular spinocerebellar ataxia, especially ataxia associated with R420H, R423H or

F448L mutations;

hearing disorders, including hearing disorders affecting central auditory processing, and tinnitus.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates may be of use for the prophylaxis or treatment of spinocerebellar ataxia, including spinocerebellar ataxia type 13, and in particular spinocerebellar ataxia associated with R420H, R423H or F448L mutations of the Kv3.3 channel. In one embodiment of the invention the disorder to be treated results from a 420H mutation of the Kv3.3 channel. In another embodiment of the invention the disorder to be treated results from a R423H mutation of the Kv3.3 channel. In a further embodiment of the invention the disorder to be treated results from a F448L mutation of the Kv3.3 channel. The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

The term "prophylaxis" is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. Symptoms of spinocerebellar ataxia which may be impacted by treatment or prophylaxis according to the present invention include the loss of motor coordination and the consequential impact on movement, balance and/or speech.

The invention also provides a method of preventing or treating a disease or disorder where a modulator of Kv3.3 channels is required, for example those diseases and disorders mentioned hereinabove, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required, for example those diseases and disorders mentioned hereinabove. The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder where a modulator of Kv3.3 channels is required, for example those diseases and disorders mentioned hereinabove.

For use in therapy the compounds of formula (I) are usually administered as a pharmaceutical composition. Also provided is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates thereof may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly. Other possible routes of administration include intratympanic and intracochlear.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates thereof which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

A liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment the composition is in unit dose form such as a tablet, capsule or ampoule.

The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05mg to lOOOmg, for example from l.Omg to 500mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from lOOmg to 400mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500mg, 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 or months.

Also provided is a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof together with a further therapeutic agent or agents. Also provided is a compound of formula (I), for use in combination with a further therapeutic agent or agents.

When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of combinations may also be administered separately, through the same or different routes. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

For use in therapy the Kv3.3 modulators are usually administered as a pharmaceutical composition for example a composition comprising a Kv3.3 modulator or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier. Examples of such compositions, and methods of administration thereof, which compositions comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, are described hereinabove. Such compositions and methods of administration may also be used for other Kv3.3 modulators or pharmaceutically acceptable salts and/or solvates thereof, in the treatment of spinocerebellar ataxia.

Experimental

The invention is illustrated by the compounds described below.

The following compounds of formula (I) wherein W is group (Wa) may be synthesised according to the procedures described in WO2012/168710: Compound 1 5,5-dimethyl-3-f2-ff3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-ylloxylpyrimidin-5- yllimidazolidine-2.4-dione (enantiomer 1) - Example 5 of WO2012/168710

Compound 2

5,5-dimethyl-3-f2-ff3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-ylloxylpyrimidin-5- yllimidazolidine-2.4-dione (enantiomer 2) - Example 6 of WO2012/168710

Compound 3

(5R)-3-[6-[(3 -dimethyl-lH-isobenzofuran-5-yl)oxyl-3-pyridyll-5-ethyl-5-methyl-imidazolidine-2,4- dione - Example 33 of WO2012/168710

Compound 4

5,5-dimethyl-3-f6-ff3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-ylloxyl-3-pyridyl1imidazolidin 2,4-dione (enantiomer 1) - Example 52 of WO2012/168710

Compound 5

5,5-dimethyl-3-[6-ff3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-ylloxyl-3-pyridyllimidazolidine- 2,4-dione (enantiomer 2) - Example 53 of WO2012/168710

Compound 6 5,5-dimethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cvclobutanel-5-yloxy-3-pyridyl)imidazolidine-2,4-dione

- Exam le 58 of WO2012/168710

Compound 7

(5R)-3-[6-[(3 -dimethyl-lH-isobenzofuran-5-yl)oxy1-5-methyl-3-pyridyl1-5-ethyl-5-methyl- imidazolidine-2,4-dione - Example 64 of WO2012/168710

Compound 8

(5R)-3-[6-[(3 -dimethyl-lH-isobenzofuran-5-yl)oxy1-3-pyridyl1-5-ethyl-imidazolidine-2,4-dione

Example 72 of WO2012/168710

Compound 9

(5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl1oxy1-3-pyridyl1imidazolidin 2,4-dione (diastereoisomer 1) - Example 73 of WO2012/168710

Compound 10

(5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl1oxy1-3-pyridyl1imidazolidin 2,4-dione (diastereoisomer 2) - Example 74 of WO2012/168710

Compound 11 (5R)-5-ethyl-3-(6-spiro[lH-isobenzofuran-3 ' ^

Exam le 75 of WO2012/168710

The following compounds of formula (I) wherein W is group (Wc) may be synthesised according to the procedures described in WO2011/069951:

Compound 12

5,5-Dimethyl-3-r2-({4-methyl-3-f(trifluoromethyl)oxylphenyl)oxy)-5-pyrimidinyll-2.4- imidazolidinedione (Example 57 of WO2011/069951)

Compound 13

(5R)-5-ethyl-5-methyl-3-r2-({4-methyl-3-r(trifluoromethyl)oxylphenyl)oxy)-5-pyrimidinyll-2.4- imidazolidinedione Example 64 of WO2011/069951)

Compound 14 (5R)-5-ethyl-3-r2-({4-methyl-3-r(trifluoromethyl)oxylphenyl)oxy)-5-pyrimidinyll-2,4- imidazolidinedione (Example 79 of WO2011/069951)

The following compounds of formula (I) wherein W is group (Wb) may be synthesised according to the procedures described in WO2012/076877:

Compound 15

(5R)-5-ethyl-3-f6-(spiro[l-benzofuran-3.1'-cvclopropanl-4-yloxy)-3-pyridinyll-2,4-imidazolidinedione

(Example 15 of WO2012/076877)

Compound 16

5,5-dimethyl-3-r6-(spiro[l-benzofuran-3 '-cvclopropanl-4-yloxy)-3-pyridinyll-2.4-imidazoli

(Example 16 of WO2012/076877)

Compound 17

5,5-dimethyl-3-r2-(7-methylspiro[2H-benzofuran-3 '-cvclopropanel-4-yl)oxypyrimidin-5- yllimidazolidine-2.4-dione (Example 58 of WO2012/076877)

Compound 18

5,5-dimethyl-3-r6-(7-methylspiro[2H-benzofuran-3 ' ^

2.4-dione (Example 70 of WO2012/076877)

The following compounds of formula (I) wherein W is group (Wa) may be synthesised according to the procedures described in WO2012/168710:

Compound 19 3-[6-[(3-tert-butyl-1 -dihvdroisobenzofuran-5-yl)oxy1-3-pyridyl1-5,5-dimethyl-imidazolidir^

(enantiomer 1) - Example 50 of WO2012/168710

Compound 20 3-[6-[(3-tert-butyl-1 -dihvdroisobenzofuran-5-yl)oxy1-3-pyridyl1-5,5-dimethyl-imidazolidine-2_^

^Example 51 of WO2012/168710

Biological Example 1

The ability of the compounds of the invention to modulate the voltage-gated potassium channel subtypes Kv3.3/Kv3.2/3.1 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.

Cell biology

To assess compound effects on human Kv3.3 channels (hKv3.3), a stable cell line expressing human Kv3.3 channels was created by transfecting Chinese Hamster Ovary (CHO)-Kl cells with a

pBacMire_KCNC-3 vector. Cells were cultured in DMEM/F12 (Gibco) supplemented with 10% Foetal Bovine Serum (Gibco), IX non-essential amino acids (Invitrogen) and geneticin (G418) 400 microg/mL. Cells were grown and maintained at 37°C in a humidified environment containing 5% C0₂ in air.

To assess compound effects on human Kv3.2 channels (hKv3.2), a stable cell line expressing human Kv3.2 channels (hKv3.2) was created by transfecting CHO-Kl cells with a pCIH5-hKv3.2 vector. Cells were cultured in DMEM/F12 medium supplemented by 10% Foetal Bovine Serum, IX non-essential amino acids (Invitrogen) and 500ug/ml of Hygromycin-B (Invitrogen). Cells were grown and maintained at 37°C in a humidified environment containing 5% C0₂ in air.

To assess compound effects on human Kv3.1 channels (hKv3.1), CHO/Gam/ElA-clone22 alias CGE22 cells were transduced using a hKv3.1 BacMam reagent. This cell line was designed to be an improved CHO-Kl-based host for enhanced recombinant protein expression as compared to wild type CHO-Kl. The cell line was generated following the transduction of CHO-Kl cells with a BacMam virus expressing the Adenovirus-Gaml protein and selection with Geneticin-G418, to generate a stable cell line, CHO/Gam-A3. CHO/Gam-A3 cells were transfected with pCDNA3-ElA-Hygro, followed by hygromycin-B selection and FACS sorting to obtain single-cell clones. BacMam-Luciferase and BacMam-GFP viruses were then used in transient transduction studies to select the clone based on highest BacMam transduction and recombinant protein expression. CGE22 cells were cultured in the same medium used for the hKv3.2 CHO-K1 stable cell line with the addition of 300ug/ml hygromycin-B and 300ug/ml G418. All other conditions were identical to those for hKv3.2 CHO-K1 cells. The day before an experiment 10 million CGE22 cells were plated in a T175 culture flask and the hKv3.1 BacMam reagent (pFBM/human Kv3.1) was added (MOI of 50). Transduced cells were used 24 hours later. Cell preparation for lonWorks Quattro™ experiments

The day of the experiment, cells were removed from the incubator and the culture medium removed. Cells were 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 was tapped to dislodge cells and 10 ml of DPBS containing calcium and magnesium was added to prepare a cell suspension. The cell suspension was then placed into a 15 ml centrifuge tube and centrifuged for 2 min at 1200 rpm. After centrifugation, the supernatant was removed and the cell pellet re-suspended in 4 ml of DPBS containing calcium and magnesium using a 5ml pipette to break up the pellet. Cell suspension volume was then corrected to give a cell concentration for the assay of approximately 3 million cells per ml. All the solutions added to the cells were pre-warmed to 37°C.

Electrophysiology

Experiments were conducted at room temperature using lonWorks Quattro™ planar array

electrophysiology technology (Molecular Devices Corp.) with PatchPlate™ PPC. Stimulation protocols and data acquisition were carried out using a microcomputer (Dell Pentium 4). Planar electrode hole resistances( p) were determined by applying a 10 mV voltage step across each well. These

measurements were performed before cell addition. After cell addition and seal formation, a seal test was performed by applying a voltage step from -80 mV to -70 mV for 160 ms. Following this, amphotericin-B solution was added to the intracellular face of the electrode to achieve intracellular access. Cells were held at -70mV. Leak subtraction was 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. For hKv3.2 and hKv3.1 assays, from the holding potential of -70 mV, a first test pulse to -15 mV was applied for 100 ms and following a further 100 ms at -70 mV, a second pulse to 40 mV was applied for 50 ms. Cells were then maintained for a further 100 ms at -100 mV and then a voltage ramp from -100 mV to 40 mV was applied over 200 ms. For hKv3.3 assays, from the holding potential of -70 mV, a first test pulse to 0 mV was applied for 500 ms and following a further 100 ms at - 70 mV, a second pulse to 40 mV was applied for 200 ms. These longer test pulses were 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. Solutions and drugs

The intracellular solution contained the following (in m/W): K-gluconate 100, KCI 54, MgCI2 3.2, HEPES 5, adjusted to pH 7.3 with KOH. Amphotericin-B solution was 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 was Dulbecco's Phosphate Buffered Saline (DPBS) and contained the following (in m/W): CaCI₂ 0.90, KCI 2.67, KH2P04 1.47, MgCI.6H20 0.493, NaCI 136.9, Na₃P0₄ 8.06, with a pH of 7.4.

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

Data analysis

The recordings were analysed and filtered using both seal resistance (>20 ΜΩ) and peak current amplitude (>500pA 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 were used to determine the positive modulation effect of each compound. Kv3 channel-mediated outward currents were measured determined from the mean amplitude of the current over the final 10ms of the -15mV voltage pulse minus the mean baseline current at -70mV over a 10ms period just prior to the -15mV step. These Kv3 channel currents following addition of the test compound were then compared with the currents recorded prior to compound addition. Data were normalised to the maximum effect of the reference compound (50microM of /V-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro-3-quinolinyl)methyl]-/V'- phenylurea) and to the effect of a vehicle control (0.5% DMSO). The normalised data were analysed using ActivityBase or Excel software. The concentration of compound required to increase currents by 50% of the maximum increase produced by the reference compound (EC50) was 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 were measured for the OmV step, considering the peak current and the decay (inactivation) of the current over the duration of the Omv test pulse (500ms).

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

All of the Example compounds were tested in the above hKv3.1 and hKv3.2 assay measuring potentiation of Kv3.1 or Kv3.2 or Kv3.1 and Kv 3.2 (herein after "Kv3.1 and/or Kv3.2"). Kv3.1 and/or Kv3.2 positive modulators produce in the above assay an increase of whole-cell currents of, on average, at least 20% of the increase observed with 50microM A/-cyclohexyl-/V-[(7,8-dimethyl-2-oxo-l,2-dihydro- 3-quinolinyl)methyl]-/V'-phenylurea. Thus, in the recombinant cell assays of Biological Example 1, all of the Example compounds act as positive modulators.

Compound 13 at 12.5 micrometer produced a mean 113% increase in human v3.3 peak current at DmV (n~4). Compound 18 at 12.5 micromo!ar produced a mean 192% increase in human Kv3.3 peak current at OmV (n=2). A secondary analysis of the data from the hKv3.1, hKv3.2, and hKv3.3 assays described in Biological Example 1 may be used to investigate the effect of the compounds on rate of rise of the current from the start of the depolarising voltage pulses. The magnitude of the effect of a compound can be determined from the time constant (Tau_art) obtained from a non-linear fit, using the equation given below, of the rise in Kv3.1 or Kv3.2 currents following the start of the -15mV depolarising voltage pulse.

Y = (Y0 - Ymax) * exp(-K*X) + Ymax where:

Y0 is the current value at the start of the depolarising voltage pulse;

Ymax is the plateau current; K is the rate constant, and Tau_art is the activation time constant, which is the reciprocal of K.

Similarly, the effect of the compounds on the time taken for Kv3.1, Kv3.2 or Kv3.3 currents to decay on closing of the channels at the end of the -15mV depolarising voltage pulses can also be investigated. In this latter case, the magnitude of the effect of a compound on channel closing can be determined from the time constant (Tau_deact) of a non-linear fit of the decay of the current ("tail current") immediately following the end of the depolarising voltage pulse.

Kv3.1, Kv3.2, and Kv3.3 channels must activate and deactivate very rapidly in order to allow neurons to fire actions potentials at high frequency (Rudy and McBain, 2001, Trends in Neurosciences 24, 517-526). Slowing of activation is likely to delay the onset of action potential repolarisation; slowing of deactivation could lead to hyperpolarising currents that reduce the excitability of the neuron and delay the time before the neuron can fire a further action potential. Together these two slowing effects on channel activation and deactivation are likely to lead to a reduction rather than a facilitation of the neurons ability to fire at high frequencies. Thus compounds that have this slowing effect on the Kv3.1 and/or Kv3.2, and/or Kv3.3 channels will effectively behave as negative modulators of the channels, leading to a slowing of neuronal firing. This latter effect has been shown for certain of the compounds disclosed in WO2011/069951, where marked increases in Tau_art can be observed from recordings made from "fast-firing" interneurons in the cortex of rat brain, using electrophysiological techniques, in vitro. The addition of the relevant compounds reduces the ability of the neurons to fire in response to trains of depolarising pulses at 300Hz.

Therefore, although compounds of the invention may be identified act as positive modulators in the recombinant cell assay of Biological Example 1, those compounds which markedly increase the value of Tau_act reduce the ability of neurons in native tissues to fire at high frequency.

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. 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. 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 following claims:

Claims

A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, for use in the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required:

wherein:

W is group (Wa), group (Wb) or group (Wc):

wherein:

R₂ is H, Ci_₄alkyl, C₃.₅ spiro carbocyclyl, haloCi_₄alkyl or halo;

R₃ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or R₃ is absent;

Ri3 is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or Ri₃ is absent;

Ri₄ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or ₁₄ is absent;

X is CH or N;

Y is CR₁₅ or N;

Ri₅ is H or Ci_₄alkyl;

R₄ is Ci_-4 alkyl;

R₅ is H or Ci_-4 alkyl;

or R₄ and R₅ can be fused to form C₃.₄ spiro carbocyclyl;

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 R_u may be attached to the same or a different ring atom. A method for the prophylaxis or treatment of a disease or disorder where a modulator channels is required, by administering to a subject a compound of formula (I) or a

pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof:

wherein:

W is group (Wa), group (Wb) or group (Wc):

wherein:

R₂ is H, Ci_₄alkyl, C₃.₅ spiro carbocyclyl, haloCi_₄alkyl or halo;

R₃ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or R₃ is absent;

Ri3 is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or Ri₃ is absent;

Ri₄ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or ₁₄ is absent;

X is CH or N;

Y is CR₁₅ or N;

Ri₅ is H or Ci_₄alkyl;

R₄ is Ci_-4 alkyl;

R₅ is H or Ci_-4 alkyl;

or R₄ and R₅ can be fused to form C₃.₄ spiro carbocyclyl;

A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, for use in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder where a modulator of Kv3.3 channels is required:

wherein:

W is group (Wa), group (Wb) or group (Wc):

wherein:

R₂ is H, Ci_₄alkyl, C₃.₅ spiro carbocyclyl, haloCi_₄alkyl or halo;

R₃ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or R₃ is absent;

Ri3 is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or Ri₃ is absent;

Ri₄ is H, Ci_₄alkyl, haloCi_₄alkyl, halo; or ₁₄ is absent;

X is CH or N;

Y is CR₁₅ or N;

Ri₅ is H or Ci_₄alkyl;

R₄ is C_1-4 alkyl;

R₅ is H or Ci_-4 alkyl;

or R₄ and R₅ can be fused to form C₃.₄ spiro carbocyclyl;

4. The compound, method or use of any one of claims 1 to 3, wherein the disease or disorder where a modulator of Kv3.3 is required is spinocerebellar ataxia.

5. The compound, method or use of claim 4, wherein the spinocerebellar ataxia is spinocerebellar ataxia type 13.

6. The compound, method or use of claim 4, wherein the spinocerebellar ataxia results from a R420H mutation of the Kv3.3 channel.

7. The compound, method or use of claim 4, wherein the spinocerebellar ataxia results from a R423H mutation of the Kv3.3 channel. 8. The compound, method or use of claim 4, wherein the spinocerebellar ataxia results from a F448L mutation of the Kv3.3 channel.

9. The compound, method or use of any one of claims 1 to 8, for use in the prophylaxis of a disease or disorder where a modulator of Kv3.3 channels is required.

10. The compound, method or use of any one of claims 1 to 8, for use in the treatment of a disease or disorder where a modulator of Kv3.3 channels is required.

11. The compound, method or use of any one of claims 1 to 10, wherein W is group (Wa).

12. The compound, method or use of any one of claims 1 to 10, wherein W is group (Wb).

13. The compound, method or use according to any one of claims 1 to 12, wherein ring A is:

14. The compound, method or use according to any one of claims 1 to 13 wherein i is H.

15. The compound, method or use according to any one of claims 1 to 13 wherein Ri is methyl.

16. The compound, method or use according to any one of claims 1 to 15 wherein R₂ is H, Ci_₄alkyl, C₃.₅spiro carbocyclyl, or haloCi_₄alkyl. 17. The compound, method or use according to claim 16, wherein R₂ is methyl, ethyl, tert-butyl, cyclopropyl or C₃-₅spiro carbocyclyl.

18. The compound, method or use according to any one of claims 1 to 17 wherein R₃ is H, Ci_₄alkyl, haloCi_₄alkyl or halo.

19. The compound, method or use according to claim 18, wherein R₃ is H, methyl, ethyl or trifluoromethyl.

20. The compound, method or use according to one of claims 1 to 17, wherein R₃ is H or is absent.

21. The compound, method or use according to any one of claims 1 to 20 wherein i₃ is H, methyl, trifluoromethyl or is absent.

22. The compound, method or use according to claim 21, wherein i₃ is H or absent.

23. The compound, method or use according to any of claims 1 to 22 wherein ₁₄ is H, methyl, trifluoromethyl or is absent.

24. The compound, method or use according to claim 23, wherein R_u is H or is absent.

25. The compound, method or use according to any one of claims 1 to 4, wherein W is group (Wc).

26. The compound, method or use according to claim 25, wherein Ri₆ is halo, Ci_₄alkyl, Ci_₄alkoxy, halo-Ci_₄alkoxy or cyano and Ri₇ is H, halo, Ci_₄alkyl and Ci_₄alkoxy; with the proviso that when Ri₇ is H, Ri6 is not in the para position.

27. The compound, method or use according to claim 25 or claim 26, wherein Ri₆ is halo, Ci_₄alkyl or Ci-4 alkoxy.

28. The compound, method or use according to claim 25 wherein Ri₆ is Ci_₄alkyl, Ci_₄alkoxy, or halo- Ci_₄alkoxy; and Ri₇ is H, cyano or alkyl. 29. The compound, method or use according to claim 25, wherein Ri₆ is propyl, butyl, methoxy, propoxy, or trifluoromethoxy; and Ri₇ is H, cyano or methyl.

30. The compound, method or use according to any one of claims 25 to 29, wherein one of Ri₆ and Ri₇ is in the para position and the remaining one of Ri₆ or R₁₇ is in the meta position.

31. The compound, method or use according to any one of claims 25 to 29, wherein one of Ri₆ and Ri₇ is in the meta position and the remaining one of Ri₆ or R₁₇ is in the ortho position.

32. The compound, method or use according to any one of claims 1 to 31, wherein X is CH.

33. The compound, method or use according to any one of claims 1 to 31, wherein X is N.

34. The compound, method or use according to any one of claims 1 to 33, wherein Y is N.

35 The compound, method or use according to any one of claims 1 to 33, wherein Y is CRi₅ and Ri₅ is H.

36. The compound, method or use according to any of claims 1 to 33, wherein Y is CRi₅ and Ri₅ is methyl.

37. The compound, method or use according to any one of claims 1 to 36, wherein R₄ is methyl or ethyl. 38. The compound, method or use according to claim 37, wherein R₅ methyl.

39. The compound, method or use according to any one of claims 1 to 38, wherein R₅ is H.

40. The compound, method or use according to any one of claims 1 to 39, wherein R₄ and R₅ have the stereochemical arrangement:

41. The compound, method or use according to any one of claims 1 to 10, wherein W is group (Wc) and the compound of formula (I) is selected from the group consisting of:

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

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

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

42. The compound, method or use according to any one of claims 1 to 10, wherein W is group (Wb) and the compound of formula (I) is selected from the group consisting of:

(5R)-5-ethyl-3-[6-(spiro[l-benzofuran-3,l'-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione; 5,5-dimethyl-3-[6-(spiro[l-benzofuran-3,l'-cyclopropan]-4-yloxy)-3-pyridinyl]-2,4-imidazolidinedione; 5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxypyrimidin-5- yl]imidazolidine-2,4-dione; and

5,5-dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-

2.4- dione.

43. The compound, method or use according to any one of claims 1 to 10, wherein W is group (Wa) and the compound of formula (I) is selected from the group consisting of:

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

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

5,5-dimethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyridyl)imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-lH-isobenzofuran-5-yl)oxy]-5-methyl-3-pyridyl]-5-ethyl-5-methyl-imidazolidine- 2,4-dione;

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

(5R)-5-ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-lH-isobenzofuran-5-yl]oxy]-3-pyridyl]imidazolidin dione (diastereoisomer 2);

(5R)-5-ethyl-3-(6-spiro[lH-isobenzofuran-3,l'-cyclobutane]-5-yloxy-3-pyrid^ 3- [6-[(3-tert-butyl-l,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dim

(enantiomer 1); and

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

44. A compound, method or use according to any one of claims 1 to 43, wherein the compound of formula (I) is a prodrug and is functionalised at the secondary nitrogen of the hydantoin, as illustrated below:

wherein L is selected from:

PO(OH)0^" ·Μ⁺, wherein M⁺ is a pharmaceutically acceptable monovalent counterion,

PO(0^~)₂ ·2Μ⁺,

c) -PO(0^~)₂ »D²⁺, wherein D²⁺ is a pharmaceutically acceptable divalent counterion,

d) -CH(R^x)-PO(OH)0^" ·Μ⁺, wherein R^x is hydrogen or alkyl,

e) -CH(R^x)-PO(0^")₂ ·2Μ⁺,

f) -CH(R^x)-PO(0^")₂ »D²⁺

g) -S0₃-»M⁺,

h) -CH(R^x)-S0₃ ^"»M⁺, and

i) -CO-CH₂CH₂-C0₂»M⁺.