JP2023523501A - KV3 modulator - Google Patents

Abstract

Compounds of formula (I) and related embodiments: TIFF2023523501000099.tif29170. [Selection diagram] None

Description

(Technical field)
The present invention relates to novel compounds, pharmaceutical compositions containing them, and therapeutics, particularly those in the prevention or treatment of hearing disorders, including deafness and tinnitus, and schizophrenia, substance abuse disorders, pain, and fragile X syndrome. regarding the use of

(Background of the Invention)
The Kv3 voltage-gated potassium channel family has four members, Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Kv3 channels are activated to voltages more positive than -20 mV by plasma membrane depolarization. Moreover, the channel deactivates rapidly upon membrane repolarization. These biophysical properties ensure that the channels open and initiate repolarization towards the peak of the depolarizing phase of neuronal action potentials. Rapid arrest of action potentials mediated by Kv3 channels allows neurons to recover more rapidly and reach subthreshold membrane potentials from which further action potentials can be triggered. Consequently, the presence of Kv3 channels in certain neurons contributes to their ability to fire at high frequencies (Rudy et al. 2001). Kv3.1-3 subtypes predominate in the central nervous system, while Kv3.4 channels are also found in skeletal muscle and sympathetic neurons (Weiser et al., 1994). Kv3.1-3 channel subtypes are distributed by interneuron subclasses in cortical and hippocampal brain regions (e.g., Chow et al. 1999; Martina et al. 1998; McDonald et al. 2006; Chang et al. 2007); Differentially expressed in the thalamus (e.g. Kasten et al. 2007), in the cerebellum (e.g. Sacco et al. 2006; Puente et al. 2010), and in the auditory brain stem nuclei (Li et al. 2001) .

Tetraethylammonium (TEA) has been shown to inhibit the channel at low millimolar concentrations (Rudy et al. 2001) and is a blood-depressing substance from the sea anemone, Anemonia sulcata. (BDS) toxins (Diochot et al. 1998) have been shown to selectively inhibit Kv3 channels with high affinity (Yeung et al. 2005).

Kv3 channels are key determinants of cerebellar function, a brain region important for motor control (Joho et al. 2009). Characterization of mice lacking one or more of the Kv3 subtypes shows that the absence of Kv3.1 results in increased locomotor activity, altered electroencephalographic activity, and fragmented sleep patterns. (Joho et al. 1999). Deletion of Kv3.2 results in reduced seizure threshold and altered cortical EEG activity (Lau et al. 2000). Deletion of Kv3.3 is associated with mild ataxia and movement disorders (McMahon et al. 2004). Double deletion of Kv3.1 and Kv3.3 results in a severe phenotype characterized by spontaneous seizures, ataxia, and increased susceptibility to the effects of ethanol (Espinosa et al. 2001; Espinosa et al. Reference 2008). Spontaneous mutations in the Kv3.1 gene (KCNC1) cause progressive myoclonic epilepsy (Muona et al. 2014). Mutations in the Kv3.3 gene (KCNC3) in humans have been associated with a form of spinocerebellar ataxia (SCA13) (Figueroa et al. 2010).

Bipolar disorder, schizophrenia, anxiety, and epilepsy are serious disorders of the central nervous system associated with impaired function of inhibitory interneurons and gamma-aminobutyric acid (GABA) transmission (Reynolds et al. 2004; Benes et al. 2008; Brambilla et al. 2003; Aroniadou-Anderjaska et al. 2007; Ben-Ari 2006). Parvalbumin-positive basket cells expressing Kv3 channels in the cortex and hippocampus play an important role in generating feedback inhibition within local circuits (Markram et al. 2004). The relative predominance of excitatory synaptic inputs over inhibitory inputs to glutamatergic pyramidal neurons in these circuits suggests that rapid firing of interneurons supplying inhibitory inputs may result in balanced inhibition. essential to ensure Moreover, precise timing of inhibitory inputs is required to maintain network synchrony, for example, in the generation of gamma-frequency field potential oscillations that have been associated with cognitive function (Fisahn et al. 2005; Engel et al. 2005). 2001). In particular, a decrease in gamma oscillations has been observed in patients with schizophrenia (Spencer et al. 2004), and evidence suggests that patients with schizophrenia who had not taken antipsychotics for at least 2 months prior to death had died. Although Kv3.2 expression is not suggested to be reduced in the patient's dorsolateral prefrontal cortex, Kv3.1 expression is suggested (Yanagi et al. 2014). Positive modulators of Kv3 channels can therefore be expected to enhance the firing capacity of specific groups of fast-firing neurons in the brain. These effects can be beneficial in disorders associated with abnormal activity of these neuronal groups. In addition, Kv3.2 channels have been shown to be expressed by neurons of the suprachiasmatic nucleus (SCN), the major circadian pacemaker in the CNS (Schulz et al. 2009).

The Kv3 family of voltage-gated ion channels are expressed at high levels in the auditory brainstem nuclei (Li et al. 2001), where they are the neurons that transmit auditory information from the cochlea to higher brain regions. enables high-speed ignition of It has been proposed that phosphorylation of Kv3.1 and Kv3.3 channels in auditory brainstem neurons contributes to rapid physiological adaptation to noise levels, which may play a protective role during noise exposure ( Desai et al. 2008; Song et al. 2005). Loss of Kv3.1 channel expression in central auditory neurons was observed in deaf mice (von Hehn et al. 2004); (Jung et al. 2005), and loss of Kv3 channel function can also occur as a result of noise-trauma-induced hearing loss (Pilati et al. 2012). Furthermore, pathological plasticity of the auditory brainstem network appears to contribute to the symptoms suffered by many people with different types of hearing loss. Recent studies have shown that regulation of Kv3.1 channel function and expression plays a major role in controlling auditory neuron excitability (Kaczmarek et al. 2005; Anderson et al. 2018; Glait 2018; Olsen et al. 2018; Chambers et al. 2017), suggesting that this mechanism may explain some of the plastic changes that give rise to tinnitus. Tinnitus can occur after noise-induced deafness as a result of adaptive changes in central auditory pathways from the brainstem to the auditory cortex (Roberts et al. 2010). Kv3.1 and/or Kv3.2 channels are expressed in many of these circuits and contribute to the function of GABAergic inhibitory interneurons that can regulate the function of these circuits.

Kv3.1 and/or Kv3.2 modulators are known to be useful in treating pain (WO2017/098254). In the broadest sense, pain can be classified into acute pain and chronic pain. Acute pain is defined as pain that is self-limiting and generally requires no more than a few weeks of treatment and includes, for example, postoperative pain or acute musculoskeletal pain such as fractures (U.S. Food and Drug Administration 2014). Chronic pain can be defined as either pain that persists for more than 1 month or pain that persists for more than 3 months after the initial trauma has healed. Chronic pain often has no clear cause and is often accompanied by many other health problems such as fatigue, depression, insomnia, mood swings, and decreased exercise.

Chronic pain can be subdivided into the following groups: neuropathic pain, chronic musculoskeletal pain, and various chronic pains. Neuropathic pain is usually associated with tissue injury and is initiated by injury to the nervous system (peripheral and/or central nervous system) such as amputation, stroke, diabetes, or multiple sclerosis. or caused. Chronic musculoskeletal pain can be a symptom of diseases such as osteoarthritis and chronic low back pain, and can follow injury to muscle tissue and trauma to certain areas, such as fractures, sprains, and dislocations. Chronic pain encompasses all other types of long-term pain and includes non-neuropathic pain conditions such as cancer pain and fibromyalgia, as well as headaches and tendonitis.

Chronic pain is a highly heterogeneous condition that remains one of the most troublesome and difficult to manage clinical manifestations (McCarberg et al. 2008; Woolf 2010; Finnerup et al. 2015). Despite years of research and drug development, little progress has been made in identifying treatments that can rival opioids in efficacy without significant side effects and addiction risks. Voltage-gated ion channels have been identified as important targets for the management of certain pain indications, especially neuropathic pain conditions. Furthermore, genetic mutations in specific ion channels have been linked to several chronic pain disorders (Bennett et al. 2014). Examples of voltage-gated ion channels under investigation as pharmaceutical targets include: sodium channels (particularly NaV1.7) - Sun et al. 2014; Dib-Hajj et al. 2013; N-type calcium channels - Zamponi et al. 2015; Kv7 potassium channel--Devulder, 2010; Wickenden et al., 2009; and SLACK--Lu et al., 2015.

The hypothesis underlying these approaches is that chronic pain states affect peripheral sensory neurons, particularly those involved in the transmission of painful sensory stimuli, such as the C-fibers of the dorsal root ganglion and specific circuits within the spinal cord. (Baranauskas et al. 1998; Cervero 2009; Woolf et al. 2011; Baron et al. 2013). Animal models of chronic neuropathic and inflammatory pain provide major support for this hypothesis, although causality has not yet been proven (Cervero 2009).

Drugs that target hyperexcitability, such as sodium channel blockers (eg, CNV1014802, lamotrigine, carbamazepine, and local anesthetics), positive modulators of Kv7 (eg, flupertine, and retigabine), and N-type calcium. Channel modulators such as gabapentin, which interacts with the α2δ subunit of N-type calcium channels, and ziconitide, derived from cone snail toxin, show efficacy in models of inflammatory and/or neuropathic pain. . However, the evidence for clinical efficacy, such as balancing efficacy and increased burden of side effects on the central nervous system, is confounded among these drugs. The discrepancy between efficacy in animal models and that in humans is likely due to a variety of factors, notably the drug concentrations achievable in humans (due to poor tolerability) and the heterogeneity of human pain states. Gender is likely to be the main cause. For pain indications, there is also a need to identify targets that can achieve pain relief with reduced tolerance or tachyphylaxis and with reduced abuse liability and/or dependence risk.

Therefore, improving the pharmacological management of pain should provide good efficacy with reduced side effect burden, reduced tolerance or tachyphylaxis, and reduced abuse liability and/or dependence risk. focuses on possible mechanisms.

In recent years, Kv3.4 channels have become attractive targets for the treatment of chronic pain. Kv3.4 channels are expressed on neurons of the dorsal root ganglion (Ritter et al. 2012; Chien et al. 2007), where Kv3.4 channels are predominantly expressed on sensory C-fibers. (Chien et al. 2007). Kv3 channels are also expressed by a specific subset of neurons in the spinal cord. Specifically, Kv3.1b (Deuchars et al. 2001; Brooke et al. 2002), Kv3.3 (Brooke et al. 2006), and Kv3.4 subunits (Brooke et al. 2004) are always have been identified in the rodent spinal cord, although they are not related to circuits involved in the processing of Kv3 channels likely shape the firing properties of spinal cord neurons, including motor neurons.

A recent study also showed that DRG nociceptor-expressed Kv3.4 channels have a significant impact on glutamatergic synaptic transmission (Muqeem et al. 2018). Animal model data suggest downregulation of Kv3.4 channel surface expression in DRG neurons after spinal cord injury, associated with hypersensitivity to painful stimuli (Ritter et al. 2015; Zemel et al. 2017; Zemel et al. 2018). Similarly, it has been observed that there is downregulation of Kv3.4 expression in rodent DRG after spinal cord ligation (Chien et al. 2007). This latter study also showed that intrathecal administration of antisense oligonucleotides to rats to inhibit Kv3.4 expression resulted in hypersensitivity to mechanical stimuli. It is suggested that Kv3.4 channel inactivation may be affected by protein kinase C-dependent phosphorylation of the channel, and that this physiological mechanism may explain the firing of DRG neurons in response to painful stimuli. It has been shown that it may allow changing properties (Ritter et al. 2012). These studies suggest a causal relationship between the appearance of mechanical allodynia and reduced Kv3.4 channel expression or function. Evaluation of Kv3.1, Kv3.2, or Kv3.3 expression in SC or DRG neurons was not performed in any of these studies, and expression of these two subtypes on DRG neurons was Not explicitly demonstrated (although, as mentioned above, they are abundant in certain regions of the spinal cord). The in vivo studies reported above provide a rationale for Kv3.4 modulation as a novel approach to the treatment of certain neuropathic pain conditions.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are severe neurodegenerative disorders associated with accumulation of a protein, alpha-synuclein, in the Lewy bodies, leading to loss of connectivity and neuronal cell death. Symptoms of DLB include progressive agnosia, particularly difficulty with planning and attention. Visual hallucinations are also common and occur in about 60% of patients. PD is initially associated with movement disorders primarily due to loss of dopamine neurons. Although there are currently no studies directly linking Kv3 channels to DLB or PD, the location and role of Kv3 channels, particularly Kv3.1, in cortical and basal ganglia circuitry is likely to be explored by modulators of these channels, either alone or It suggests that current treatments, such as either acetylcholinesterase inhibitors for DLB or in combination with L-DOPA for PD, may improve symptoms of DLB or PD.

Patent Applications Nos. WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994, WO2013/182850, WO2017/103604, WO2018/020263, and WO2018/109484 discloses compounds that are modulators of Kv3.1 and Kv3.2. Additionally, the utility of such compounds has been demonstrated in animal models of seizures, hyperactivity, sleep disorders, psychiatric disorders, hearing disorders, and bipolar disorders.

Patent application WO2013/182851 discloses modulation of Kv3.3 channels by certain compounds.

Patent application WO2013/175211 states that modulation of Kv3.1, Kv3.2 and/or Kv3.3 channels is beneficial in preventing or limiting the establishment of permanent hearing loss resulting from acute noise exposure. Disclose that it has been found that Such prophylactic benefit may be observed even after administration of the Kv3.1, Kv3.2 and/or Kv3.3 modulator is discontinued.

Patent application WO2017/098254 discloses that modulation of Kv3.1, Kv3.2, and/or Kv3.3 channels is beneficial in the prevention or treatment of pain, particularly neuropathic or inflammatory pain. do.

の「メタ-連結された」ピリジニル化合物を開示する。 Patent application WO2019/222816 is said to be modulators of Kv3.1 and/or Kv3.2 channels, the general formula:

Disclosed are "meta-linked" pyridinyl compounds of

の「メタ-連結された」ジアジン及びトリアジン化合物を開示する。 Patent application WO2020/000065 is said to be modulators of Kv3.1 and/or Kv3.2 channels, the general formula:

discloses "meta-linked" diazine and triazine compounds.

There remains a specific need for further modulators of Kv3.1, Kv3.2 and/or Kv3.3, in particular modulators of Kv3.1 and/or Kv3.2. Such modulators may have increased in vivo potency, channel selectivity, improved safety profile, or desired pharmacokinetic parameters, such as increased brain availability to reduce the dose required for therapeutic effect in vivo. and/or may exhibit low clearance rates. Alternative modulators may offer benefits by having different metabolites than known modulators. Compounds with balanced Kv3.1, Kv3.2 and/or Kv3.3 modulatory properties, eg, compounds that modulate Kv3.1 and Kv3.2 to the same or similar extent, may be desirable. Compounds with different modulatory effects on Kv3.1, Kv3.2 and/or Kv3.3 channels, e.g. altering the kinetics of channel gating or channel deactivation, and in vivo for specific therapeutic efficacy There is also a need to identify compounds that can behave as negative modulators of the channel at .

(式中:
R₁は、H又はメチルであり;
R₂及びR₃は双方ともメチルであるか、又はR₂及びR₃は、それらが結合している炭素原子と一緒になって、スピロシクロプロピル環であり;
R₄は、メチル又はエチルであり;
R₅は、H又はメチルであり;
或いはR₄及びR₅は、それらが結合している炭素原子と一緒になって、C₃-C₄スピロカルボシクリルを形成する)
の化合物を提供する。 (Outline of invention)
The present invention provides a compound of formula (I):

(in the formula:
R ₁ is H or methyl;
_R2 and _R3 are both methyl, or _R2 and _R3 together with the carbon atom to which they are attached are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
_R5 is H or methyl;
Alternatively _R4 and _R5 together with the carbon atom to which they are attached form a _C3 - _C4 spirocarbocyclyl)
provides a compound of

The compounds of formula (I) may be provided in the form of their salts and/or solvates. Suitably the compounds of formula (I) may be provided in the form of their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof. In one embodiment of the invention, compounds of formula (I) are provided in the form of pharmaceutically acceptable salts.

The compounds of formula (I) are used as medicaments, in particular as medicaments for use in the prevention or treatment of hearing disorders, including deafness and tinnitus, and schizophrenia, substance abuse disorders, pain, or fragile X syndrome. obtain.

Further provided are methods for the prevention or treatment of hearing disorders, including deafness and tinnitus, and hearing disorders, including deafness and tinnitus, as well as schizophrenia, substance abuse disorders, pain, or fragile X syndrome.

The compounds of formula (I) may be used in the manufacture of a medicament for the prevention or treatment of hearing disorders, including deafness and tinnitus, as well as schizophrenia, substance abuse disorders, pain, or fragile X syndrome.

Also provided are pharmaceutical compositions containing a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

Also provided are processes for preparing compounds of formula (I) and novel intermediates for use in preparing compounds of formula (I).

Further provided are prodrug derivatives of the compounds of formula (I).

(式中:
R₁は、H又はメチルであり;
R₂及びR₃は双方ともメチルであるか、又はR₂及びR₃は、それらが結合している炭素原子と一緒になって、スピロシクロプロピル環であり;
R₄は、メチル又はエチルであり;
R₅は、H又はメチルであり;
或いはR₄及びR₅は、それらが結合している炭素原子と一緒になって、C₃-C₄スピロカルボシクリルを形成する)
の化合物、又はそれらの医薬として許容し得る塩及び/もしくは溶媒和物及び/もしくはそれらの誘導体を提供する。 (detailed description of the invention)
The present invention provides a compound of formula (I):

(in the formula:
R ₁ is H or methyl;
_R2 and _R3 are both methyl, or _R2 and _R3 together with the carbon atom to which they are attached are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
_R5 is H or methyl;
Alternatively _R4 and _R5 together with the carbon atom to which they are attached form a _C3 - _C4 spirocarbocyclyl)
or pharmaceutically acceptable salts and/or solvates and/or derivatives thereof.

The embodiments described below with respect to the relative stereochemistry and properties of the groups, including R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , will be used where appropriate to the circumstances (i.e., where chemically reasonable). ) are independently and fully combinable with each other and are envisaged to form further inventive embodiments. Such embodiments include intermediates that may be useful in the synthesis of compounds of formula (I), such as formula (II), formula (IV), formula (VI), formula (VII), and formula The same applies to compounds of (XVI).

Compounds of formula (I) may optionally be provided in the form of pharmaceutically acceptable salts and/or solvates. In one embodiment of the invention, compounds of formula (I) are provided in the form of pharmaceutically acceptable salts. In a second embodiment of the invention, compounds of formula (I) are provided in the form of pharmaceutically acceptable solvates. In a third embodiment of the invention the compounds of formula (I) are not in the form of salts or solvates.

In one embodiment, R ₁ is H. In a second embodiment, R ₁ is methyl.

が形成されるような、スピロシクロプロピルである。 In one embodiment, _R2 is methyl and _R3 is methyl. In another embodiment, _R2 and _R3 are the following moieties:

is spirocyclopropyl such that is formed.

In one embodiment, _R4 is methyl. In a second embodiment, _R4 is ethyl.

In one embodiment, _R5 is hydrogen. In a second embodiment, _R5 is methyl.

In one embodiment, _R4 and _R5 are the same (ie, methyl).

を有し得る。 In embodiments where R ₄ and R ₅ are different, they have the following stereochemical configurations:

can have

In this embodiment, for example, _R4 is methyl _and R5 is H, _R4 is ethyl and R5 is H, _{or R4} is ethyl. and R ₅ is methyl.

を有し得る。 Alternatively, in embodiments in which R ₄ and R ₅ are different, they have the following stereochemical configurations:

can have

In this embodiment, for example, _R4 is methyl _and R5 is H, _R4 is ethyl and R5 is H, _{or R4} is ethyl. and R ₅ is methyl.

In one embodiment, _R4 and _R5 together with the carbon atom to which they are attached form spirocyclopropyl.

In another embodiment, _R4 and _R5 together with the carbon atom to which they are attached form spirocyclobutyl.

In one embodiment, the compound of formula (I) is:
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione;
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione ;
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 ,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione ;
5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- Dione;
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione or pharmaceutically acceptable salts and/or solvates thereof and/or derivatives thereof.

In one embodiment, compounds of formula (I) are:
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione or pharmaceutically acceptable salts and/or solvates thereof, and/or derivatives thereof.

In one embodiment, compounds of formula (I) are:
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione or pharmaceutically acceptable salts and/or solvates thereof, and/or derivatives thereof.

When said compound contains a C _1-3 alkyl group, whether alone or forming part of a larger group, said alkyl group may be linear, branched or cyclic. obtain. Examples of C _1-3 alkyl are methyl, ethyl, n-propyl, isopropyl and cyclopropyl. References to "propyl" include n-propyl, isopropyl and cyclopropyl.

The term "halo" or "halogen" as used herein refers to a fluorine, chlorine, bromine or iodine atom. Particular examples of halo are fluorine, chlorine and bromine, for example chlorine or bromine.

二級炭素が、該環状環内の3～4個の炭素原子のうちの1つとなるように、スピロ中心を介して該二級炭素に結合している。 The term “C _3-4 spirocarbocyclyl” as used herein means a cyclic ring system containing 3 or 4 carbon atoms, i.e. a cyclopropyl or cyclobutyl group, wherein the cyclic The ring system is as follows:

A secondary carbon is attached to the secondary carbon through a spiro center such that the secondary carbon is one of the 3-4 carbon atoms in the cyclic ring.

It will be appreciated that for use in medicine the salts of the compounds of formula (I) must 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 such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids such as succinic acid. , maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Non-pharmaceutically acceptable salts may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.

Some of the compounds of formula (I) are capable of forming acid addition salts with one or more equivalents of acids. 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 amorphous form, and, if crystalline, may optionally be solvated, eg as the hydrate. This invention includes within its scope stoichiometric solvates (eg hydrates) as well as compounds containing variable amounts of solvent (eg water).

It will be understood that the present invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of this invention.

As used herein, a "pharmaceutically acceptable derivative" is a compound of formula (I) that can (directly or indirectly) provide a compound of formula (I) or an active metabolite or residue thereof upon administration to a recipient. It includes any pharmaceutically acceptable ester of a compound of (I) or a salt of such an ester.

(式中、R₄及びR₅は、上述の通りである)。 Pharmaceutically acceptable prodrugs can be formed, for example, by functionalizing the secondary nitrogen of the hydantoin with the group "L" as shown below:

(wherein R ₄ and R ₅ are as described above).

In one embodiment of the invention, the compound of formula (I) is functionalized via the secondary nitrogen of the hydantoin with the group L, wherein L is:
a) —PO(OH)O ⁻ ·M ⁺ , where M ⁺ is a pharmaceutically acceptable monovalent counterion,
b) -PO(O ^- ) ₂ 2M ⁺ ,
c) —PO(O ⁻ ) ₂ ·D ²⁺ (wherein D ²⁺ is a pharmaceutically acceptable divalent counterion),
d) —CH(R ^x )—PO(OH)O ⁻ ·M ⁺ , wherein R ^x is hydrogen or C _1-3 alkyl,
e) —CH(R ^X )—PO(O ⁻ ) ₂ 2M ⁺ ,
f)-CH( ^Rx )-PO( ^O- ) _2.D2 ⁺ ,
g) _-SO3 ^- .M ⁺ ,
h) -CH( ^Rx ) _-SO3 ^- .M ⁺ , and
i)-CO _{- CH2CH2} - _CO2.M ⁺
is selected from

The present invention includes all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric, and optical isomeric forms, and mixtures thereof (e.g., racemic mixtures). should be understood. Where additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. Different isomeric forms can be separated or resolved from one another by conventional methods, or one isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

The present disclosure provides that (i) all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (herein referred to as the "natural isotopic form"). or (ii) a form in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from that of the atom that predominates in nature. Including all isotopic forms of the compounds of the invention provided herein, whether in any (referred to herein as "unnatural variant isotopic forms"). . It is understood that atoms can occur naturally in mixtures of mass numbers. The term "non-naturally occurring isotopic form" also means that the proportion of atoms of a given atomic number with mass numbers not commonly found in nature (referred to herein as "rare isotopes") is , an increase compared to the naturally occurring proportion, e.g., >20%, >50%, >75%, >90%, >95%, or >99% in number of atoms of that atomic number levels (the latter embodiments are referred to as "isotopically enriched variant forms"). The term "non-naturally occurring variant isotopic form" also includes embodiments in which the proportion of rare isotopes is reduced relative to the proportion that is naturally occurring. Isotopic forms can include radioactive forms (ie, they incorporate a radioactive isotope) and non-radioactive forms. The radioactive form will typically be an isotopically enriched variant form.

Non-naturally occurring isotopic forms of a compound thus include one or more artificial or rare isotopes at one or more atoms, such as deuterium ( ² H or D), carbon-11 ( ¹¹ C). , carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C), nitrogen-13 ( 13 N), nitrogen-15 ( ¹⁵ N), ^oxygen -15 ( ¹⁵ O), oxygen-17 ( ¹⁷ O), oxygen -18 ( ¹⁸ O), phosphorus-32 ( ³² P), sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), fluorine-18 ( ¹⁸ F), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), etc., or may contain an increased proportion of such isotopes compared to the proportion that predominates in nature at one or more atoms.

Non-naturally occurring isotope forms, including radioisotopes, can be used, for example, in drug and/or substrate tissue distribution studies. The radioisotopes tritium, ie, ³ H, and carbon-14, ie, ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Non-naturally occurring variant isotopic forms incorporating deuterium, i.e., ² H or D, offer certain therapeutic advantages due to higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. can be preferred in some situations. In addition, non-naturally occurring variant isotope forms may be prepared incorporating positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N to provide positron emission for investigating substrate receptor occupancy. It can be useful in emission tissue distribution (PET) studies.

In one embodiment, the compounds of the invention are provided in their natural isotopic form.

In one embodiment, compounds of the invention are provided in non-naturally occurring isotopic forms. In specific embodiments, said non-naturally occurring isotopic forms have deuterium (i.e., ² H or D) incorporated in the chemical structure where hydrogen is designated at one or more atoms of the compound of the invention. It is in the form of In one embodiment, the atoms of the compounds of the invention are in non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the invention are in radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-naturally occurring isotopic form is a pharmaceutically acceptable form.

In one embodiment, compounds of the invention are provided in which a single atom of the compound is present in a non-naturally occurring variant isotopic form. In another embodiment, compounds of the invention are provided in which two or more atoms are present in non-naturally occurring variant isotopic forms.

Non-naturally occurring isotopic variant forms are generally described in the prior art known to those skilled in the art or the processes described herein, such as the examples for preparing the naturally occurring isotopic forms attached herein. can be prepared by processes similar to those in Thus, non-naturally occurring isotopic variant forms can be prepared by substituting appropriate isotopic variant (or labeling) reagents for the common reagents employed in the examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions, they are each in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably It will be readily understood that the is preferably provided at least 85% pure, especially at least 98% pure (% is on a weight to weight basis). Impure preparations of compounds may be used to prepare the purer forms used in pharmaceutical compositions.

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

In general, the compounds of formula (I) can be prepared according to organic synthetic techniques known to those skilled in the art, as well as by the representative methods, examples and modifications thereof described below.

Patent Applications Nos. WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994, WO2013/182850, WO2017/103604, WO2018/020263 , and WO2018/109484 provide methods for the synthesis of intermediates that may be useful in the preparation of compounds of the invention.

(general synthesis scheme)
The following schemes detail synthetic routes to the compounds of the present invention and intermediates in the synthesis of such compounds. In the schemes below, reactive groups can be protected with protecting groups and deprotected by established techniques well known to those skilled in the art.

Compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined below. In the following description, the groups R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the meanings already defined for the compounds of formula (I) unless stated otherwise.

(工程(i):)
式(I)の化合物を、金属を触媒とするクロスカップリング反応によって調製することができる。本反応においては、通常X=Brである式(II)のハロ-ピラジン誘導体及び式(III)のヒダントインを、酸化銅(I)などの金属触媒の存在下、適当な溶媒中で、例えば、N,N-ジメチルアセトアミド中で、慣用の加熱又はマイクロ波加熱を行って反応させる。 (Scheme 1a)

(Step (i):)
Compounds of formula (I) can be prepared by a metal-catalyzed cross-coupling reaction. In this reaction, a halo-pyrazine derivative of formula (II), where X=Br, and a hydantoin of formula (III) are combined in the presence of a metal catalyst such as copper(I) oxide in a suitable solvent, for example Reaction in N,N-dimethylacetamide with conventional or microwave heating.

R₄及びR₅が、Hではない式(I)の化合物は、芳香族求核置換によって調製することができる。本反応において、通常Y=Clである式(IV)のハロ-ピラジン誘導体及び式(V)のフェノールを、炭酸カリウムなどの適当な塩基の存在下、適当な溶媒中、例えば、N,N-ジメチルホルムアミド中又はアセトニトリル中で、慣用の加熱又はマイクロ波加熱を行って反応させる。 (Scheme 1b)

Compounds of formula (I) in which R ₄ and R ₅ are not H can be prepared by nucleophilic aromatic substitution. In this reaction, a halo-pyrazine derivative of formula (IV), usually Y=Cl, and a phenol of formula (V) are combined in the presence of a suitable base such as potassium carbonate in a suitable solvent, for example N,N- React in dimethylformamide or in acetonitrile with conventional or microwave heating.

(工程(ii):)
式(I)の化合物は、適当な溶媒、例えば、ジクロロメタン中での、カルボニル化剤、例えば、優先的に同じ溶媒中に予め希釈され、かつ2回目は0℃で添加されるトリホスゲンを用いる、適当な塩基、例えば、トリエチルアミンの存在下での式(VI)の化合物の環化によって調製することができる。或いは、式(I)の化合物は、酢酸エチルなどの適当な溶媒中で、トリエチルアミン又はDIPEAなどの塩基の存在下、カルボニルジイミダゾールなどのカルボニル化剤を用いる式(VI)の化合物の環化によって調製することができる。 (Scheme 1c)

(Step (ii):)
A compound of formula (I) is prepared in a suitable solvent, such as dichloromethane, with a carbonylating agent, such as triphosgene, preferentially pre-diluted in the same solvent and added a second time at 0°C. It may be prepared by cyclization of a compound of formula (VI) in the presence of a suitable base such as triethylamine. Alternatively, compounds of formula (I) can be prepared by cyclization of compounds of formula (VI) using a carbonylating agent such as carbonyldiimidazole in the presence of a base such as triethylamine or DIPEA in a suitable solvent such as ethyl acetate. can be prepared.

(Step (i):)
Compounds of formula (VI) can be prepared by deprotection of compounds of formula (VII). wherein PG is a protecting group, suitably the protecting group is BOC, and BOC is protected under acidic conditions, eg TFA, in a suitable solvent, eg dichloromethane, at about 0° C. to room temperature. can be removed.

(工程(ii):)
式(I)の化合物は、メタノールなどの適当な溶媒中で、0℃～室温の範囲の温度で、式(XVII)のウレア及びナトリウムメトキシドなどの適当な塩基の反応によって調製することができる。 (Scheme 1d)

(Step (ii):)
Compounds of formula (I) can be prepared by reaction of urea of formula (XVII) and a suitable base such as sodium methoxide in a suitable solvent such as methanol at temperatures ranging from 0°C to room temperature. .

(Step (i):)
The urea of formula (XVII) can be prepared in a suitable solvent such as dichloromethane or ethyl acetate with a carbonylating agent such as triphosgene preferentially prediluted in the same solvent with a suitable base such as triethylamine or It can be prepared by reaction of an aniline of formula (XVI) and an aminoester of formula (IX) (such as the hydrochloride salt) in the presence of diisopropylethylamine at temperatures ranging from 0°C to room temperature.

(工程(ii):)
式(IV)の化合物は、メタノールなどの適当な溶媒中で、0℃～室温の範囲の温度で、式(VIII)のウレア及びナトリウムメトキシドなどの適当な塩基の反応によって調製することができる。 (Scheme 2a)

(Step (ii):)
Compounds of formula (IV) can be prepared by reaction of urea of formula (VIII) and a suitable base such as sodium methoxide in a suitable solvent such as methanol at temperatures ranging from 0°C to room temperature. .

(Step (i):)
The urea of formula (VIII) can be prepared in a suitable solvent such as dichloromethane or ethyl acetate with a carbonylating agent such as triphosgene preferentially prediluted in the same solvent with a suitable base such as triethylamine or Reaction of a commercially available halo-pyrazine derivative of formula (X), typically Y=Cl, and an amino ester of formula (IX) (such as the hydrochloride salt) in the presence of diisopropylethylamine at temperatures ranging from 0°C to room temperature. can be prepared by

(工程(ii):)
式(IV)の化合物は、適当な溶媒、例えば、ジクロロメタン中での、カルボニル化剤、例えば、優先的に同じ溶媒中に予め希釈され、かつ2回目は0℃で添加されるトリホスゲンを用いる、適当な塩基、例えば、トリエチルアミンの存在下での式(XI)の化合物の環化によって調製することができる。 (Scheme 2b)

(Step (ii):)
Compounds of formula (IV) are prepared in a suitable solvent, such as dichloromethane, with a carbonylating agent, such as triphosgene, preferentially pre-diluted in the same solvent and added a second time at 0°C. It may be prepared by cyclization of a compound of formula (XI) in the presence of a suitable base such as triethylamine.

(Step (i):)
Compounds of formula (XI) are generally prepared from an aniline of formula (X) where Y=Cl and an amino acid of formula (XII) (as the free base or hydrochloride salt) in the presence of a coupling agent such as ethyl acetate , acetonitrile, or mixtures thereof in a suitable solvent.

(工程(ii):)
式(IV)の化合物は、金属を触媒とするクロスカップリング反応によって調製することができる。本反応においては、通常X=Brである式(II)のハロ-ピラジン誘導体及び式(XIII)のアミドを、トリス(ジベンジリデンアセトン)ジパラジウム(0)などの金属触媒、ジシクロヘキシル-[2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスファン(XPhos)などの適当なリガンド、及び炭酸セシウムなどの適当な塩基の存在下で、適当な溶媒中で、例えば、1,4-ジオキサン中で、慣用の加熱又はマイクロ波加熱を行って反応させる。或いは、本反応においては、通常X=Brである式(II)のハロ-ピラジン誘導体及び式(XIII)のアミドを、ヨウ化銅(I)などの金属触媒、N,N'-ジメチルエタン-1,2-ジアミンなどの適当なリガンド、及び炭酸カリウムなどの適当な塩基の存在下で、適当な溶媒中で、例えば、1-ブタノール中で、慣用の加熱又はマイクロ波加熱を行って反応させる。式(IV)の化合物の調製のためのさらに別の選択肢は、通常X=Brである式(II)のハロ-ピラジン誘導体及び式(XIII)のアミドを、酢酸パラジウム(II)などの金属触媒、Xantphosなどの適当なリガンド、及び炭酸セシウムなどの適当な塩基の存在下、適当な溶媒中で、例えば、1,4-ジオキサン中で、慣用の加熱又はマイクロ波加熱を行って反応させることである。 (Scheme 3)

(Step (ii):)
Compounds of formula (IV) can be prepared by a metal-catalyzed cross-coupling reaction. In this reaction, the halo-pyrazine derivative of formula (II), where X=Br, and the amide of formula (XIII) are usually combined with a metal catalyst such as tris(dibenzylideneacetone)dipalladium(0), dicyclohexyl-[2- In the presence of a suitable ligand such as (2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) and a suitable base such as cesium carbonate in a suitable solvent, for example in 1,4-dioxane. Then, conventional heating or microwave heating is applied to react. Alternatively, in this reaction, the halo-pyrazine derivative of formula (II), where X=Br, and the amide of formula (XIII) are combined with a metal catalyst such as copper(I) iodide, N,N'-dimethylethane- Reaction in the presence of a suitable ligand such as 1,2-diamine and a suitable base such as potassium carbonate in a suitable solvent, e.g. 1-butanol, with conventional or microwave heating. . Yet another option for the preparation of compounds of formula (IV) is to react the halo-pyrazine derivative of formula (II), usually X=Br, and the amide of formula (XIII) with a metal catalyst such as palladium(II) acetate. , in the presence of a suitable ligand such as Xantphos, and a suitable base such as cesium carbonate, in a suitable solvent, for example 1,4-dioxane, with conventional or microwave heating. be.

(Step (i):)
Compounds of formula (XIII) are prepared from N-protected (e.g. BOC) amino acids of formula (XIV) and amines such as hexamethyldisilazane in the presence of a base such as DIPEA and a coupling agent such as HATU or TBTU. can be prepared by amide coupling in a solvent such as N,N-dimethylformamide, below.

(工程(i):)
通常X=Brである式(II)の化合物は、芳香族求核置換によって調製することができる。本反応においては、通常X=Z=Brである式(XV)のハロ-ピラジン誘導体及び式(V)のフェノールを、炭酸カリウムなどの塩基の存在下、適当な溶媒中で、例えば、N,N-ジメチルホルムアミド中で、慣用の加熱又はマイクロ波加熱を行って反応させる。 (Scheme 4)

(Step (i):)
Compounds of formula (II), where usually X=Br, can be prepared by nucleophilic aromatic substitution. In this reaction, the halo-pyrazine derivative of formula (XV) where X=Z=Br and the phenol of formula (V) are combined in the presence of a base such as potassium carbonate in a suitable solvent, for example N, Reaction in N-dimethylformamide with conventional or microwave heating.

(工程(i):)
式(XVI)のアニリンは、金属を触媒とするクロスカップリング反応によって調製することができる。本反応においては、通常Z=Brである式(XVIII)のハロ-ピラジン誘導体及び式(V)のフェノールを、ヨウ化銅(I)などの金属触媒、ピコリン酸のような適当なリガンドの存在下、適当な溶媒中で、例えば、N,N-ジメチルホルムアミド又はN,N-ジメチルアセトアミド中で、慣用の加熱又はマイクロ波加熱を行って反応させる、任意に、炭酸カリウム又は炭酸セシウムなどの適当な塩基を使用することができる。 (Scheme 5)

(Step (i):)
Anilines of formula (XVI) can be prepared by a metal-catalyzed cross-coupling reaction. In this reaction, the halo-pyrazine derivative of formula (XVIII), where Z=Br, and the phenol of formula (V) are usually combined in the presence of a metal catalyst such as copper(I) iodide, a suitable ligand such as picolinic acid. under conventional heating or microwave heating in a suitable solvent, for example N,N-dimethylformamide or N,N-dimethylacetamide, optionally potassium carbonate or cesium carbonate. any base can be used.

上記スキーム6において、PG₁及びPG₂は、適当な保護基を表す。工程(i)～工程(iii)におけるPG₁は、工程(iv)～(vii)におけるPG₁と異なっていてもよい。適当な保護基には、ベンジル、テトラヒドロピラニル、又はメチルオキシメチルが含まれる。好適には、PG₂は、PG₁と同じであり、例えば、双方ともベンジルである。 (Scheme 6)

In Scheme 6 above, PG ₁ and PG ₂ represent suitable protecting groups. PG ₁ in steps (i)-(iii) may be different from PG ₁ in steps (iv)-(vii). Suitable protecting groups include benzyl, tetrahydropyranyl or methyloxymethyl. Suitably PG ₂ is the same as PG ₁ , eg both are benzyl.

(Scheme description where PG ₁ and PG ₂ are both benzyl)
(Step (vii):)
The phenol of formula (V) can be obtained from the benzylated compound of formula (XIX) by deprotection, for example with a metal catalyst such as palladium-carbon and a hydrogen atmosphere or a hydrogen source such as ammonium formate, followed by a suitable reaction such as ethanol or methanol. It can be prepared by using a solvent at a temperature in the range of room temperature to reflux.

(Step (vi):)
The benzylated compound of formula (XIX) is prepared from the diol of formula (XX) using a base such as potassium tert-butoxide and a suitable solvent such as dimethyl carbonate at temperatures ranging from room temperature to reflux. be able to.

(Process (v):)
Diols of formula (XX) can be prepared from lactones of formula (XXI) using a reducing agent such as lithium aluminum hydride in a suitable solvent such as THF at temperatures ranging from 0°C to room temperature.

(Step (iv):)
Lactones of formula (XXI) can be prepared from phenols of formula (XXII) in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile or THF or mixtures thereof at temperatures ranging from room temperature to reflux. It can be prepared using benzylating agents such as bromides.

(Step (iii):)
Phenols of formula (XXII) can be prepared from dibenzylated esters of formula (XXIII) where Rx is a suitable alkyl group such as methyl or ethyl in a suitable solvent such as ethanol or methanol at room temperature. It can be prepared using a metal catalyst such as palladium-carbon and a hydrogen atmosphere or a hydrogen source such as ammonium formate at temperatures in the flux range.

(Step (ii):)
Dibenzylated esters of formula (XXIII), wherein Rx is a suitable alkyl group such as methyl or ethyl, are preformed from dibenzylated bromo-derivatives of formula (XXIV), wherein Rx is methyl or An organozinc derivative of formula (XXVI) with a suitable alkyl group such as ethyl is reacted with THF or DMF or mixtures thereof in the presence of a metal catalyst complex such as bis(tri-tert-butylphosphine)palladium(0). in a suitable solvent at a temperature ranging from room temperature to reflux.

(Step (i):)
The dibenzylated bromo derivative of formula (XXIV) can be obtained from the commercially available derivative of formula (XXV) in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile or THF or acetone or mixtures thereof at room temperature. can be prepared using benzylating agents such as benzyl bromide at temperatures ranging from to reflux.

When PG ₁ and/or PG ₂ are protecting groups such as tetrahydropyranyl or methyloxymethyl, normal protection/deprotection conditions apply:
The conditions for the protection of phenol with tetrahydropyranyl are the dihydrogenation of phenol in the presence of a catalyst such as C:Py.p-MePhSO ₃ H in a suitable solvent such as dichloromethane at temperatures ranging from 0°C to reflux. Including reactions with -2H-pyran.
- Cleavage conditions for the tetrahydropyranyl protecting group from the phenol are in the presence of an acid such as sulfuric acid or p- _MePhSO3H or HCl in a suitable solvent such as methanol or ethanol at temperatures ranging from 0°C to reflux. including the reaction of a THP-protected phenol at .
The conditions for protection of phenol with methyloxymethyl are phenol with chloromethyl methyl ether in the presence of a base such as potassium carbonate in a suitable solvent such as tetrahydrofuran or acetonitrile at temperatures ranging from 0°C to reflux. Including reactions.
- Cleavage conditions for the methyloxymethyl protecting group from the phenol are in the presence of an acid such as sulfuric acid or p- _MePhSO3H or HCl in a suitable solvent such as methanol or ethanol at temperatures ranging from 0°C to reflux. involving the reaction of a MOM-protected phenol.

(工程(i):)
Rxが、メチル又はエチルなどの適当なアルキル性基である式(XXVI)の有機亜鉛誘導体は、THFなどの適当な溶媒中で、1,2-ジブロモエタン及びクロロトリメチルシランの存在下、亜鉛(0)の還流懸濁液に、市販の式(XXVII)のブロモエステルを添加することにより調製することができる。 (Scheme 7)

(Step (i):)
An organozinc derivative of formula (XXVI), wherein Rx is a suitable alkyl group such as methyl or ethyl, can be treated with zinc ( It can be prepared by adding a commercially available bromoester of formula (XXVII) to the refluxing suspension of 0).

(Process of the present invention)
Further aspects of the invention provide processes for the preparation of compounds of formula (I) and their derivatives, as well as processes for preparing intermediates in the synthesis of compounds of formula (I).

The process of the invention is described above and includes any individual step of a multi-step scheme.

(Intermediate)
The invention also relates to novel intermediates in the synthesis of compounds of formula (I). Such novel intermediates include formula (II), formula (IV), formula (VI), formula (VII), formula (VIII), formula (XI), formula (XVI), and formula (XVII) contains compounds of Also of interest are the intermediates of formulas (XIX)-(XXIV). Salts, including pharmaceutically acceptable salts, of such intermediates are also provided by the present invention.

(式中、R₁、R₂、及びR₃は、既に定義された通りであり、Xは、ハロ(Brなど)である);
-式(IV)の化合物:

(式中、R₁、R₂、及びR₃は、既に定義された通りであり、Yは、ハロ(Clなど)である);
-式(VI)の化合物:

(式中、R₁、R₂、R₃、R₄、及びR₅は、既に定義された通りである);
-式(VII)の化合物:

(式中、R₁、R₂、R₃、R₄、及びR₅は、既に定義された通りであり、PGは、BOCなどの適当な保護基である);
-式(XVI)の化合物:

(式中、R₁、R₂、及びR₃は、既に定義された通りである)
を含む。 Accordingly, the intermediates of the invention are:
- compounds of formula (II):

(wherein R ₁ , R ₂ and R ₃ are as previously defined and X is halo (such as Br));
- compounds of formula (IV):

(wherein R ₁ , R ₂ and R ₃ are as previously defined and Y is halo (such as Cl));
- compounds of formula (VI):

(wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as previously defined);
- compounds of formula (VII):

(wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as previously defined and PG is a suitable protecting group such as BOC);
- compounds of formula (XVI):

(wherein R ₁ , R ₂ and R ₃ are as previously defined)
including.

(Kv3.1, Kv3.2, and/or Kv3.3 regulation)
The compounds of formula (I) of the present invention are modulators of Kv3.1. Compounds of formula (I) may also be modulators of Kv3.2 and/or Kv3.3. Compounds of the invention may be tested in the assay of Biological Example 1 to determine their modulatory properties on Kv3.1 and/or Kv3.2 and/or Kv3.3 channels.

A "modulator" as used herein is at least It refers to compounds that are capable of producing a 10% enhancement, preferably at least a 20% enhancement.

The terms "Kv3.1, Kv3.2 and/or Kv3.3" should be construed to mean the same as "Kv3.1 and/or Kv3.2 and/or Kv3.3". Yes, sometimes referred to as "Kv3.1/Kv3.2/Kv3.3".

In one embodiment, said modulator has the ability to provide at least a 10% enhancement, preferably at least a 20% enhancement of whole-cell current mediated by recombinantly expressed human Kv3.1 channels in mammalian cells. have. Suitably the pEC ₅₀ of the modulator is in the range of 4-7 (eg 5-6.5).

In one embodiment, said modulator has the ability to provide at least a 10% enhancement, preferably at least a 20% enhancement, of whole-cell current mediated by recombinantly expressed human Kv3.2 channels in mammalian cells. have. Suitably the pEC ₅₀ of the modulator is in the range of 4-7 (eg 5-6.5).

In one embodiment, said modulator has the ability to provide at least a 10% enhancement, preferably at least a 20% enhancement, of the whole-cell current mediated by recombinantly expressed human Kv3.3 channels in mammalian cells. have. Suitably the pEC ₅₀ of the modulator is in the range of 4-7 (eg 5-6.5).

In another embodiment, said modulator enhances whole cell currents mediated by human Kv3.1 and Kv3.2 channels recombinantly expressed in mammalian cells by at least 10%, preferably by at least 20%. Has the ability to provide augmentation.

In another embodiment, said modulator enhances whole cell currents mediated by human Kv3.1 and Kv3.3 channels recombinantly expressed in mammalian cells by at least 10%, preferably by at least 20%. Has the ability to provide augmentation.

In another embodiment, said modulator enhances whole cell currents mediated by human Kv3.2 and Kv3.3 channels recombinantly expressed in mammalian cells by at least 10%, preferably by at least 20%. Has the ability to provide augmentation.

In a further embodiment, said modulator enhances whole cell currents mediated by human Kv3.1, Kv3.2 and Kv3.3 channels recombinantly expressed in mammalian cells by at least 10%, preferably Has the ability to provide an enhancement of at least 20%.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives are required modulators of Kv3.1 or Kv3.2 channels or Kv3.1 and Kv3.2 channels It may be useful in the treatment or prevention of the disease or disorder referred to. As used herein, modulators of Kv3.1 or Kv3.2 or Kv3.1 and Kv3.2 are compounds that alter the properties of these channels, either positively or negatively. In certain embodiments of the invention, compounds of formula (I) are positive modulators. Compounds of the invention can be tested in the assay of Biological Example 1 to determine their modulatory properties.

In one embodiment of the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof are more effective in modulating Kv3.2 channels than in modulating Kv3.2 channels. Selective for 1-channel regulation. By "selective" is meant that the compound exhibits, for example, at least 2-fold, 5-fold, or 10-fold greater activity against Kv3.1 channels than against Kv3.2 channels. A compound's activity is preferably quantified by its potency as indicated by an Ec50 value.

In another embodiment of the invention, the compounds of formula (I), or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof, modulate Kv3.2 channels rather than modulate Kv3.1 channels. is selective to the regulation of Again, by "selective" is meant that the compound exhibits, for example, at least 2-fold, 5-fold or 10-fold greater activity against Kv3.2 channels than against Kv3.1 channels. .

In a particular embodiment of the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof are capable of Comparable activity, eg activity on one channel less than twice that on the other channel, eg less than 1.5 times or less than 1.2 times.

In certain disorders it is beneficial to utilize modulators of Kv3.3 or Kv3.1, or Kv3.3 and Kv3.1, which exhibit a particular selectivity profile between the two channels. there is a possibility. For example, the compound may be selective for modulating Kv3.3 channels over modulating Kv3.1 channels, e.g., at least 2-fold for Kv3.3 channels over Kv3.1 channels, It can show 5-fold or 10-fold activity.

In another embodiment of the invention, the compounds of formula (I), or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof, modulate Kv3.1 channels rather than modulate Kv3.3 channels. is selective to the regulation of Again, by "selective" is meant that the compound exhibits, for example, at least 2-fold, 5-fold or 10-fold greater activity against Kv3.1 channels than against Kv3.3 channels. .

In certain embodiments of the invention, compounds may exhibit comparable activity between modulating Kv3.3 and Kv3.1 channels, e.g., activity of each channel is less than twice that of the other channel , for example less than 1.5 times or less than 1.2 times.

In certain disorders, it is beneficial to utilize modulators of Kv3.3 or Kv3.2, or Kv3.3 and Kv3.2, which exhibit a particular selectivity profile between the two channels. There is a possibility. The compound may be selective for modulating Kv3.3 channels over modulating Kv3.2 channels, e.g., at least 2-fold, 5-fold, or It can show 10-fold more activity.

In another embodiment of the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof inhibit Kv3.2 channels rather than modulate Kv3.3 channels. is selective to the regulation of Again, by "selective" is meant that the compound exhibits, for example, at least 2-fold, 5-fold, or 10-fold greater activity against Kv3.2 channels than Kv3.3 channels.

In another specific embodiment, the compound may exhibit comparable activity between modulating Kv3.3 and Kv3.2 channels, e.g., activity on each channel is less than twice that on the other channel, e.g. Less than 1.5 times or less than 1.2 times.

In still further specific embodiments of the invention, compounds may exhibit comparable activity between modulating Kv3.3, Kv3.2 and Kv3.1 channels, e.g. channel, for example less than 1.5 times or less than 1.2 times. A compound's activity is suitably quantified by its potency as indicated by an EC50 value.

(Method of treatment)
The present invention also provides for use in the treatment or prevention of diseases or disorders in which modulators of Kv3.1, Kv3.2 and/or Kv3.3 are indicated, such as the diseases and disorders referred to herein below. or pharmaceutically acceptable salts and/or solvates (eg salts) and/or derivatives thereof of formula (I) for

The present invention is a method of treating or preventing diseases or disorders for which modulators of Kv3.1, Kv3.2, and/or Kv3.3 are required, such as the diseases and disorders referred to herein below. administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g., salt) and/or derivative thereof to a subject in need thereof, provide a way.

The present invention also provides for the treatment or prevention of diseases or disorders in which modulators of Kv3.1, Kv3.2, and/or Kv3.3 are required, such as the diseases and disorders referred to herein below. Provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (eg salt) and/or derivative thereof, in the manufacture of a medicament.

In one embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or a derivative thereof for use as a pharmaceutical.

The term "treatment" or "treating" as used herein includes management, alleviation, reduction or modulation of a disease state or its symptoms.

The term "prevention" is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an afflicted subject; It is not limited to complete prophylaxis.

Preferably, the subject is human.

Diseases or disorders that may be mediated by modulation of Kv3.1 and/or Kv3.2 channels may be selected from the list below. The numbers in parentheses after the disorders listed below refer to the "Diagnostic and Statistical Manual of Mental Disorders", Part 4, published by the American Psychiatric Association. It refers to the classification code in the edition (DSM-IV) and/or the International Classification of Diseases, 10th edition (ICD-10).

In one embodiment of the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives are used for hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and disturbances of loudness perception, Meniere's disease, balance disorders, and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, selected from the group consisting of autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (such as neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Parkinson's disease It may be useful in treating or preventing disease or disorders.

In one embodiment of the invention, the compounds of formula (I) or pharmaceutically acceptable salts and/or solvates and/or derivatives thereof are used to treat hearing disorders including deafness and tinnitus, schizophrenia, substance abuse. Disorders, pain (such as neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Parkinson's disease. be.

In one embodiment of the invention, the compounds of formula (I) or pharmaceutically acceptable salts and/or solvates and/or derivatives thereof are selected from the group consisting of fragile X, Rett's disorder and Alzheimer's disease. may be useful in the treatment or prevention of any disease or disorder.

Deafness, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders, and inner ear disorders, impulsivity Control disorder, personality disorder, attention deficit hyperactivity disorder, autism spectrum disorder, eating disorder, cognitive disorder, ataxia, pain (neuropathic pain, inflammatory pain, various pains, etc.), Lewy body type A method for the prevention or treatment of a disease or disorder selected from the group consisting of dementia and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical thereof The method is provided comprising administering an acceptable salt and/or solvate (eg, salt) and/or derivative.

The invention also provides for hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders, and disorders of the inner ear, Impulse control disorder, personality disorder, attention deficit hyperactivity disorder, autism spectrum disorder, eating disorder, cognitive disorder, ataxia, pain (neuropathic pain, inflammatory pain, various pains, etc.), Lewy small A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the production of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of somatic dementia and Parkinson's disease Use of the products (eg salts) and/or derivatives thereof is provided.

In a particular embodiment of the invention, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or for use in treating or preventing hearing disorders. Derivatives thereof are provided. Hearing impairment includes auditory neuropathy, auditory processing disorder, sudden deafness, noise-induced deafness, substance-induced deafness, and hearing loss in adults over 60, over 65, over 70, or over 75 years of age. Hearing loss, including loss (presbycusis), as well as tinnitus.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful for the treatment or prevention of Meniere's disease, balance disorders and disorders of the inner ear. could be.

In a particular embodiment of the invention, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or for use in the treatment or prevention of schizophrenia. Alternatively, derivatives thereof are provided. Schizophrenia includes subtypes paranoid (295.30), disorganized (295.10), catatonic (295.20), atypical (295.90), and residual (295.60); schizophreniform disorder (295.40) schizoaffective disorder (295.70), including subtypes bipolar and depressive; delusional disorder, including subtypes erotomania, megalomaniac, jealousy, victimizing, somatic, mixed, and unspecified (297.1); short-term psychotic disorders (298.8); shared psychotic disorders (297.3); 293.81) and subtypes with hallucinations (293.82); and psychotic disorders not specified (298.9).

Compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may be used to treat depression, including major depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. State and mood disorders; depressive disorders including major depressive disorder, dysthymic disorder (300.4), depressive disorder not specified (311); bipolar I disorder, bipolar II disorder (recurrent with hypomanic episodes) Bipolar disorders, including major depressive episodes (296.89), cyclothymic disorder (301.13), and bipolar disorder not specified (296.80); subtypes with depressive features, subtypes with major depressive-like episodes other mood disorders, including mood disorders caused by systemic medical conditions (293.83), including subtypes with manic features, and subtypes with mixed features; substance-induced mood disorders (subtypes with depressive features); , subtypes with manic features, and subtypes with mixed features), and mood disorders not specified (296.90); may be useful in the treatment or prevention of seasonal affective disorder.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful in treating epilepsy (including but not limited to localization associated epilepsy, generalized epilepsy, seizures associated with Lennox-Gastaut syndrome, seizures as a complication of a disease or condition (e.g., encephalopathy, phenylketonuria, juvenile Gaucher disease, Lundborg progressive seizures associated with myoclonic epilepsy, stroke, head injury, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infections, etc.), essential tremor, restless limbs syndrome, partial and Generalized seizures (including tonic seizures, clonic seizures, tonic-clonic seizures, atonic seizures, myoclonic seizures, and absence seizures), secondary generalized seizures, temporal lobe epilepsy, absence epilepsy (childhood, (including juvenile, myoclonic, photo- and pattern-induced), severe epileptic encephalopathy (including hypoxia-related and Rasmussen's syndrome), febrile convulsions, persistent partial epilepsy, progressive myoclonic epilepsy ( post-traumatic seizures/epilepsy including those associated with head injury), simple reflex epilepsy (including photosensive, somatosensory and proprioceptive, audiogenic metabolic disorders commonly associated with epilepsy, e.g., pyridoxine-dependent epilepsy, Menkes' trichotillomania, Krabbe's disease, epilepsy caused by alcohol and drug abuse (e.g., cocaine), epilepsy Treatment of associated cortical malformations (e.g., bicortical syndrome or subcortical zonal heterotopic gray matter), chromosomal anomalies associated with seizures or epilepsy, e.g., partial monosomy (15Q)/Angelman syndrome) or May be useful in prevention.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may be used to treat substance use disorders such as substance dependence, substance craving and substance abuse. substance-induced disorders, e.g., substance addiction, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced Anxiety disorders, substance-induced sexual dysfunction, substance-induced sleep disorders, and hallucinogenic persistent perceptual disorders (flashbacks); alcohol-related disorders such as alcohol dependence (303.90), alcohol abuse (305.00), alcoholism ( 303.00), alcohol withdrawal (291.81), alcoholic delirium, alcohol withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent amnestic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced Sexual anxiety disorders, alcohol-induced sexual dysfunction, alcohol-induced sleep disorders, and alcohol-related disorders not specified (291.9); amphetamine (or amphetamine-like)-related disorders, e.g., amphetamine dependence (304.40), amphetamine abuse (305.70) , amphetamine addiction (292.89), amphetamine withdrawal (292.0), amphetamine toxic delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and amphetamine-related disorders unspecified (292.9); caffeine-related disorders such as caffeine addiction (305.90), caffeine-induced anxiety disorders, caffeine-induced sleep disorders, and caffeine-related disorders unspecified (292.9) cannabis-related disorders, e.g., cannabis dependence (304.30), cannabis abuse (305.20), cannabis addiction (292.89), cannabis-addicted delirium, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder, and cannabis-related disorders not specified (292.9); cocaine-related disorders, e.g., cocaine dependence (304.20), cocaine abuse (305.60), cocaine addiction (292.89), cocaine withdrawal (292.0), cocaine addictive delirium, cocaine-induced psychotic disorder, cocaine-induced mood disorders, cocaine-induced anxiety disorders, cocaine-induced sexual dysfunction, cocaine-induced sleep disorders, and cocaine-related disorders not specified (292.9); 305.30), hallucinogen intoxication (292.89), hallucinogen persistent paresthesia (flashbacks) (292.89), hallucinogen-induced delirium, hallucinogen-induced psychotic disorder, hallucinogen-induced mood disorder, hallucinogen-induced anxiety Disorders, and hallucinogen-related disorders not specified (292.9); inhalant-related disorders, e.g., inhalant dependence (304.60), inhalant abuse (305.90), inhalant poisoning (292.89), inhalant toxic delirium, inhalant Induced persistent dementia, inhalant-induced psychotic disorder, inhalant-induced mood disorder, inhalant-induced anxiety disorder, and inhalant-related disorders not specified (292.9); nicotine-related disorders, e.g., nicotine dependence (305.1), nicotine withdrawal (292.0), and nicotine-related disorders not specified (292.9); opioid-related disorders, e.g., opioid dependence (304.00), opioid abuse (305.50), opioid addiction (292.89), opioid withdrawal (292.0) , opioid-addicted delirium, opioid-induced psychotic disorder, opioid-induced mood disorder, opioid-induced sexual dysfunction, opioid-induced sleep disorder, and opioid-related disorders not specified (292.9); lysine-like)-related disorders, e.g., phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine intoxication (292.89), phencyclidine-toxic delirium, phencyclidine-induced psychotic disorder, phencyclidine Lysine-induced mood disorders, phencyclidine-induced anxiety disorders, and phencyclidine-related disorders not specified (292.9); Sedative-, hypnotic-, or anxiolytic-related disorders, e.g., sedative-, hypnotic-, or anxiolytic Dependence (304.10), Sedative, hypnotic, or anxiolytic drug abuse (305.40), Sedative, hypnotic, or anxiolytic drug addiction (292.89), Sedative, hypnotic, or anxiolytic withdrawal (292.0), Sedative, Hypnotics or anxiolytics Addictive delirium, sedatives, hypnotics, or anxiolytics Withdrawal delirium, sedatives, hypnotics, or anxiolytics Persistent amnestic disorder , sedative, hypnotic, or anxiolytic-induced psychotic disorder, sedative, hypnotic, or anxiolytic-induced mood disorder, sedative, hypnotic, or anxiolytic-induced anxiety disorder, sedative, hypnotic, or Anxiolytic-induced sexual dysfunction, sedative-, hypnotic-, or anxiolytic-induced sleep disorders, and sedative-, hypnotic-, or anxiolytic-related disorders unspecified (292.9); drug dependence (304.80); and other (or unknown) substance-related disorders such as anabolic steroids, nitrate inhalants, and nitrous oxide.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are effective in treating anxiety disorders including panic attacks; panic disorder without agoraphobia ( 300.01) and Panic Disorders with Agoraphobia (300.21); Agoraphobia; Agoraphobia without History of Panic Disorder (300.22), subtype zoomorphic, natural environment, blood-injection-injury Specific phobia (300.29, formerly simple phobia), social phobia (social anxiety disorder, 300.23), obsessive-compulsive disorder (300.3), post-traumatic stress disorder ( 309.81), acute stress disorders (308.3), generalized anxiety disorders (300.02), anxiety disorders due to systemic medical conditions (293.84), substance-induced anxiety disorders, separation anxiety disorders (309.21), adjustment disorders with anxiety (309.24) ), and in the treatment or prevention of anxiety disorders not specified (300.00).

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful in treating primary sleep disorders, e.g. sleep disturbances, e.g. primary insomnia. (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorders (780.59), circadian rhythm sleep disorders (307.45), and sleep disorders not specified (307.47); For example, parasomnias such as nightmare disorder (307.47), sleep startle disorder (307.46), sleepwalking disorder (307.46), and parasomnia not otherwise specified (307.47); associated with other psychiatric disorders. Sleep disorders such as insomnia associated with other psychiatric disorders (307.42) and hypersomnia associated with other psychiatric disorders (307.44); sleep disorders caused by systemic conditions, especially neuropathy, neuropathic pain sleep disorders associated with diseases such as restless leg syndrome, heart and lung disease; and substance-induced sleep disorders, including the subtypes insomnia, hypersomnia, parasomnia, and mixed; It may be useful in treating or preventing sleep disorders, including sleep apnea and jet lag.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful for treating hyperacusis and loudness disorders including fragile X syndrome and autism. It may be useful in therapy or prevention.

Compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g., salts) and/or derivatives thereof may be used to treat intermittent explosive disorder (312.34), thievery (312.32), Treatment of impulse control disorders, including target gambling (312.31), pyromania (312.33), trichotillomania (312.39), impulse control disorders not specified (312.3), overeating, shopping addiction, compulsive sexual behavior, and compulsive hoarding or may be useful in prevention.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may be used in sexual desire disorders such as hypoactive sexual desire disorder (302.71), and sexual aversion disorders (302.79); sexual arousal disorders, e.g. female sexual arousal disorders (302.72) and male erectile dysfunction (302.72); orgasmic disorders, e.g. female orgasmic disorders (302.73), male orgasmic disorders (302.74), and premature ejaculation (302.75); sexual pain disorders such as dyspareunia (302.76) and vaginismus (306.51); sexual dysfunction not specified (302.70); 302.4), fetishism (302.81), tactility (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transvestite fetishism (302.3), voyeurism (302.82), and specific sexual perversions of impotence (302.9); gender identity disorders, including gender identity disorders in children (302.6) and gender identity disorders in adolescents or adults (302.85); and sexual disorders not specified (302.9) It may be useful in treating or preventing functional impairment.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are used for the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20 ), Schizophrenic Personality Disorder (301,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81) , avoidant personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personality disorder (301.4), and personality disorder not otherwise specified (301.9) .

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof have the subtype mixed attention-deficit/hyperactivity disorder (314.01), Attention deficit multiple, including attention-deficit/hyperactivity disorder predominantly inattentive type (314.00), attention-deficit/hyperactivity disorder hyperactivity-impulsive type (314.01), and attention-deficit/hyperactivity disorder unspecified (314.9) Mobility disorders; hyperactivity disorders; disruptive behavior disorders, e.g., subtypes childhood-onset (321.81), adolescent-onset (312.82) and unspecified onset (312.89), oppositional defiant disorder (313.81) and Disruptive Behavior Disorder not otherwise specified; and tic disorders, such as Tourette's Disorder (307.23).

Compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are used in Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett May be useful in the treatment or prevention of autism spectrum disorders, including disorder (299.80), childhood disintegrative disorder (299.10), and pervasive disorder not specified (299.80, including atypical autism). be.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may be used to treat eating disorders, e.g. bulimia nervosa (307.51) including subtypes purging and non-purging; obesity; compulsive eating disorder; bulimic eating disorder; 307.50) may be useful in the treatment or prevention of

Compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may be used in other diseases such as schizophrenia, bipolar disorder, depressive conditions , may be useful for enhancing cognition, including the treatment of cognitive impairment, such as cognitive impairment in other mental disorders and psychotic conditions associated with Alzheimer's disease. Alternatively, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates thereof may be used in diseases such as cognitive disorders such as schizophrenia, bipolar disorder, depression and other psychiatric disorders. Such as cognitive impairment that may accompany it, and may be useful in the prevention of psychotic conditions associated with cognitive impairment, such as Alzheimer's disease.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are used to treat ataxia, in particular spinocerebellar ataxia, especially R420H, R423H, Or it may be useful for treating or preventing ataxia including ataxia associated with F448L mutation.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are used to treat nociceptive pain, neuropathic pain, inflammatory pain, or various may be useful in the treatment or prevention of pain, including pain in

Nociceptive pain represents the normal response to nociceptive damage or injury of tissues such as skin, muscles, internal organs, joints, tendons, or bones. Examples of nociceptive pain that form part of the present invention include: somatic pain: musculoskeletal (arthralgia, myofascial pain) or cutaneous (which is often highly localized); or visceral pain: including hollow organs or smooth muscle.

Neuropathic pain is pain initiated or caused by a primary lesion or disease in the somatosensory nervous system. Sensory disturbances range from deficits perceived as dysesthesia (numbness) to hypersensitivity (hyperalgesia or allodynia) and dysesthesia (tingling and other sensations). Examples of neuropathic pain that form part of the present invention include diabetic neuropathy, post-herpetic neuralgia, spinal cord injury pain, phantom limb (post amputation) pain, and post-stroke central pain, It is not limited to these. Other causes of neuropathic pain include trauma, chemotherapy, and heavy metal exposure.

Inflammatory pain results from activation and sensitization of nociceptive pain pathways by various mediators released at sites of tissue inflammation. Mediators that have been implicated as key players in inflammatory pain are proinflammatory cytokines released by infiltrating leukocytes, vascular endothelial cells, or tissue-resident mast cells, such as IL-1-alpha, IL- 1-beta, IL-6, and TNF-alpha, chemokines, reactive oxygen species, vasoactive amines, lipids, ATP, acids, and other factors. Examples of causes of inflammatory pain that form part of this invention include appendicitis, rheumatoid arthritis, inflammatory bowel disease, and shingles.

Various pains refer to pain conditions or disorders that are not easily categorized. Although specific therapies for these disorders are well known, current understanding of their underlying mechanisms is still rudimentary; and other primary headaches, as well as widespread pain of the fibromyalgia type.

A specific pain indication which may preferably be mediated by modulators of Kv3.1 and/or Kv3.2 and/or Kv3.3 channels is neuropathic pain and/or inflammatory pain.

Pain is a subjective condition and in clinical practice tends to be measured by the patient's self-assessment. Therefore, pain thresholds can be difficult to measure and quantify. Chronic pain typically uses a subjective 11-point rating scale, where 0 is no pain and 10 is the worst pain imaginable. Subjects generally record their worst pain for a given period of time, usually one day. A minimum mean baseline score is also recorded and response to drug therapy is measured relative to baseline, e.g., at least 10%, 20%, 30%, 40%, or 50% A reduction in pain can be observed.

Because an individual's response to the drug may vary, it is possible that not all individuals will experience a reduction in pain from their baseline score. Suitably, therefore, the reduction is observed in at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or all of the individuals tested.

Thus, in one embodiment of the invention, a reduction in pain of at least 10%, 20%, 30%, 40%, or 50% from a baseline score is Kv3.1/ observed upon administration of Kv3.2/Kv3.3 modulators, eg compounds of formula (I) or pharmaceutically acceptable salts, solvates and/or derivatives thereof.

Administration of the Kv3.1/Kv3.2/Kv3.3 modulator can be prior to the expected onset of pain or after the onset of pain. Kv3.1/Kv3.2/Kv3.3 modulators, e.g. compounds of formula (I) or their pharmaceutically acceptable The resulting salts, solvates and/or derivatives can be administered. Kv3.1/Kv3.2/Kv3.3 modulators, such as compounds of formula (I) or pharmaceutically acceptable salts, solvates and/or derivatives thereof, if the subject is already suffering from pain , may be administered to a subject in need thereof.

Treatment of a subject in need thereof, for as long as treatment is required, for example, for 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 6 months, 1 year, more than 1 year, more than 2 years, May continue for more than 5 years or more than 10 years. Thus, in one embodiment of the invention, a therapeutically effective amount of a Kv3.1/Kv3.2/Kv3.3 modulator, such as a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof, and/or the derivative is administered to a subject in need thereof for 1 day to 1 month, 1 week to 3 months, 1 month to 6 months, 3 months to 1 year, or more than 1 year.

Reduction of pain in a subject can be measured by assessing responses to external stimuli, such as mechanical or thermal stimuli (eg, cold stimuli) (as described in the experimental section). Said reduction is calculated by measuring the percentage reversal (pre- and post-dose thresholds of affected pain sites along with unaffected pain sites, e.g. described in more detail in the data analysis part of the experimental section). or by measuring the withdrawal threshold of the affected pain site. Preferably, a percentage inversion calculation is used.

Thus, in one embodiment of the invention, susceptibility to pain (e.g., neuropathic or inflammatory pain) is associated with a therapeutically effective amount of a Kv3.1/Kv3.2/Kv3.3 modulator, e.g., the formula ( more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70% upon administration of a compound of I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof; More than 80% or more than 90% inverted. Suitably, sensitivity to pain is reversed by greater than 80% or greater than 90%.

Subjects receiving Kv3.1/Kv3.2/Kv3.3 modulators may experience one of the secondary benefits, e.g., improved function, mood, sleep, quality of life, reduced time off work. You may experience more than one.

In certain embodiments, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful for the treatment or prevention of neuropathic pain. could be.

In certain embodiments, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful for the treatment or prevention of inflammatory pain. There is a possibility.

In certain embodiments, compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof are useful for the treatment or prevention of various pains. There is a possibility.

In one embodiment, compounds of formula (I) are provided for use in preventing acute noise-induced hearing loss.

In one embodiment, a method for the prevention of acute noise-induced hearing loss is provided comprising administering a compound of formula (I) to a subject in need thereof.

In one embodiment there is provided the use of a compound of formula (I) in the manufacture of a medicament for the prevention of acute noise-induced hearing loss.

Acute noise-induced hearing loss can be caused by events such as exposure to loud noises or explosions. In those cases where future events are predicted to be likely to cause acute noise-induced hearing loss, compounds of formula (I) or their pharmaceutically acceptable salts, solvates and/or derivatives are treated with acute noise-induced hearing loss. It may be administered prior to the event to prevent or reduce hearing loss. Administration of Compound (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof can prevent or reduce the severity of any acute noise-induced hearing loss. or alleviate other symptoms resulting from acute noise-induced hearing loss, such as tinnitus.

"Acute hearing loss" is defined as hearing loss that occurs rapidly over a period of hours or days. For example, hearing loss may occur over a period of minutes, hours, or days (e.g., up to 1 day, e.g., up to 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days). ) can happen. Acute hearing loss is typically caused by exposure to loud noises or explosions. Hearing loss caused by exposure to loud sounds or explosions is referred to herein as "noise-induced hearing loss." Thus, "acute noise-induced hearing loss" is hearing loss that occurs rapidly over hours or days caused by exposure to loud sounds or explosive sounds.

Important symptoms of acute hearing loss include:
1. A change in the threshold of hearing, i.e. an increase in the lowest sound level of a pure tone that can be heard in the absence of any other sound;
2. tinnitus; and
3. Impaired central auditory processing, eg, impaired auditory temporal processing and/or speech comprehension.

A "loud" noise or explosion can be at least 90 dB, such as at least 100 dB, at least 110 dB, at least 120 dB, or at least 130 dB.

In one embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof is initiated prior to an event expected to cause noise-induced acute hearing loss. be done. For example, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof up to 2 weeks prior to an event expected to cause noise-induced acute hearing loss, For example, up to 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or May start up to 15 minutes early. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered on multiple occasions prior to an event expected to cause noise-induced acute hearing loss. good.

In one embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts, solvates and/or derivatives thereof are administered to noise or explosions expected to cause acute noise-induced hearing loss. to prevent or reduce the occurrence of persistent tinnitus; to prevent or reduce the occurrence of persistent shifts in the auditory threshold; or, for example, auditory temporal processing and/or It is administered to prevent or reduce the occurrence of persistently deteriorating central auditory processing, including speech comprehension.

Prior dosing may occur in situations where the subject would be at risk of exposure to noise or explosions expected to cause acute noise-induced deafness, but such exposure will eventually occur. It will be appreciated that the situation is not limited.

In one embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof is initiated during an event expected to cause noise-induced acute hearing loss. be done. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered on multiple occasions during an event expected to cause noise-induced acute hearing loss. good.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof is administered initially to prevent or reduce the occurrence of persistent tinnitus; acute noise to prevent or reduce the occurrence of persistent shifts; or to prevent or reduce the occurrence of persistently deteriorating central auditory processing, including e.g. Administered during a noise or explosion expected to cause deafness.

In one embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof is initiated after an event expected to cause acute noise-induced hearing loss. be.

Thus, in one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof is administered initially to prevent or reduce the occurrence of persistent tinnitus; or to prevent or reduce the occurrence of persistently deteriorating central auditory processing, e.g., including auditory temporal processing and/or speech comprehension; It is administered after a noise or explosion expected to cause noise-induced deafness.

When a compound of formula (I) is administered after an event expected to cause acute noise-induced hearing loss, such administration is usually administered during the "acute phase", i.e., when hearing loss has been established. You can start before it wears off.

In one embodiment, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, and/or derivative thereof, results in up to 2 events expected to cause noise-induced acute hearing loss. Months later, e.g., 1 month, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 24 hours, 12 hours up to an event expected to cause acute noise-induced hearing loss , 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or up to 15 minutes later. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered on multiple occasions after an event expected to cause noise-induced acute hearing loss. good.

Compounds of formula (I) or their pharmaceutically acceptable salts, solvates and/or derivatives thereof may be administered for up to 7 days (e.g. up to 1 day, up to 2 days, up to 3 days, for a period of up to 4 days, up to 5 days, up to 6 days, or up to 7 days) or for 1-2 weeks (e.g., 7-8 days, 7-9 days, 7-10 days, 7-8 days) 11 days, 7-12 days, 7-13 days, or 7-14 days), 2-4 weeks (eg, 2-3 weeks or 2-4 weeks), or 1-2 months (eg, 4-6 weekly or 4-8 weeks).

A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered up to 1 day prior to a noise or explosion expected to cause acute noise-induced hearing loss, e.g. It can be administered for the first time up to 2 days, up to 3 days, up to 5 days, up to 1 week, up to 2 weeks, or up to 1 month. Administration initiated at any time prior to exposure to noise or explosions expected to cause acute noise-induced hearing loss is typically or up to 2 months after exposure to the explosion, e.g., up to 1 month, 3 weeks, up to 2 weeks, up to 1 week, up to 5 days, up to 3 days, up to 2 days, or a maximum of 1 day.

In one embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof for use in preventing or reducing the occurrence of a permanent shift in audible threshold, wherein With, the permanent shift in audibility threshold is reduced by at least 10 dB, such as at least 15 dB, at least 20 dB, at least 30 dB, at least 40 dB, or completely.

(pharmaceutical composition)
For use in therapy, the compounds of the invention are usually administered as a pharmaceutical composition. The present invention also provides a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof and a pharmaceutically acceptable carrier or excipient A composition is provided.

In one embodiment, hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders, and disorders of the inner ear, Impulse control disorder, personality disorder, attention deficit hyperactivity disorder, autism spectrum disorder, eating disorder, cognitive disorder, ataxia, pain (neuropathic pain, inflammatory pain, various pains, etc.), Lewy small A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prevention of a disease or disorder selected from the group consisting of somatic dementia and Parkinson's disease ( Pharmaceutical compositions are provided that include, for example, salts) and/or derivatives.

In a further embodiment, hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders, and disorders of the inner ear, Impulse control disorder, personality disorder, attention deficit hyperactivity disorder, autism spectrum disorder, eating disorder, cognitive disorder, ataxia, pain (neuropathic pain, inflammatory pain, various pains, etc.), Lewy small A method for the prevention or treatment of a disease or disorder selected from the group consisting of somatic dementia and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical thereof The above methods are provided, comprising administering a pharmaceutical composition comprising an acceptable salt and/or solvate (eg, salt) and/or derivative as a

The invention also provides for hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders, and disorders of the inner ear, Impulse control disorder, personality disorder, attention deficit hyperactivity disorder, autism spectrum disorder, eating disorder, cognitive disorder, ataxia, pain (neuropathic pain, inflammatory pain, various pains, etc.), Lewy small A compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the production of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of somatic dementia and Parkinson's disease Use of pharmaceutical compositions comprising the compounds (eg salts) and/or derivatives thereof is provided.

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

Compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof that are active when administered orally can be formulated as liquids or solids, e.g. syrups, suspensions It can be formulated as a tablet, emulsion, tablet, capsule or lozenge.

Liquid formulations generally comprise the active ingredient (of formula (I)) in a suitable liquid carrier(s), e.g. aqueous solvents such as water, ethanol, or glycerin, or non-aqueous solvents such as polyethylene glycol or oils. It consists of a suspension or solution of the compounds or their pharmaceutically acceptable salts and/or solvates (eg salts and/or derivatives etc.). The formulations may also contain suspending agents, preservatives, flavoring and/or coloring agents.

A composition in tablet form can be prepared utilizing any suitable pharmaceutical carrier(s) routinely used in the preparation of solid dosage forms, 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. ) and/or derivatives etc.) can be prepared using standard carriers and then filled into hard gelatin capsules. Alternatively, dispersions or suspensions can be prepared utilizing any suitable pharmaceutical carrier(s) such as aqueous gums, celluloses, silicates, or oils, and then the dispersions or suspensions are placed into soft gelatin capsules. can be filled to

A typical parenteral composition comprises active ingredients (compounds of formula (I) or their A solution or suspension of a pharmaceutically acceptable salt and/or solvate (eg, salt and/or derivative, etc.) of Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent immediately prior to administration.

Compositions for intranasal administration can 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 usually take the form of cartridges or refills for use with a nebulizing device. Supplied in single or multi-dose sterile form in sealed containers. Alternatively, the closed container may be a disposable dispensing device such as a single dose intranasal 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 such as air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomizers.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with carriers 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, eg from 10% to 60% by weight of active agent, depending on the method of administration. The composition may contain 0% to 99% by weight, eg 40% to 90% by weight, of carrier, depending on the method of administration. The composition may contain from 0.05 mg to 1000 mg, eg from 1.0 mg to 500 mg of active substance, depending on the method of administration. The composition may contain 50 mg to 1000 mg, eg 100 mg to 400 mg, of carrier depending on the method of administration. Dosages of the compounds utilized in treating the disorders described above will normally vary according to the severity of the disorder, the patient's weight, and other similar factors. However, as a general rule, a suitable unit dose may be between 0.05 mg and 1000 mg, more preferably between 1.0 mg and 500 mg, and such unit dose may be administered twice a day or more, such as twice a day or It can be administered 3 times. Such therapy may continue for weeks or months.

The dose provided to a subject is generally a safe and effective dose, ie, an acceptable balance of desired benefits and undesirable side effects.

The present invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof together with a further pharmaceutically acceptable active ingredient(s) (e.g. , a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof).

The present invention provides compounds of formula (I) for use in combination with a further pharmaceutically acceptable active ingredient(s).

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

The combination referred to above may conveniently be provided for use in the form of a pharmaceutical formulation, thus the combination as defined above together with a pharmaceutically acceptable carrier or excipient. A pharmaceutical formulation comprising comprises 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 the combination can also be administered separately, by 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 is may differ from the case. Suitable doses will be readily recognized by those skilled in the art.

Suitably, compounds of formula (I) or pharmaceutically acceptable salts, solvates and/or derivatives thereof are administered orally.

Suitably the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is 2-400 mg per day, such as 2-300 mg per day, especially Doses range from 5 to 250 mg.

Suitably the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered once or twice per day.

Suitably the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered for a period of at least 3 months.

Desirably the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered at 2 to 400 mg per day, for example 2 mg per day, once or twice per day. ~300 mg, especially 5-250 mg orally administered per day.

A human subject can be an adult, such as an adult between the ages of 18-65. Alternatively, the human subject can be 66 years of age or older. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered to a human subject under the age of 18, such as between 4 and 17 years of age. Administration to human subjects under the age of 18 is particularly relevant in the context of progressive myoclonic epilepsy and fragile X syndrome.

For convenience and to aid patient compliance, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered for an extended period of time using delivery techniques such as patches or implants. For example, it may be delivered for at least 1 week or for at least 4 weeks.

(experiment)
The invention is illustrated by the compounds described below. The following examples illustrate laboratory syntheses of specific compounds of the invention and are in no way intended to limit the scope of the invention with respect to compounds or processes. Although specific reagents, solvents, temperatures, and durations are used, it is understood that there are many acceptable equivalent options that can be used to produce similar results. The present invention is intended to include such equivalents.

(analytical instrument)
Unless otherwise noted, starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all compounds with chiral centers are racemic. Where a reaction is described as being carried out in an analogous fashion to a more fully described previous reaction, the general reaction conditions employed are essentially the same. Workup conditions used were of the type standard in the art, although variations were sometimes made from one reaction to another. Starting materials may not necessarily have been prepared from the batches referred to. The synthesized compounds can have various purities ranging, for example, from 85% to 99%. In some cases, moles and yield calculations were adjusted accordingly.

HPLC-mass spectra (HPLC-MS) were measured on an Agilent 1100 series LC/MSD mass spectrometer coupled with an Agilent 1100 series HPLC instrument operating in positive electrospray ionization mode and acidic gradient conditions.

Quality control (3 min method): LC/MS-ES+ under acidic conditions was performed on a Zorbax SB C18 column (1.8 μm, 3×50 mm). Mobile phase: A: (H2O + 0.05 vol% TFA)/B: (CH3CN + 0.05 vol% TFA). Gradient: t = 0 min, 0% (B), 0-95% (B) in 2.5 min, 95% (B) in 0.2 min, 95-100% (B) in 0.2 min, 100% (B) in 0.4 min. , 100% to 0% (B) in 0.1 min. Stop time 4 minutes. Column T = 60°C. Flow rate: 1.5ml/min. Mass range ES+: (100-1000 amu, F=60). UV detection wavelength: DAD 1A = 220.8, DAD 1B = 254.8. The use of this method in the analytical characterization of the compounds described is indicated by "QC_3_MIN".

Chiral Control: LC/MS-ES+ under acidic conditions was performed on CHIRALCEL® OD-H (250 x 4,6 mm-5um). Mobile phase: A: (H2O + 0.05 vol% TFA)/B: (CH3CN + 0.05 vol% TFA). Gradient: t = 0-6 min, 35% (B), t = 6-40 min, 35%-50% (B), t = 40-45 min, 50%-70% (B), t = 45 ~50 min, 70%-35% (B), t = 50-55 min, 35% (B). Stop time 60 minutes. Column T = 40°C. Flow rate: 1.0ml/min. UV detection wavelength: DAD 1A = 220.8, DAD 1B = 254.8.

Proton magnetic resonance (NMR) spectra were recorded at either 300, 400, 500, or 600 MHz on a Varian instrument or at 400 MHz on a Bruker instrument. Chemical shifts are reported in ppm (δ) using the residual solvent signal as internal standard. s (singlet), br.s (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets) , dt (doublet of triplet), and m (multiplet). NMR spectra were recorded at temperatures in the range 25-60°C.

2D NMR NOESY experiments were acquired using a spectral width of 3355 Hz in both f1 and f2 with a mixing time of 500 ms. A total of 256 increments were collected and processed to 1K using linear prediction (8 scans for each). Data were processed using sine bell shifts in both dimensions and lb=0.3 Hz for f1. In some preparations, purification was performed using Biotage automated flash chromatography (SP1 and SP4) or Flash Master Personal system.

Flash chromatography was performed using silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or silica gel 300-400 mesh (supplied by Sinopharm Chemical Reagent), Varian Mega Be-Si prepacked cartridges, prepacked Biotage silica cartridges (e.g. Biotage SNAP cartridge).

N,N-ジメチルホルムアミド(14mL)中の7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-オール(中間体156、WO2012076877、1.11g、6,30mmol)、2,5-ジブロモピラジン(1.5g、6,30mmol)、及び炭酸カリウム(1.31g、9.46mmol)の混合物を、120℃で3時間撹拌した。冷却後、反応混合物を、MTBE(100ml)で希釈し、ブライン(50ml)で洗浄した。相を分離し、水層を、MTBE(100ml)及びEtOAc(100ml)で洗浄した。全ての有機相を集め、Na₂SO₄で乾燥し、濾過し、蒸発させた。残渣を、カラムとしてSNAP 100g及び溶離液として100:0～90:10のシクロヘキサン:酢酸エチルを用いるシリカゲルでのフラッシュクロマトグラフィー(Biotage System)によって精製して、2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(1.8g)を白色固体として得た。
LC/MS: QC_3_MIN: Rt＝2.705分; m/z 333 & 335 [M+H]+。 (Compound Examples)
(Intermediate 1)
(2-bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy-pyrazine)

7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-ol (Intermediate 156, WO2012076877, 1.11 g, 6,30 mmol), 2,5- in N,N-dimethylformamide (14 mL) A mixture of dibromopyrazine (1.5 g, 6.30 mmol) and potassium carbonate (1.31 g, 9.46 mmol) was stirred at 120° C. for 3 hours. After cooling, the reaction mixture was diluted with MTBE (100ml) and washed with brine (50ml). The phases were separated and the aqueous layer was washed with MTBE (100ml) and EtOAc (100ml). All organic phases were collected, dried _{over Na2SO4} , filtered and evaporated. The residue was purified by flash chromatography on silica gel (Biotage System) using SNAP 100 g as column and 100:0 to 90:10 cyclohexane:ethyl acetate as eluent to give 2-bromo-5-(7-methylspiro [2H-Benzofuran-3,1′-cyclopropan]-4-yl)oxy-pyrazine (1.8 g) was obtained as a white solid.
LC/MS: QC_3_MIN: Rt = 2.705 min; m/z 333 & 335 [M+H]+.

Using the methods described above, substituting the appropriate phenol for 7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-ol, the following compounds were prepared. The final product was purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system).

0℃の酢酸エチル(30mL)中の炭酸ビス(トリクロロメチル)(950mg、3.20mmol)の溶液に、酢酸エチル(12mL)中の5-クロロピラジン-2-アミン(0.75g、5.79mmol)/N,N-ジイソプロピルエチルアミン(6.05ml、34.74mmol)の溶液を滴下し、反応混合物を、15分間同温度で撹拌した。反応混合物を0℃に維持しながら、過剰のホスゲンを除去するために真空引きした(5分間)。酢酸エチル(8mL)/ジクロロメタン(2mL)中の4-(ジメチルアミノ)ピリジン(710mg、5.81mmol)の溶液を添加し、反応混合物を、5分間同温度で撹拌した。その後、メチル 2-アミノ-2-メチル-プロパノエート塩酸塩(1.4g、9.1mmol)を0℃で添加し、反応混合物を、30分間同温度で撹拌した。反応を、HCl(100ml)の0.2N溶液でクエンチし、2相を分離した。有機層を、ブライン(100ml)で洗浄し、Na₂SO₄で乾燥し、濾過し、蒸発させて、ウレア中間体を得た。 (intermediate 5 pathway 1)
(3-(5-chloropyrazin-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione)

To a solution of bis(trichloromethyl)carbonate (950 mg, 3.20 mmol) in ethyl acetate (30 mL) at 0° C. was added 5-chloropyrazin-2-amine (0.75 g, 5.79 mmol)/N in ethyl acetate (12 mL). ,N-diisopropylethylamine (6.05ml, 34.74mmol) was added dropwise and the reaction mixture was stirred for 15 minutes at the same temperature. While maintaining the reaction mixture at 0° C., a vacuum was applied (5 minutes) to remove excess phosgene. A solution of 4-(dimethylamino)pyridine (710 mg, 5.81 mmol) in ethyl acetate (8 mL)/dichloromethane (2 mL) was added and the reaction mixture was stirred for 5 minutes at the same temperature. Methyl 2-amino-2-methyl-propanoate hydrochloride (1.4 g, 9.1 mmol) was then added at 0° C. and the reaction mixture was stirred for 30 min at the same temperature. The reaction was quenched with a 0.2N solution of HCl (100ml) and the two phases were separated. The organic layer was washed with brine (100ml) _, dried over _Na2SO4 , filtered and evaporated to give the urea intermediate.

The urea was dissolved in dichloromethane (20 mL) and at 0° C. sodium methoxide (315 mg, 5.83 mmol) was added. The reaction mixture was stirred for 15 min at the same temperature; the reaction was quenched with a saturated solution of NH ₄ Cl to pH 3-4. The mixture was extracted with ethyl acetate (50ml); the phases were separated and the organic layer was washed with brine (50ml), dried over _Na2SO4 , filtered and evaporated _. The residue was purified by reverse-phase flash chromatography (Biotage System) on phase C-18 using SNAP 30 g as column and 95:5 to 40:60 water:acetonitrile as eluent. Appropriate fractions were combined and evaporated to dryness to give 3-(5-chloropyrazin-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione (220mg) as a pale brown solid. obtained as
LC/MS: QC_3_MIN: Rt = 1.649 min; m/z 241 & 243 [M+H]+.

Using the method described above, substituting the appropriate amino ester hydrochloride for 2,2-dimethylglycine methyl ester hydrochloride, the following compounds were prepared. The final product was either purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system) or triturated in or crystallized from a suitable solvent.

アセトニトリル(10mL)中の5-クロロピラジン-2-アミン(500mg、3.86mmol)及び2-アミノ-2-メチル-プロパン酸塩酸塩(646mg、4.63mmol)の溶液に、酢酸エチル中のプロピルホスホン酸無水物溶液≧50重量％(3.68g、5.78mmol)を、室温でゆっくり添加した。反応混合物を、80℃で6時間撹拌した。反応混合物を、酢酸エチル(10ml)で希釈し、pHを約8に到達させつつ、NaOHの1N水溶液を添加した。2相を分離し、有機相を、ブライン(10ml)で洗浄し、Na₂SO₄で乾燥させ、真空下濃縮し、粗体を、カラムとしてSNAP 25g及び溶離液として99/1～90/10のDCM:MEOHを用いて、シリカゲル(BIOTAGE SYSTEM)でのフラッシュクロマトグラフィーによって精製し、2-アミノ-N-(5-クロロピラジン-2-イル)-2-メチル-プロパンアミド(190mg)を黄色固体として得た。
LC/MS: QC_3_MIN: Rt＝1.181分; m/z 215 & 217 [M+H]+。 (intermediate 5 pathway 2)
(3-(5-chloropyrazin-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione)

To a solution of 5-chloropyrazin-2-amine (500 mg, 3.86 mmol) and 2-amino-2-methyl-propanoic acid hydrochloride (646 mg, 4.63 mmol) in acetonitrile (10 mL) was added propylphosphonic acid in ethyl acetate. An anhydride solution ≧50 wt % (3.68 g, 5.78 mmol) was slowly added at room temperature. The reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and a 1N aqueous solution of NaOH was added while allowing the pH to reach ~8. The two phases were separated, the organic phase was washed with brine (10 ml), dried over Na ₂ SO ₄ , concentrated under vacuum and the crude was applied with SNAP 25 g as column and 99/1 to 90/10 as eluent. Purified by flash chromatography on silica gel (BIOTAGE SYSTEM) using DCM:MEOH to give 2-amino-N-(5-chloropyrazin-2-yl)-2-methyl-propanamide (190 mg) as a yellow color. Obtained as a solid.
LC/MS: QC_3_MIN: Rt = 1.181 min; m/z 215 & 217 [M+H]+.

To a solution of 2-amino-N-(5-chloropyrazin-2-yl)-2-methyl-propanamide (190 mg, 0.88 mmol) and triethylamine (268 mg, 2,6555 mmol) in dichloromethane (5 mL) was stirred at 0°C. A solution of bis(trichloromethyl)carbonate (105.07 mg, 0.3541 mmol) in dichloromethane (4 mL) was added slowly and the reaction mixture was stirred for 30 min at the same temperature. The reaction mixture was diluted in DCM (10 mL) and washed with 0.2N aqueous HCl (10 mL) and brine (10 mL). The organic phase was concentrated under vacuum and the crude was purified by flash chromatography on silica gel (Biotage system) using SNAP 25 g as column and C hexane/EtOAc from 80/20 to 0/100 as eluent. gave 3-(5-chloropyrazin-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione (130 mg) as a white solid.
LC/MS: QC_3_MIN: Rt = 1.598 min; m/z 241 & 243 [M+H]+.

乾燥N,N-ジメチルホルムアミド(8mL)中の[ジメチルアミノ-(3-オキシドトリアゾロ[4,5-b]ピリジン-3-イウム-1-イル)メチレン]-ジメチル-アンモニウム テトラフルオロボレート(1,1084g、3,4415mmol)、N,N-ジイソプロピルエチルアミン(0,7939g、6,1431mmol)、及び(2R)-2-(tert-ブトキシカルボニルアミノ)ブタン酸(0,5000g、2,4601mmol)の混合物を、室温で10分間撹拌した。ヘキサメチルジシラザン(0,5960g、3,6928mmol)を添加し、混合物を18時間撹拌した。 (Intermediate 7)
(tert-butyl N-[(1R)-1-carbamoylpropyl]carbamate)

[dimethylamino-(3-oxidetriazolo[4,5-b]pyridin-3-ium-1-yl)methylene]-dimethyl-ammonium tetrafluoroborate (1 , 1084 g, 3,4415 mmol), N,N-diisopropylethylamine (0,7939 g, 6,1431 mmol), and (2R)-2-(tert-butoxycarbonylamino)butanoic acid (0,5000 g, 2,4601 mmol). The mixture was stirred at room temperature for 10 minutes. Hexamethyldisilazane (0,5960 g, 3,6928 mmol) was added and the mixture was stirred for 18 hours.

The reaction mixture was partitioned in MTBE (30 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed. The oil obtained was triturated in MTBE (3 mL) and the precipitate obtained was washed with MTBE and dried in vacuo to give tert-butyl N-[(1R)-1-carbamoylpropyl]carbamate ( 0,3000 g, 1,4833 mmol, 60,294%) as a white solid.
LC/MS: QC_3_MIN: m/z 147 [M-tBu+H]+.

Using the methods described above, substituting the appropriate protected amino acid for (2R)-2-(tert-butoxycarbonylamino)butanoic acid, the following compounds were prepared.

1,4-ジオキサン(2mL)中の2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(中間体1、50mg、0.15mmol)、tert-ブチル N-[(1R)-1-カルバモイルプロピル]カルバメート(中間体7、46mg、0.23mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(10.3mg、0.011mmol)、ジシクロヘキシル-[2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスファン(XPhos)(5.4mg、0.011mmol)、及び炭酸セシウム(73mg、0.22mmol)の混合物を、窒素雰囲気下80℃で3時間撹拌した。 (Intermediate 9 (Route 1))
(tert-butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]propyl] carbamate)

2-bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy-pyrazine (Intermediate 1, 50 mg, 0.15 mmol in 1,4-dioxane (2 mL) ), tert-butyl N-[(1R)-1-carbamoylpropyl]carbamate (intermediate 7, 46mg, 0.23mmol), tris(dibenzylideneacetone)dipalladium(0) (10.3mg, 0.011mmol), dicyclohexyl- A mixture of [2-(2,4,6-triisopropylphenyl)phenyl]phosphane (XPhos) (5.4 mg, 0.011 mmol) and cesium carbonate (73 mg, 0.22 mmol) was stirred at 80° C. for 3 hours under a nitrogen atmosphere. bottom.

The reaction was partitioned between ethyl acetate and brine. The organic layer was separated, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 10 g column and cyclohexane and EtOAc from 100/0 to 0/100 as eluents. Appropriate fractions were combined and evaporated to dryness to give tert-butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4 -yl)oxypyrazin-2-yl]carbamoyl]propyl]carbamate (10 mg) was obtained.
LC/MS: QC_3_MIN: Rt = 2.696 min; m/z 455 [M+H]+.

アルゴンを流した後の1,4-ジオキサン(150mL)中の2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(中間体1、16g、48.0mmol)、tert-ブチル N-[(1R)-1-カルバモイルプロピル]カルバメート(中間体7、10g、49.4mmol)、炭酸セシウム(24.16g、74.17mmol)の混合物に、ジアセトキシパラジウム(0.555g、2.47mmol)及び(5-ジフェニルホスファニル-9,9-ジメチル-キサンテン-4-イル)-ジフェニル-ホスファン(2.15g、3.71mmol)を添加した。真空/アルゴンのサイクルを3回実施し、反応混合物を95℃で1.5時間撹拌した。反応混合物を、外付けの氷浴を用いて冷却し、その後、真空下濾過して、炭酸セシウムを除去した。濾液を集め、EtOAc(150ml)で希釈し、NH₄Clの飽和水溶液(100ml)、次いでNaClの飽和水溶液(100ml)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、乾固するまで蒸発させた。残渣を、2×SNAP 100gカラム(200gシリカ)及び溶離液として0～40％のシクロヘキサン/EtOAcを用いて、シリカゲル(Biotage system)でのフラッシュクロマトグラフィーによって精製して、tert-ブチル N-[(1R)-1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]プロピル]カルバメート(16.8g)を黄色固体として得た。 (intermediate 9 (pathway 2))
(tert-butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]propyl] carbamate)

2-Bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy-pyrazine (intermediate 1, 16 g, 48.0 mmol), tert-butyl N-[(1R)-1-carbamoylpropyl]carbamate (Intermediate 7, 10 g, 49.4 mmol), cesium carbonate (24.16 g, 74.17 mmol), diacetoxy Palladium (0.555 g, 2.47 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (2.15 g, 3.71 mmol) were added. Three vacuum/argon cycles were performed and the reaction mixture was stirred at 95° C. for 1.5 hours. The reaction mixture was cooled using an external ice bath and then filtered under vacuum to remove cesium carbonate. The filtrate was collected, diluted with EtOAc (150ml), washed with a saturated aqueous solution of _NH4Cl (100ml), then a saturated aqueous solution of NaCl (100ml), dried over sodium sulfate, filtered and evaporated to dryness. . The residue was purified by flash chromatography on silica gel (Biotage system) using 2×SNAP 100 g columns (200 g silica) and 0-40% cyclohexane/EtOAc as eluents to afford tert-butyl N-[( 1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]propyl]carbamate (16.8 g) was a yellow solid. obtained as

2-Bromo-5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxy-pyrazine (intermediate Substituting the appropriate bromopyrazine for compound 1), the following compounds were prepared. The final product was purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system).

ジクロロメタン(2mL)中のtert-ブチル N-[(1R)-1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]プロピル]カルバメート(中間体9、16mg、0.035mmol)及び2,2,2-トリフルオロ酢酸(0.50mL、6.53mmol)の混合物を、室温で2時間撹拌した。 (Intermediate 13)
((2R)-2-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]butanamide)

tert-Butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl in dichloromethane (2 mL) A mixture of]carbamoyl]propyl]carbamate (Intermediate 9, 16 mg, 0.035 mmol) and 2,2,2-trifluoroacetic acid (0.50 mL, 6.53 mmol) was stirred at room temperature for 2 hours.

The reaction mixture was diluted with dichloromethane (20 ml) and a saturated aqueous solution of NaHCO ₃ was added while allowing the pH to reach 8. The phases were separated and the organic layer was washed with brine (20ml), dried over _Na2SO4 , filtered and evaporated to give ( _2R )-2-amino-N-[5-(7-methylspiro[ 2H-Benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]butanamide (13 mg) was obtained and used in the next step without further purification.
LC/MS: QC_3_MIN: Rt = 2.009 min; m/z 355 [M+H]+.

tert-Butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazine-2- Substituting the appropriate Boc amine for yl]carbamoyl]propyl]carbamate (Intermediate 9), the following compounds were prepared.

1-ブタノール(5mL)中のtert-ブチル N-[(1R)-1-カルバモイル-1-メチル-プロピル]カルバメート(中間体8、100mg、0,4624mmol)及び炭酸カリウム(191,71mg、1,3871mmol)の混合物を、窒素雰囲気下95℃で1晩撹拌した。冷却後、炭酸カリウムを濾過して取り除き、反応混合物を、酢酸エチル(30ml)で希釈し、0.1N HCl水溶液(30ml)で洗浄し、次に、ブライン(30ml)で洗浄した。相を分離し、有機層を集め、Na₂SO₄で乾燥し、濾過し、蒸発させて、(5R)-5-エチル-5-メチル-イミダゾリジン-2,4-ジオン(60mg、0,4221mmol、91,283％)を得た。
LC/MS: QC_3_MIN: m/z 285 [2M+H]+。 (Intermediate 17)
((5R)-5-ethyl-5-methyl-imidazolidine-2,4-dione)

tert-Butyl N-[(1R)-1-carbamoyl-1-methyl-propyl]carbamate (Intermediate 8, 100 mg, 0,4624 mmol) and potassium carbonate (191,71 mg, 1,91,71 mg, 1,4624 mmol) in 1-butanol (5 mL). 3871 mmol) was stirred overnight at 95° C. under a nitrogen atmosphere. After cooling, the potassium carbonate was filtered off and the reaction mixture was diluted with ethyl acetate (30ml) and washed with 0.1N HCl aqueous solution (30ml) followed by brine (30ml). The phases were separated and the organic layer _was combined, dried over _Na2SO4 , filtered and evaporated to give (5R)-5-ethyl-5-methyl-imidazolidine-2,4-dione (60 mg, 0,4-dione). 4221 mmol, 91,283%).
LC/MS: QC_3_MIN: m/z 285 [2M+H]+.

中間体7に関して説明した方法を用いて、(2R)-2-(tert-ブトキシカルボニルアミノ)ブタン酸の代わりに1-(tert-ブトキシカルボニルアミノ)シクロブタンカルボン酸を用いて、中間体18を調製した。
LC/MS: QC_3_MIN: m/z 159 [M-tBu+H]+。 (Intermediate 18)
(tert-butyl N-(1-carbamoylcyclobutyl)carbamate)

Intermediate 18 was prepared using the method described for intermediate 7, substituting 1-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid for (2R)-2-(tert-butoxycarbonylamino)butanoic acid. bottom.
LC/MS: QC_3_MIN: m/z 159 [M-tBu+H]+.

1-ブタノール(1mL)中の2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(中間体1、50mg、0.1501mmol)、tert-ブチル N-(1-カルバモイルシクロブチル)カルバメート(中間体18、64mg、0.2987mmol)、炭酸カリウム(62mg、0,4486mmol)、ヨウ化銅(I)(2.9mg、0.0152mmol)、及びN,N'-ジメチルエタン-1,2-ジアミン(0.0065mL,0.0601mmol)の混合物を、窒素雰囲気下95℃で4時間撹拌した。冷却後、反応混合物を、酢酸エチル(30ml)で希釈し、0.1M HCl水溶液(30ml)で洗浄し、その後、ブライン(30ml)で洗浄した。相を分離し、有機層を集め、Na₂SO₄で乾燥し、濾過し、蒸発させた。残渣を、カラムとしてSNAP 10g及び溶離液として100:0～30:70のシクロヘキサン:酢酸エチルを用いて、シリカゲルでのフラッシュクロマトグラフィー(Biotage System)によって精製して、tert-ブチル N-[1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]シクロブチル]カルバメート(18mg)を得た。
LC/MS: QC_3_MIN: Rt＝2.675分; m/z 467 [M+H]+。 (Intermediate 19)
(tert-butyl N-[1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]cyclobutyl]carbamate)

2-bromo-5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxy-pyrazine (intermediate 1, 50 mg, 0.1501 mmol) in 1-butanol (1 mL), tert-butyl N-(1-carbamoylcyclobutyl)carbamate (Intermediate 18, 64 mg, 0.2987 mmol), potassium carbonate (62 mg, 0,4486 mmol), copper(I) iodide (2.9 mg, 0.0152 mmol), and N A mixture of ,N′-dimethylethane-1,2-diamine (0.0065 mL, 0.0601 mmol) was stirred at 95° C. for 4 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate (30ml) and washed with 0.1M HCl aqueous solution (30ml) followed by brine (30ml). The phases were separated and _the organic layer was collected, dried over _Na2SO4 , filtered and evaporated. The residue was purified by flash chromatography on silica gel (Biotage System) using SNAP 10 g as column and 100:0 to 30:70 cyclohexane:ethyl acetate as eluent to give tert-butyl N-[1- [[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]cyclobutyl]carbamate (18 mg) was obtained.
LC/MS: QC_3_MIN: Rt = 2.675 min; m/z 467 [M+H]+.

中間体13に関して説明した方法を用いて、tert-ブチル N-[(1R)-1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]プロピル]カルバメート(中間体9)の代わりにtert-ブチル N-[1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]シクロブチル]カルバメート(中間体19)を用いて、中間体20を調製した。
LC/MS: QC_3_MIN: Rt＝1.979分; m/z 367 [M+H]+。 (Intermediate 20)
(1-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]cyclobutanecarboxamide)

tert-Butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy was prepared using the method described for intermediate 13. tert-butyl N-[1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4 instead of pyrazin-2-yl]carbamoyl]propyl]carbamate (Intermediate 9) Intermediate 20 was prepared using -yl)oxypyrazin-2-yl]carbamoyl]cyclobutyl]carbamate (Intermediate 19).
LC/MS: QC_3_MIN: Rt = 1.979 min; m/z 367 [M+H]+.

中間体7に関して説明した方法を用いて、(2R)-2-(tert-ブトキシカルボニルアミノ)ブタン酸の代わりに1-(tert-ブトキシカルボニルアミノ)シクロプロパンカルボン酸を用いて、中間体21を調製した。 (Intermediate 21)
(tert-butyl N-(1-carbamoylcyclopropyl)carbamate)

Using the method described for intermediate 7, intermediate 21 was prepared using 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid in place of (2R)-2-(tert-butoxycarbonylamino)butanoic acid. prepared.

1,4-ジオキサン(1mL)中のジシクロヘキシル-[2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスファン(12mg、0.0252mmol)、tert-ブチル N-(1-カルバモイルシクロプロピル)カルバメート(中間体21、67mg、0.3346mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(22mg、0.0240mmol)、2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(中間体1、79.518mg、0.2387mmol)及び炭酸セシウム(116mg、0.3560mmol)の混合物を、窒素雰囲気下95℃で2時間撹拌した。追加のtert-ブチル N-(1-カルバモイルシクロプロピル)カルバメート(中間体21、67mg、0.3346mmol)及びトリス(ジベンジリデンアセトン)ジパラジウム(0)(22mg、0.0240mmol)を添加し、反応混合物を、95℃で窒素下さらに2時間撹拌し、それに続き、さらなるジシクロヘキシル-[2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスファン(12mg、0.0252mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(22mg、0.0240mmol)、及び炭酸セシウム(58mg)を添加し、混合物を、窒素下さらに2時間撹拌した。その後、反応混合物を、水(10mL)、NH₄Cl(10mL)でクエンチし、酢酸エチル(20mL)で抽出した。その後、有機層を、ブライン(15mL)で洗浄し、Na₂SO₄で乾燥し、濾過し、その後、真空下濃縮した。粗体を、カラムとしてSNAP 10g及び溶離液としてシクロヘキサン:酢酸エチル90:10～70:30を用いて、シリカゲルでのフラッシュクロマトグラフィー(Biotage System)によって精製して、tert-ブチル N-[1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]シクロプロピル]カルバメート(55mg)を黄色固体として得た。
LC/MS: QC_3_MIN: Rt＝2.634分; m/z 453 [M+H]+。 (Intermediate 22)
(tert-butyl N-[1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]cyclopropyl]carbamate)

Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (12 mg, 0.0252 mmol), tert-butyl N-(1-carbamoylcyclopropyl)carbamate (1 mL) in 1,4-dioxane (1 mL) Intermediate 21, 67 mg, 0.3346 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.0240 mmol), 2-bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane A mixture of ]-4-yl)oxy-pyrazine (Intermediate 1, 79.518 mg, 0.2387 mmol) and cesium carbonate (116 mg, 0.3560 mmol) was stirred at 95° C. for 2 hours under a nitrogen atmosphere. Additional tert-butyl N-(1-carbamoylcyclopropyl)carbamate (Intermediate 21, 67 mg, 0.3346 mmol) and tris(dibenzylideneacetone) dipalladium(0) (22 mg, 0.0240 mmol) were added and the reaction mixture was , at 95° C. under nitrogen for an additional 2 hours, followed by additional dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (12 mg, 0.0252 mmol), tris(dibenzylideneacetone)dipalladium. (0) (22 mg, 0.0240 mmol) and cesium carbonate (58 mg) were added and the mixture was stirred under nitrogen for a further 2 hours. The reaction mixture was then quenched with water (10 mL), NH ₄ Cl (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was then washed with brine (15 mL), dried over _Na2SO4 , filtered and then concentrated in vacuo _. The crude was purified by flash chromatography on silica gel (Biotage System) using SNAP 10 g as column and cyclohexane:ethyl acetate 90:10 to 70:30 as eluent to give tert-butyl N-[1- [[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]cyclopropyl]carbamate (55 mg) was obtained as a yellow solid.
LC/MS: QC_3_MIN: Rt = 2.634 min; m/z 453 [M+H]+.

tert-ブチル N-[1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]シクロプロピル]カルバメート(中間体22、55mg、0.1215mmol)を、ジクロロメタン(4mL)に溶解させ、0℃に冷却した。2,2,2-トリフルオロ酢酸(1154.7mg、10.026mmol)(0.8mL)を滴下し、反応を、室温で1時間撹拌した。その後、反応混合物を、0℃に冷却し、pHが8に達するまでNaHCO₃を添加した。その後、混合物を室温まで昇温させ、DCM(10mL)で抽出した。有機層を、Na₂SO₄で乾燥し、濾過し、減圧濃縮して、1-アミノ-N-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]シクロプロパンカルボキサミド(40mg)を黄色オイルとして得た。
LC/MS: QC_3_MIN: Rt＝1.935分; m/z 353 [M+H]+。 (Intermediate 23)
(1-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]cyclopropanecarboxamide)

tert-butyl N-[1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]cyclopropyl]carbamate (intermediate 22, 55 mg, 0.1215 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0°C. 2,2,2-trifluoroacetic acid (1154.7 mg, 10.026 mmol) (0.8 mL) was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and NaHCO ₃ was added until pH 8 was reached. The mixture was then warmed to room temperature and extracted with DCM (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl. )oxypyrazin-2-yl]cyclopropanecarboxamide (40 mg) was obtained as a yellow oil.
LC/MS: QC_3_MIN: Rt = 1.935 min; m/z 353 [M+H]+.

アセトン(200mL)中の2-ブロモベンゼン-1,3-ジオール(20g、105.8mmol)の溶液に、炭酸カリウム(43.87g、317.4mmol)を添加し、それに続き、ベンジルブロミド(40.72g、238.1mmol)(28ml)を添加し、反応混合物を、1.5時間還流させた。冷却後、反応混合物を真空下濾過し、濾液を、乾固するまで濃縮した。酢酸エチル(100ml)で希釈した残渣を、水(100ml)で洗浄し、次いで、ブライン(100ml)で洗浄した。相を分離し、有機層を、Na₂SO₄で乾燥し、濾過し、濃縮した。残渣を、イソプロパノール(8体積)中に懸濁させ、混合物を、80℃で加熱し、その温度で1時間撹拌した(クリアな溶液を得た)。その後、混合物を、室温に到達させ(1時間で)、得られた懸濁液を濾過した。固体を、氷冷イソプロパノールで洗浄し、その後、乾燥させて、表題化合物1,3-ジベンジルオキシ-2-ブロモ-ベンゼン(34g)を、淡桃色の固体として得た。
LC/MS: QC_3_MIN: Rt＝2.688分。 (Intermediate 24)
(1,3-dibenzyloxy-2-bromo-benzene)

To a solution of 2-bromobenzene-1,3-diol (20 g, 105.8 mmol) in acetone (200 mL) was added potassium carbonate (43.87 g, 317.4 mmol) followed by benzyl bromide (40.72 g, 238.1 mmol). ) (28 ml) was added and the reaction mixture was refluxed for 1.5 hours. After cooling, the reaction mixture was filtered under vacuum and the filtrate was concentrated to dryness. The residue diluted with ethyl acetate (100ml) was washed with water (100ml) and then brine (100ml). The phases were separated and the organic layer was dried _{over Na2SO4} , filtered and concentrated. The residue was suspended in isopropanol (8 volumes) and the mixture was heated at 80° C. and stirred at that temperature for 1 hour (a clear solution was obtained). The mixture was then allowed to reach room temperature (in 1 hour) and the resulting suspension was filtered. The solid was washed with ice-cold isopropanol and then dried to give the title compound 1,3-dibenzyloxy-2-bromo-benzene (34g) as a pale pink solid.
LC/MS: QC_3_MIN: Rt = 2.688 min.

2つ口丸底フラスコ内に、活性化亜鉛粉末(6.84g、104.6mmol)を加え、該粉末を、真空下加熱した。系を、アルゴン下とし、乾燥テトラヒドロフラン(58mL)を添加した。その後、1,2-ジブロモエタン(2.18g、11.62mmol)を添加し、混合物を、還流加熱した。クロロトリメチルシラン(505mg、4.65mmol)を一回で添加し、混合物を、リフラックス温度で撹拌し続けた。乾燥テトラヒドロフラン(12mL)中のメチル 1-ブロモシクロプロピルカルボキシレート(10.4g、58.1mmol)の溶液を、同温度でゆっくり添加し、反応混合物を、1.5時間還流させた。反応混合物を、室温まで冷却し、亜鉛を沈降させて、THF中0.83M(理論値)のブロモ-(1-メトキシカルボニルシクロプロピル)亜鉛溶液(70mL)を得て、それを、さらにワークアップすることなく次の工程で用いた。 (Intermediate 25)
(bromo-(1-methoxycarbonylcyclopropyl)zinc)

Activated zinc powder (6.84 g, 104.6 mmol) was added to a two-necked round bottom flask and the powder was heated under vacuum. The system was placed under argon and dry tetrahydrofuran (58 mL) was added. 1,2-dibromoethane (2.18 g, 11.62 mmol) was then added and the mixture was heated to reflux. Chlorotrimethylsilane (505 mg, 4.65 mmol) was added in one portion and the mixture was kept stirring at the reflux temperature. A solution of methyl 1-bromocyclopropylcarboxylate (10.4 g, 58.1 mmol) in dry tetrahydrofuran (12 mL) was added slowly at the same temperature and the reaction mixture was refluxed for 1.5 hours. The reaction mixture is cooled to room temperature and the zinc is precipitated to give a 0.83M (theoretical) bromo-(1-methoxycarbonylcyclopropyl)zinc solution in THF (70 mL), which is worked up further. used in the next step without

70℃で前もって加熱したN,N-ジメチルホルムアミド(150mL)中の1,3-ジベンジルオキシ-2-ブロモ-ベンゼン(中間体24、16g、43.33mmol)及びビス(トリ-tert-ブチルホスフィン)パラジウム(0)(221mg、0.43mmol)の溶液に、THF中0.83M(理論値)のブロモ-(1-メトキシカルボニルシクロプロピル)亜鉛溶液(中間体25、60ml)を、(カニューレを通して)添加し、反応混合物を、同温度で40分間撹拌した。冷却後、反応混合物を、約30mlまで真空下濃縮し、残渣を、酢酸エチル(450ml)で希釈し、1NのHCl水溶液(2×100ml)で2回洗浄し、その後、氷冷ブライン(3×100ml)で3回洗浄した。相を分離し、有機層を、濾紙及びセルロースを用いて組み立てたGoochフィルターで真空下濾過し、酢酸エチルで洗浄した。濾液を、Na₂SO₄で乾燥し、濾過し、蒸発させて、表題化合物メチル 1-(2,6-ジベンジルオキシフェニル)シクロプロパンカルボキシレート(15.5g)を得て、それを、さらに精製することなく次の工程で用いた。
LC/MS: QC_3_MIN: Rt＝2.606分; m/z 389 [M+H]+。 (Intermediate 26)
(methyl 1-(2,6-dibenzyloxyphenyl)cyclopropanecarboxylate)

1,3-dibenzyloxy-2-bromo-benzene (intermediate 24, 16 g, 43.33 mmol) and bis(tri-tert-butylphosphine) in N,N-dimethylformamide (150 mL) preheated at 70 °C To a solution of palladium(0) (221 mg, 0.43 mmol) was added (via cannula) a 0.83 M (theoretical) solution of bromo-(1-methoxycarbonylcyclopropyl)zinc in THF (Intermediate 25, 60 ml). , the reaction mixture was stirred at the same temperature for 40 minutes. After cooling, the reaction mixture was concentrated under vacuum to approximately 30 ml and the residue was diluted with ethyl acetate (450 ml) and washed twice with 1N HCl aqueous solution (2×100 ml), then ice-cold brine (3×100 ml). 100 ml) was washed three times. The phases were separated and the organic layer was filtered under vacuum through a Gooch filter assembled with filter paper and cellulose and washed with ethyl acetate. The filtrate was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound methyl 1-(2,6-dibenzyloxyphenyl)cyclopropanecarboxylate (15.5g) which was further purified used in the next step without
LC/MS: QC_3_MIN: Rt = 2.606 min; m/z 389 [M+H]+.

反応を、各回約20gの出発材料を用いて別々に3回行った。
(一般手順:)
エタノール(200ml)中のメチル 1-(2,6-ジベンジルオキシオヘニル)シクロプロパンカルボキシレート(methyl 1-(2,6-dibenzyloxyohenyl)cyclopropanecarboxylate)(中間体26、20.4g、52.52mmol)及びパラジウム炭素(5重量％、1.02g)の混合物に、ギ酸アンモニウム(16.56g、262.6mmol)を添加し、反応混合物を、80℃で1時間撹拌した。冷却後、触媒をセルロースパッドで濾過して取り除き、濾液を、約20mlまで真空下濃縮した。 (Intermediate 27)
(4-hydroxyspiro[benzofuran-3,1'-cyclopropan]-2-one)

The reaction was run three separate times using approximately 20 g of starting material each time.
(General procedure:)
Methyl 1-(2,6-dibenzyloxyohenyl)cyclopropanecarboxylate (Intermediate 26, 20.4g, 52.52mmol) and Palladium in Ethanol (200ml) To a mixture of carbon (5 wt%, 1.02 g) was added ammonium formate (16.56 g, 262.6 mmol) and the reaction mixture was stirred at 80°C for 1 hour. After cooling, the catalyst was filtered off through a cellulose pad and the filtrate was concentrated under vacuum to approximately 20 ml.

The residues from the three reactions were combined, diluted with ethyl acetate (400ml) and washed twice with water (2x300ml). The two phases are separated and the organic phase is washed with brine (300 ml), dried over Na ₂ SO ₄ and concentrated under vacuum to give 4-hydroxyspiro[benzofuran-3,1′-cyclopropane]-2- One (27.55 g) (containing about 10-15% uncyclized methyl 1-(2,6-dihydroxyphenyl)cyclopropanecarboxylate intermediate) was obtained, which was used in the next step without further purification. used in
LC/MS: QC_3_MIN: Rt = 1.707 min.

アセトニトリル(200mL)/テトラヒドロフラン(50mL)中の4-ヒドロキシスピロ[ベンゾフラン-3,1'-シクロプロパン]-2-オン(中間体27、28.5g、161.8mmol)(約10～15％の未環化メチル 1-(2,6-ジヒドロキシフェニル)シクロプロパンカルボキシレート中間体を含有)の溶液に、炭酸カリウム(33.54g、242,7mmol)を添加し、反応混合物を70℃で1.5時間撹拌した。その後、反応混合物を、室温に冷却し、ベンジルブロミド(27.67g、161.8mmol)を、ゆっくり添加した。反応混合物を、60℃で5時間撹拌した。冷却後、反応混合物を、真空下濾過し、固体を廃棄し、濾液を50mlまで濃縮し、酢酸エチル(250ml)で希釈し、ブライン(2×100ml)で2回洗浄した。相を分離し、有機層を、Na₂SO₄で乾燥し、濾過し、蒸発させて、表題化合物4-ベンジルオキシスピロ[ベンゾフラン-3,1'-シクロプロパン]-2-オン(42,4g)を得て、それを、さらに精製することなく次の工程で用いた。
LC/MS: QC_3_MIN: Rt＝2.389分; m/z 267 [M+H]+。 (Intermediate 28)
(4-benzyloxyspiro[benzofuran-3,1'-cyclopropan]-2-one)

4-Hydroxyspiro[benzofuran-3,1′-cyclopropan]-2-one (Intermediate 27, 28.5 g, 161.8 mmol) (~10-15% uncyclic To a solution of methyl chloride 1-(2,6-dihydroxyphenyl)cyclopropanecarboxylate intermediate) was added potassium carbonate (33.54 g, 242.7 mmol) and the reaction mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was then cooled to room temperature and benzyl bromide (27.67 g, 161.8 mmol) was added slowly. The reaction mixture was stirred at 60° C. for 5 hours. After cooling, the reaction mixture was filtered under vacuum, solids were discarded and the filtrate was concentrated to 50ml, diluted with ethyl acetate (250ml) and washed twice with brine (2x100ml). The phases were separated and the organic layer was dried over _Na2SO4 , filtered and evaporated to give the title compound 4-benzyloxyspiro[benzofuran-3,1'-cyclopropan]-2-one (42.4 _g ), which was used in the next step without further purification.
LC/MS: QC_3_MIN: Rt = 2.389 min; m/z 267 [M+H]+.

乾燥テトラヒドロフラン(300mL)中の4-ベンジルオキシスピロ[ベンゾフラン-3,1'-シクロプロパン]-2-オン(中間体28、42.4g、159.2mmol)の溶液に、THF中1Mのリチウムアルミニウムヒドリド溶液(79.6ml、79,6mmol)を、0℃でゆっくり添加し、反応混合物を同温度で30分間撹拌した。反応を、氷、水(400ml)、及び1MのHCl水溶液(160ml)でクエンチし、その後、酢酸エチル(700ml)で希釈した。相を分離し、水層を、酢酸エチル(500ml)で逆抽出した。合わせた有機相を、ブライン(600ml)で洗浄し、Na₂SO₄で乾燥し、濾過し、蒸発させて、表題化合物3-ベンジルオキシ-2-[1-(ヒドロキシメチル)シクロプロピル]フェノール(43g)を得て、それを、さらに精製することなく次の工程で用いた。
LC/MS: QC_3_MIN: Rt＝2.148分; m/z 271 [M+H]+、m/z 293 [M+Na]+、m/z 253 [M-OH]+。 (Intermediate 29)
(3-benzyloxy-2-[1-(hydroxymethyl)cyclopropyl]phenol)

To a solution of 4-benzyloxyspiro[benzofuran-3,1′-cyclopropan]-2-one (Intermediate 28, 42.4 g, 159.2 mmol) in dry tetrahydrofuran (300 mL) was added a 1 M solution of lithium aluminum hydride in THF. (79.6 ml, 79.6 mmol) was slowly added at 0° C. and the reaction mixture was stirred at the same temperature for 30 min. The reaction was quenched with ice, water (400ml), and 1M aqueous HCl (160ml), then diluted with ethyl acetate (700ml). The phases were separated and the aqueous layer was back extracted with ethyl acetate (500ml). The combined organic phases were washed with brine (600ml), dried over _Na2SO4 , filtered and evaporated to give the title _compound 3-benzyloxy-2-[1-(hydroxymethyl)cyclopropyl]phenol ( 43g), which was used in the next step without further purification.
LC/MS: QC_3_MIN: Rt = 2.148 min; m/z 271 [M+H]+, m/z 293 [M+Na]+, m/z 253 [M-OH]+.

炭酸ジメチル(430mL)中の3-ベンジルオキシ-2-[1-(ヒドロキシメチル)シクロプロピル]フェノール(中間体29、43g、159.1mmol)の溶液に、カリウムtert-ブトキシド(35.7g、318.1mmol)を、ゆっくり添加し、反応混合物を、85℃で3.5時間撹拌した。反応混合物を、室温まで冷却し、150mLまで真空下濃縮し、MTBE(400ml)で希釈し、水(400ml)で洗浄した。相を分離し、水層を、MTBE(250ml)で逆抽出した。合わせた有機層を、ブライン(350ml)で洗浄し、Na₂SO₄で乾燥し、濾過し、濃縮して、表題化合物4-ベンジルオキシスピロ[2H-ベンゾフラン-3,1'-シクロプロパン](40g)を得て、それを、さらに精製することなく次の工程で用いた。
LC/MS: QC_3_MIN: Rt＝2.457分; m/z 253 [M+H]+。 (Intermediate 30)
(4-benzyloxyspiro[2H-benzofuran-3,1'-cyclopropane])

To a solution of 3-benzyloxy-2-[1-(hydroxymethyl)cyclopropyl]phenol (Intermediate 29, 43 g, 159.1 mmol) in dimethyl carbonate (430 mL) was added potassium tert-butoxide (35.7 g, 318.1 mmol). was slowly added and the reaction mixture was stirred at 85° C. for 3.5 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo to 150 mL, diluted with MTBE (400 ml) and washed with water (400 ml). The phases were separated and the aqueous layer was back extracted with MTBE (250ml). The combined organic layers were washed with brine (350ml), dried over _Na2SO4 , filtered and concentrated to give _the title compound 4-benzyloxyspiro[2H-benzofuran-3,1'-cyclopropane]( 40g), which was used in the next step without further purification.
LC/MS: QC_3_MIN: Rt = 2.457 min; m/z 253 [M+H]+.

各回20gの出発材料を用いて反応を2回行った。エタノール(160ml)中の4-ベンジルオキシスピロ[2H-ベンゾフラン-3,1'-シクロプロパン](中間体30、20g、79.27mmol)及びギ酸アンモニウム(24.99g、396.34mmol)の混合物に、パラジウム炭素(5重量％、2.0g)を添加し、反応混合物を80℃で10分間撹拌した。冷却後、触媒をセルロースパッドで濾過して取り除き、濾液を、約20mlまで真空下濃縮した。2回の反応で得られた残渣を合わせ、混合物を、酢酸エチル(300ml)で希釈し、水(3×200ml)で3回洗浄し、その後、ブライン(200ml)で洗浄した。2相を分離し、有機相を、Na₂SO₄で乾燥し、真空下濃縮した。残渣を、溶離液として99:1～85:15のシクロヘキサン:酢酸エチルを用いて、シリカゲルでのフラッシュクロマトグラフィー(Biotage System)によって精製して、スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-オール(17,75g)を白色固体として得た。
LC/MS: QC_3_MIN: Rt＝1.723分; m/z 163 [M+H]+。 (Intermediate 31 (Intermediate 85, WO2012/076877))
(1spiro[2H-benzofuran-3,1'-cyclopropan]-4-ol)

The reaction was run twice using 20 g of starting material each time. To a mixture of 4-benzyloxyspiro[2H-benzofuran-3,1′-cyclopropane] (intermediate 30, 20 g, 79.27 mmol) and ammonium formate (24.99 g, 396.34 mmol) in ethanol (160 ml) was added palladium on carbon. (5 wt %, 2.0 g) was added and the reaction mixture was stirred at 80° C. for 10 minutes. After cooling, the catalyst was filtered off through a cellulose pad and the filtrate was concentrated under vacuum to approximately 20 ml. The residues from the two reactions were combined and the mixture was diluted with ethyl acetate (300ml) and washed three times with water (3x200ml) followed by brine (200ml). The two phases were separated and the organic phase was dried _{over Na2SO4} and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage System) using 99:1 to 85:15 cyclohexane:ethyl acetate as eluent to give spiro[2H-benzofuran-3,1′-cyclopropane. ]-4-ol (17.75 g) was obtained as a white solid.
LC/MS: QC_3_MIN: Rt = 1.723 min; m/z 163 [M+H]+.

中間体7の合成と同じ方法によって、(2R)-2-(tert-ブトキシカルボニルアミノ)ブタン酸の代わりに(2S)-2-(tert-ブトキシカルボニルアミノ)ブタン酸を用いて、表題化合物を合成した。
LC/MS: QC_3_MIN: m/z 147 [M-tBu+H]+、m/z 427 [2M+Na]+ (Intermediate 32)
(tert-butyl N-[(1S)-1-carbamoylpropyl]carbamate)

By the same method as for the synthesis of intermediate 7, using (2S)-2-(tert-butoxycarbonylamino)butanoic acid instead of (2R)-2-(tert-butoxycarbonylamino)butanoic acid, the title compound was obtained. Synthesized.
LC/MS: QC_3_MIN: m/z 147 [M-tBu+H]+, m/z 427 [2M+Na]+

中間体9の合成に使用した「経路1」の方法によって、tert-ブチル N-[(1R)-1-カルバモイルプロピル]カルバメート(中間体7)の代わりにtert-ブチル N-[(1S)-1-カルバモイルプロピル]カルバメート(中間体32)を用いて、表題化合物を合成した。
LC/MS: QC_3_MIN: Rt＝2.65分; m/z 455 [M+H]+。 (Intermediate 33)
(tert-butyl N-[(1S)-1-[[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]propyl] carbamate)

tert-Butyl N-[(1S)- 1-Carbamoylpropyl]carbamate (Intermediate 32) was used to synthesize the title compound.
LC/MS: QC_3_MIN: Rt = 2.65 min; m/z 455 [M+H]+.

中間体13の合成に使用したものと同じ方法によって、tert-ブチル N-[(1R)-1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]プロピル]カルバメート(中間体9)の代わりにtert-ブチル N-[(1S)-1-[[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]カルバモイル]プロピル]カルバメート(中間体33)を用いて、表題化合物を合成した。
LC/MS: QC_3_MIN: Rt＝1.98分; m/z 355 [M+H]+。 (Intermediate 34)
((2S)-2-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]butanamide)

tert-Butyl N-[(1R)-1-[[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4- tert-butyl N-[(1S)-1-[[5-(7-methylspiro[2H-benzofuran-3,1] instead of yl)oxypyrazin-2-yl]carbamoyl]propyl]carbamate (Intermediate 9) '-Cyclopropan]-4-yl)oxypyrazin-2-yl]carbamoyl]propyl]carbamate (Intermediate 33) was used to synthesize the title compound.
LC/MS: QC_3_MIN: Rt = 1.98 min; m/z 355 [M+H]+.

N,N-ジメチルアセトアミド(1mL)中の2-ブロモ-5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシ-ピラジン(中間体1、30mg、0.069mmol)の溶液に、5,5-ジメチルイミダゾリジン-2,4-ジオン(44.4mg、0.345mmol)及び酸化銅(I)(5mg、0.035mmol)を添加した。フラスコに、窒素ガスを流し、1晩135℃で撹拌したままとした。反応を、EtOAc(10mL)で希釈し、先ず、塩化アンモニウムの飽和水溶液(20mL)で洗浄し、次いで、ブライン(20mL)で洗浄した。有機層を集め、硫酸ナトリウムで乾燥させ、乾固するまで蒸発させた。その後、残渣を、溶離液として80:20～40:60のシクロヘキサン:酢酸エチルを用いるフラッシュカラムクロマトグラフィーを用いて精製して、5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン(17mg)を白色固体として得た。

(Example 1 Route 1)
(5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione)

2-Bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy-pyrazine (Intermediate 1, 30 mg, 0.069 in N,N-dimethylacetamide (1 mL) mmol), 5,5-dimethylimidazolidine-2,4-dione (44.4 mg, 0.345 mmol) and copper(I) oxide (5 mg, 0.035 mmol) were added. The flask was flushed with nitrogen gas and left stirring at 135° C. overnight. The reaction was diluted with EtOAc (10 mL) and washed first with a saturated aqueous solution of ammonium chloride (20 mL) and then with brine (20 mL). The organic layers were collected, dried over sodium sulphate and evaporated to dryness. The residue was then purified using flash column chromatography using 80:20 to 40:60 cyclohexane:ethyl acetate as eluent to yield 5,5-dimethyl-3-[5-(7-methylspiro[2H). -Benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione (17 mg) was obtained as a white solid.

2-Bromo-5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxy-pyrazine (Intermediate 1) was replaced with the appropriate bromopyrazine using the methods previously described. and replacing 5,5-dimethylimidazolidine-2,4-dione with the appropriate hydantoin, the following compounds were prepared. The final product was purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 cartridge; water/acetonitrile or other suitable solvent system). .

アセトニトリル(1mL)中の3-(5-クロロピラジン-2-イル)-5,5-ジメチル-イミダゾリジン-2,4-ジオン(中間体5、20mg、0.083mmol)及び7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-オール(中間体156 WO2012076877、22mg、0.125mmol)の溶液に、炭酸カリウム(17.2mg、0.12mmol)を添加した。反応混合物を、1晩60℃で撹拌し、その後、3時間80℃で撹拌した。反応混合物を、真空下濃縮し、粗体を、カラムとしてSNAP 10g及び溶離液として80/20～20/80のCヘキサン/EtOAcを用いて、シリカゲル(BIOTAGE SYSTEM)でのフラッシュクロマトグラフィーによって精製した。画分は、まだ純粋ではなく、これらを、カラムとしてSNAP C-18及び溶離液として95/5～5/95のH2O/ACNを用いて、逆相クロマトグラフィーによって精製して、5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン(9.4mg)を白色固体として得た。
LC/MS: QC_3_MIN: Rt＝2.224分; m/z 381 [M+H]+。 (Example 1 route 2)
(5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione)

3-(5-Chloropyrazin-2-yl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 5, 20 mg, 0.083 mmol) and 7-methylspiro[2H- To a solution of benzofuran-3,1′-cyclopropan]-4-ol (Intermediate 156 WO2012076877, 22 mg, 0.125 mmol) was added potassium carbonate (17.2 mg, 0.12 mmol). The reaction mixture was stirred overnight at 60°C and then at 80°C for 3 hours. The reaction mixture was concentrated under vacuum and the crude was purified by flash chromatography on silica gel (BIOTAGE SYSTEM) using SNAP 10 g as column and 80/20 to 20/80 C hexane/EtOAc as eluent. . The fractions were still impure and were purified by reverse phase chromatography using SNAP C-18 as column and HO/ACN from 95/5 to 5/95 as eluent to yield 5,5- Dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione (9.4mg) to white Obtained as a solid.
LC/MS: QC_3_MIN: Rt = 2.224 min; m/z 381 [M+H]+.

Using the methods described above, substituting the appropriate phenol for 7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-ol and 3-(5-chloropyrazin-2-yl)- Using 5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 5) or alternatively using the appropriate chloropyrazine intermediate, the following compounds were prepared. The final product was purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 cartridge; water/acetonitrile or other suitable solvent system). .

ジクロロメタン(2mL)中の(2R)-2-アミノ-N-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]ブタンアミド(中間体13、13mg、0.037mmol)及びN,N-ジエチルエタンアミン(11mg、0.11mmol)の混合物を、0℃に冷却した。ジクロロメタン(0.5mL)中の炭酸ビス(トリクロロメチル)(4,5mg、0.015mmol)の溶液を滴下し、反応混合物を1時間同温度で撹拌した。追加のジクロロメタン(0.5mL)中の炭酸ビス(トリクロロメチル)(1.5mg)を添加し、撹拌を30分間継続した。混合物を、室温まで昇温させた。反応混合物を、ジクロロメタン(20ml)で希釈し、有機相を、0.1N HCl水溶液(20ml)で洗浄し、その後、ブライン(20ml)で洗浄した。相を分離し、有機層を、Na₂SO₄で乾燥し、濾過し、蒸発させた。残渣を、SNAP C-18カラムを用いて、90:10～0:100の水:アセトニトリルで溶出させて、逆相クロマトグラフィーによって精製した。適当な画分を合わせ、乾固するまで蒸発させて、(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン(7.5mg)を白色固体として得た。
LC/MS: QC_3_MIN: Rt＝2.305分; m/z 381 [M+H]+。エナンチオマー純度は、キラル管理法を用いて＞95％と確認された。 (Example 9 (Route 1))
((5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4- Zeon)

(2R)-2-Amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]butanamide in dichloromethane (2 mL) A mixture of intermediate 13, 13 mg, 0.037 mmol) and N,N-diethylethanamine (11 mg, 0.11 mmol) was cooled to 0°C. A solution of bis(trichloromethyl)carbonate (4.5 mg, 0.015 mmol) in dichloromethane (0.5 mL) was added dropwise and the reaction mixture was stirred for 1 hour at the same temperature. Additional bis(trichloromethyl) carbonate (1.5 mg) in dichloromethane (0.5 mL) was added and stirring continued for 30 minutes. The mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane (20ml) and the organic phase was washed with 0.1N HCl aqueous solution (20ml) followed by brine (20ml). The phases were separated and the organic layer was dried _{over Na2SO4} , filtered and evaporated. The residue was purified by reverse phase chromatography using a SNAP C-18 column, eluting with 90:10 to 0:100 water:acetonitrile. Appropriate fractions are combined and evaporated to dryness to give (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl) Oxypyrazin-2-yl]imidazolidine-2,4-dione (7.5 mg) was obtained as a white solid.
LC/MS: QC_3_MIN: Rt = 2.305 min; m/z 381 [M+H]+. Enantiomeric purity was confirmed to be >95% using chiral control methods.

酢酸エチル(500mL)中の(2R)-2-アミノ-N-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]ブタンアミド(中間体13、21g、59.26mmol)の溶液に、1-1'-カルボニルジイミダゾール(10.57g、65.18mmol)を、各回約2gの5回で添加し、室温で4時間撹拌した。反応を、氷でクエンチし、0.2NのHCl水溶液(250ml)を添加した。2相を分離し、有機層を、0.2N HCl水溶液(250ml)及びブライン(200ml)で洗浄し、その後、硫酸ナトリウムで乾燥させ、濾過し、乾固するまで蒸発させた。粗体を、各約4.2gの4つのアリコートに分割し、各アリコートを、カラムとしてSNAP(100G)及び溶離液として80/20～20/80のシクロヘキサン/酢酸エチルを用いて、シリカゲルでのフラッシュクロマトグラフィーによって精製した。各試行から得た所望の画分を集め、溶媒乾固するまで蒸発させた。得られた薄黄色固体を、シクロヘキサン/酢酸エチル(1/1、3体積)(90ml)の溶液中に懸濁させ、2時間50℃で撹拌した。その後、混合物を、室温まで放冷し、真空下濾過した。湿ったケーキを、氷冷シクロヘキサン(15ml)で洗浄し、固体を集め、乾燥して、表題化合物(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン(13.6g)を白色固体として得た。

(Example 9 (route 2))
((5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4- Zeon)

(2R)-2-Amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]butanamide in ethyl acetate (500 mL) To a solution of (Intermediate 13, 21 g, 59.26 mmol) was added 1-1′-carbonyldiimidazole (10.57 g, 65.18 mmol) in 5 portions of about 2 g each time and stirred at room temperature for 4 hours. The reaction was quenched with ice and 0.2N HCl aqueous solution (250ml) was added. The two phases were separated and the organic layer was washed with 0.2N HCl aqueous solution (250ml) and brine (200ml) then dried over sodium sulphate, filtered and evaporated to dryness. The crude was split into 4 aliquots of approximately 4.2 g each and each aliquot was flashed over silica gel using SNAP (100 G) as column and cyclohexane/ethyl acetate from 80/20 to 20/80 as eluent. Purified by chromatography. The desired fractions from each run were pooled and solvent evaporated to dryness. The pale yellow solid obtained was suspended in a solution of cyclohexane/ethyl acetate (1/1, 3 volumes) (90 ml) and stirred at 50° C. for 2 hours. The mixture was then allowed to cool to room temperature and filtered under vacuum. The wet cake was washed with ice cold cyclohexane (15ml) and the solid collected and dried to give the title compound (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1 '-Cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione (13.6 g) was obtained as a white solid.

(2R)-2-Amino-N-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4- Substituting the appropriate butanamide for yl)oxypyrazin-2-yl]butanamide (Intermediate 13), the following compounds were prepared. The final product was purified by flash chromatography (silica cartridge; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 cartridge; water/acetonitrile or other suitable solvent system). .

中間体9の合成に使用した「経路1」の方法によって、(2R)-2-アミノ-N-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]ブタンアミド(中間体13)の代わりに(2S)-2-アミノ-N-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]ブタンアミド(中間体34)を用いて、表題化合物を合成した。
LC/MS: QC_3_MIN: Rt＝2.29分; m/z 381 [M+H]+。 (Example 15)
((5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4- Zeon)

(2R)-2-Amino-N-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl by the method of 'pathway 1' used for the synthesis of intermediate 9 (2S)-2-amino-N-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-instead of )oxypyrazin-2-yl]butanamide (Intermediate 13) yl)oxypyrazin-2-yl]butanamide (Intermediate 34) was used to synthesize the title compound.
LC/MS: QC_3_MIN: Rt = 2.29 min; m/z 381 [M+H]+.

(Biological Example)
(Biological Example 1: Measurement of Kv3.1, Kv3.2, and Kv3.3 Channel Modulation)
The ability of compounds of the invention to modulate voltage-gated potassium channel subtype Kv3.3/Kv3.2/Kv3.1 can be determined using the following assay. Analogous methods can be used to examine the ability of compounds of the invention to modulate other channel subtypes.

(cell biology)
To assess the effects of compounds on human Kv3.3 channels (hKv3.3), stable cell lines expressing human Kv3.3 channels were established in Chinese hamster ovary (CHO)-K1 cells in the pBacMire_KCNC-3 vector. It is produced by transfecting with Cells were cultured in DMEM/F12 (Gibco) supplemented with 10% fetal bovine serum (Gibco), 1× non-essential amino acids (Invitrogen), and 400 μg/mL geneticin (G418). Cells are grown and maintained at 37° C. in a humidified environment containing 5% CO ₂ in air.

To assess the effects of compounds on the human Kv3.2 channel (hKv3.2), stable cell lines expressing the human Kv3.2 channel (hKv3.2) were generated by transfecting CHO-K1 cells with pCIH5-hKv3. It is produced by transfecting with 2 vectors. Cells are cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum, 1× non-essential amino acids (Invitrogen), and 500 μg/ml hygromycin-B (Invitrogen). Cells are grown and maintained at 37° C. in a humidified environment containing 5% CO ₂ in air.

To evaluate the effects of compounds on human Kv3.1 channels (hKv3.1): human embryonic kidney (HEK)-hKv3.1 cell line, HEK-293 cells with human Kv3.1 (NM_004976.4). It is produced by transfection with an expression vector containing Cells are cultured with MEM supplemented with 10% heat-inactivated FBS, 2 mM L-glutamine, 1% penicillin-streptomycin, and 0.6 mg/mL geneticin (G418). HEK-hKv3.1b cells were grown in T175 cm 2 flasks at 37° C., 5% CO 2 using MEM growth medium containing G418 selective antibiotic (0.6 mg/ml). Cells were detached every 3-4 days using DPBS, washing flasks twice, after which they were displaced using TrypLE and replated at a density of 2-4×10 6 cells/flask. .

(Cell preparation for IonWorks Quattro™ experiments)
On the day of the experiment, remove the cells from the incubator and remove the medium. Cells were washed with 5 ml Dulbecco's PBS without calcium and magnesium (DPBS) and detached by the addition of 3 ml Versene (Invitrogen, Italy), followed by a brief incubation at 37° C. for 5 min. do. A cell suspension is prepared by tapping the flask to dislodge the cells and adding 10 ml of DPBS containing calcium and magnesium. The cell suspension is then placed in a 15 ml centrifuge tube and centrifuged at 1200 rpm for 2 minutes. After centrifugation, the supernatant is removed, the cell pellet is resuspended in 4 ml DPBS containing calcium and magnesium using a 5 ml pipette, and the pellet is triturated. The cell suspension volume is then corrected to give a cell concentration of approximately 3 million cells per ml for the assay.
All solutions added to the cells are pre-warmed to 37°C.

(electrophysiology)
(Ionworks)
Experiments are performed at room temperature using the IonWorks Quattro™ planar array electrophysiology technology (Molecular Devices) with PatchPlate™ PPC. Stimulation protocols and data acquisition are performed using a microcomputer (Dell Pentium 4). Planar electrode hole resistance (Rp) is determined by applying a voltage step of 10 mV between each well. These measurements are performed prior to cell addition. After cell addition and seal formation, a seal test is performed by applying a voltage step of -80 mV to -70 mV for 160 ms. After this, an amphotericin-B solution is added to the intracellular surface of the electrode to gain intracellular access. Maintain cells at -70 mV. Leak subtraction is performed in all experiments by applying a 50 ms hyperpolarizing (10 mV) pre-pulse to induce leak currents, followed by a 20 ms period at the holding potential before the test pulse.

For the hKv3.2 and hKv3.1 assays, from a holding potential of -70 mV, a first test pulse at -15 mV was applied for 100 ms, followed by -70 mV for 100 ms followed by a second pulse at +40 mV for 50 ms. . Cells were then held at −100 mV for 100 ms, another pulse of −70 mV to +40 mV (50 ms duration) was applied, after which the voltage was limited to −40 mV for 200 ms.

For the hKv3.3 assay, from a holding potential of −70 mV, a first test pulse to 0 mV is applied for 500 ms, followed by an additional 100 ms at −70 mV followed by a second pulse to 40 mV for 200 ms. These longer test pulses are used to test the inactivation of hKv3.3 channels. The test pulse protocol can be performed in the absence (pre-read) and presence (post-read) of the test compound. Pre-reading and post-reading can be separated by compound addition followed by a 3 minute incubation.

(solutions and drugs)
Intracellular fluid contains (mM): potassium gluconate 100, KCl 54, _MgCl2 3.2, HEPES 5, adjusted to pH 7.3 with KOH. Amphotericin-B solution is prepared as a stock solution in DMSO at 50 mg/ml and diluted with intracellular solution to a final working concentration of 0.1 mg/ml. The external solution is Dulbecco's phosphate buffered saline (DPBS) containing (mM): _CaCl2 0.90, KCl 2.67, _{KH2PO4 1.47} , _MgCl.6H2O 0.493, NaCl 136.9, Na3 _{. PO4} 8.06, pH 7.4.

Compounds of use in the present invention (or reference compounds such as N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N'-phenylurea) , dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO in 384 compound plates using a Biomek FX (Beckman Coulter). Transfer each dilution (1 μL) to another compound plate and add external solution (66 μL) containing 0.05% pluronic acid. Add 3.5 μL from each plate containing a compound of the invention and incubate with the cells during the IonWorks Quattro™ experiment. Final assay dilution is 200 and final compound concentrations range from 50 μM to 50 nM.

(data analysis)
Analyze and filter recordings using both seal resistance (>20 MΩ) and peak current amplitude (>500 pA at 40 mV voltage steps) in the absence of compound to eliminate inappropriate cells from further analysis. . The hKv3.2 and hKv3.1 assays utilize pairwise comparisons of evoked currents between pre- and post-drug addition measured at −15 mV voltage steps to determine the positive regulatory effect of each compound. Outward currents mediated by Kv3 channels are measured and determined by subtracting the average baseline current at -70 mV over the 10 ms period immediately preceding the -15 mV step from the average intensity of the current over the last 10 ms of the -15 mV voltage pulse. . These Kv3 channel currents after addition of test compound are then compared to currents recorded before addition of compound. Data represent maximal effect of reference compound (50 μM N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N′-phenylurea) and vehicle. Normalized to the effect of control (0.5% DMSO). Normalized data are analyzed using ActivityBase or Excel software. The concentration of compound required to increase the current by 50% of the maximal increase produced by the reference compound ( _EC50 ) is determined by fitting the concentration-response data utilizing a 4-parameter logistic function in ActivityBase. In the hKv3.3 assay, pairwise comparisons of evoked currents between pre- and post-drug addition were performed in 0 mV steps taking into account the peak current and the current decay (inactivation) over the duration of the 0 mv test pulse (500 ms). Measure in

N-Cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N'-phenylurea is obtained from ASINEX (registration number: 552311- 06-5).

^＋n=10。n=18の場合は、pEC50は、5.56であり、maxR％は、152であった。 Incorporation of the pyrazine ring may have detrimental effects on the pEC50 and maxR of Kv3.1 modulators, as shown by studies of RE1-RE4.

⁺ n=10. For n=18, pEC50 was 5.56 and maxR% was 152.

^＋n=10。n=18の場合には、pEC50は、5.56であり、maxR％は、152であった。
^＊n=4。n=22の場合には、pEC50は、5.90であり、maxR％は、146であった。
^＄n=2。n=26の場合には、pEC50は、5.63であり、maxR％は、147であった。

As shown by testing RE5-RE9 compared to Example 1, incorporation of the para-pyrazine ring in Example 1 unexpectedly results in higher pEC50 and higher maxR in the Kv3.1 assay. RE10 shows that the central meta-pyrazine ring significantly reduces pEC50 and maxR compared to Example 1 para-pyrazine.

⁺ n=10. For n=18, pEC50 was 5.56 and maxR% was 152.
^* n=4. For n=22, pEC50 was 5.90 and maxR% was 146.
^＄ n=2. For n=26, pEC50 was 5.63 and maxR% was 147.

All examples of compounds of formula (I) that were tested are shown above and show good pEC50 and maxR properties in the Kv3.1 assay. Previous disclosure of Kv3.1 data for control compounds may differ slightly due to the lower number of measurements.

Secondary analysis of data from the hKv3.1, hKv3.2, and hKv3.3 assays described can be used to investigate the effect of compounds on the rate of current rise from the onset of the depolarizing voltage pulse. The magnitudes of compound effects are time constants obtained from nonlinear fits of the onset of Kv3.1, Kv3.2, and Kv3.3 currents after initiation of a -15 mV depolarizing voltage pulse, using the equations shown below. (Tau _act ).
Y=(Y0-Ymax)*exp(-K*X)+Ymax
(In the formula,
Y0 is the current value at the beginning of the depolarizing voltage pulse;
Ymax is the plateau current;
K is the rate constant and Tau _act is the activation time constant, the reciprocal of K).

Similarly, the effect of compounds on the time it takes for Kv3.1, Kv3.2, or Kv3.3 currents to decay upon channel closure at the end of a −15 mV depolarizing voltage pulse can be investigated. In this latter case, the magnitude of the compound's effect on channel closure can be determined from the time constant (Tau _deact ) of the nonlinear fit of the current decay (“tail current”) immediately after the end of the depolarizing voltage pulse.

Kv3.1, Kv3.2 and Kv3.3 channels must be activated and deactivated very rapidly to allow neurons to fire action potentials at high frequency (Rudy et al. 2001). ). The slowing of activation is likely to delay the onset of action potential repolarization. Slowing down inactivation can produce hyperpolarizing currents that reduce neuronal excitability and delay the time before the neuron can fire further action potentials. Together, these two slowing effects on channel activation and deactivation appear to result in a decrease rather than an enhancement in the ability of neurons to fire at high frequencies. Compounds with this slowing effect on Kv3.1 and/or Kv3.2 and/or Kv3.3 channels will therefore effectively behave as negative modulators of said channels leading to slowing of neuronal firing. . This latter effect has been demonstrated in some of the compounds disclosed in WO2011/069951, from "fast-firing" interneurons in the cortex of the rat brain using in vitro electrophysiological techniques. A significant increase in Tau _act can be observed from the recordings made. Addition of related compounds reduces the ability of neurons to fire in response to trains of 300 Hz depolarizing pulses.

Thus, while certain compounds can be identified as acting as positive modulators in recombinant cell assays, those compounds that significantly increase Tau _act values may reduce the ability of native tissue neurons to fire at high frequencies. can be done.

(Biological Example 2: Determination of Blood and Brain Tissue Connectivity)
(Materials and methods)
Sprague Dawley rat whole blood collected during the week of the experiment using K3-EDTA as anticoagulant is diluted in isotonic phosphate buffer 1:1 (v/v). Sprague Dawley rat whole brains stored frozen at -20°C are thawed and homogenized in artificial cerebrospinal fluid (CSF) 1:2 (w/v).

An appropriate amount of test compound is dissolved in DMSO to give a 10 millimolar solution. Further dilutions are then prepared with 50% acetonitrile in MilliQ water to obtain a 166.7 micromolar working solution. This working solution is used to spike blood to obtain a final concentration of 0.5 micromolar in whole blood. Similarly, the working solution is used to spike brain samples to obtain a final concentration of 5 micromolar in whole brain. Control samples (n=3) are immediately extracted from these spiked blood and brain preparations and used to calculate the initial recovery of the test article.

With the two half-wells separated by a semi-permeable membrane, 150 μL of compound-free buffer (isotonic phosphate buffer for blood or artificial CSF buffer for brain) is placed in one half-well and spiked with 150 μL. The other half-well is filled with the mixed matrix (blood or brain). After an equilibration period of 5 hours at 37° C., 50 μL of dialyzed matrix (blood or brain) was added to 50 μL of the corresponding compound-free buffer and Reverse the operation so that the volumes of buffer are the same. Samples are then extracted by protein precipitation using 300 μL of acetonitrile containing rolipram (control for positive ionization mode) or diclofenac (control for negative ionization mode) as internal standard and centrifuged at 3000 rpm for 10 minutes. do. The supernatant was taken (100 μL), diluted with 27% AcN in MilliQ water (200 μL) and then injected into an HPLC-MS/MS or UPLC-MS/MS system to determine the concentration of test compounds present. do.

(式中:fucr=補正された非結合画分;D=マトリックス希釈係数(血液ではD=2、脳ではD=3)である)。
従って:
％結合率=(1-fucr)×100
％非結合率=100-％結合率。 (analysis)
Blood and brain tissue connections are then determined using the following formula:
Afu=buffer/blood or Afu=CSF/brain
(Where Afu = apparent unbound fraction; buffer = ratio of analyte/internal standard determined in the buffer compartment; blood = ratio of analyte/internal standard determined in the blood compartment; brain = in the brain compartment determined analyte/internal standard ratio)

(wherein: fucr=corrected unbound fraction; D=matrix dilution factor (D=2 for blood, D=3 for brain)).
Therefore:
% binding = (1-fucr) x 100
% unbound = 100-% bound.

(Brain/blood partition ratio (Kbb) determination)
For compounds that can freely cross the blood/brain barrier (BBB), unbound concentrations in blood and brain will be equivalent under steady-state distribution conditions. The Kbb value is therefore:
Fu (blood)/Fu (brain)
, which is expected to be equivalent to the ratio of brain concentration to blood concentration (Ct(brain)/Ct(blood)) if no efflux pump transporters are involved.

*水中18％のAcNで希釈した上清 (result)
Examples 1, 9, and 10, and certain control compounds were tested in the manner described above to determine the unbound brain fraction. The results were as follows:

*supernatant diluted with 18% AcN in water

The pyrazine compounds of the invention exhibited increased unbound brain fractions compared to their pyridine control compounds.

(Biological Example 3: Determination of pharmacokinetic parameters in vivo)
(material and method)
Adult male rats (Charles River, Italy) were dosed orally with test compounds at 1 mg/kg (5 ml/kg, in 5% v/v DMSO in water, 0.5% w/v HPMC) and 0.5 mg/kg. kg (2 ml/kg in 5% v/v DMSO, 40% w/v PEG400 in saline) intravenously. After oral administration, blood samples are taken from the portal vein and heart of each rat (one rat per time point) under deep isofluorane anesthesia. Serial blood samples are taken from the lateral tail vein of each rat after intravenous administration. An additional group of rats (n=1 per test compound) received a single dose of the PgP transport inhibitor elacridar (3 mg/kg) immediately prior to oral administration of the test compound at 1 mg/kg as described above. received intravenously. Blood and brain samples are collected at a single time point, 0.5 hours after dosing in these animals. In all cases, blood samples are collected in potassium EDTA tubes.

Blood and brain samples can be assayed for concentrations of test compounds using methods based on protein precipitation with acetonitrile followed by HPLC/MS-MS analysis with optimized analytical methods.

(analysis)
Concentrations of test compounds in blood (expressed as ng/ml) and brain (expressed as ng/g) at various time points after either oral or intravenous dosing were determined using WinNonLin Professional version 4.1 in a non-compartmental assay. Analysis is performed using a pharmacokinetic model. You will get the following parameters:

Intravenous administration: maximum concentration over time (Cmax), integrated concentration over time (AUC), clearance (Clb), volume of distribution (Vss), and half-life (t1/2).

Oral administration: Cmax, time of maximum concentration (Tmax), AUC, bioavailability (F%), fraction absorbed (Fa%), blood-to-brain ratio (AUC BB), and AUC BB in the presence of elacridar fold change of .

Compounds of the invention can be expected to show good availability in brain tissue.

(Biological Example 4: In Vitro Metabolic Stability Test in Human Hepatocytes)
(Method)
The purpose of this study was to determine the metabolic stability in mixed-gender human cryopreserved hepatocytes. Testosterone and 7-hydroxycoumarin were used as positive controls for phase I and phase II metabolism, respectively.

Incubation medium was prepared by combining William's medium E, HEPES buffer 1 M, and L-glutamine 200 mM, respectively, in the following ratios: 88%, 10%, and 2% (440 mL, 50 mL, and 10 mL, respectively). The resulting medium was bubbled with carbogen (5% _CO2 , 95% _O2 ) for 30 minutes before use. Cryopreserved hepatocytes were thawed and suspended in pre-warmed incubation medium at 37°C. Cells were centrifuged, resuspended in medium and counted using a hemocytometer (Burker's chamber). Cell viability was measured using the trypan blue exclusion test.

Test compounds were dissolved separately in DMF to give 50 mM stock solutions. These were further diluted in water/acetonitrile 50/50 (v/v) to give the corresponding 50 uM working solutions. Testosterone and 7-hydroxy-coumarin were dissolved in DMF to obtain a 50 mM testosterone solution and a 5 mM 7-hydroxy-coumarin solution. These solutions were then diluted in incubation medium to obtain a 1 mM testosterone working solution and a 500 uM 7-hydroxy-coumarin working solution.

10 uL of each working solution, i.e. 50 uM test compound, 1 mM testosterone and 500 uM 7-hydroxy-coumarin, 990 uL of 0.5 x 10 ⁶ cell suspension to obtain final concentrations of 0.5 uM, 10 uM and 5 uM respectively. was added to The concentration of organic solvent in each incubation was constant and <1% (v/v).

Test compounds were separately sexed at 0.5uM in 24-well plates at 37°C for 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 180 minutes (12 time points). Incubated with mixed human cryopreserved hepatocytes. At each time point, the robotic processor aspirates 50 uL of the incubation mixture from each well and dispenses it into a chilled 96-well plate containing 100 uL of acetonitrile along with the corresponding internal standard at 150 ng/mL, The reaction was stopped. An aliquot of water (120 uL) was then added to equilibrate the organic solvent content to 37%. Samples were centrifuged (approximately 3500 g for 10 min) prior to LC MS/MS analysis.

Positive controls testosterone and 7-hydroxy-coumarin were administered in single doses (n=1) at 10 and 5 uM, respectively, at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 180 min (12 time points) incubated with mixed sex human cryopreserved hepatocytes under the same conditions reported above for the test article to demonstrate phase I and phase II metabolism in the hepatocyte lineage. rice field. At each time point, the robotic processor aspirates 50 uL of the incubation mixture from each well and dispenses it into a chilled 96-well plate containing 100 uL of acetonitrile along with rolipram as an internal standard to stop the reaction. rice field. An aliquot of water (120 uL) was then added to equilibrate the organic solvent content at 37%. Samples were centrifuged (approximately 3500 g for 10 min) prior to LC MS/MS analysis.

Metabolic stability was calculated from the peak area ratio of residual test compound to internal standard versus time.

Intrinsic clearance (CLint) was calculated using the actual volume of incubation V (mL), the amount of hepatocytes in the incubation M (million cells), and the hepatocellularity number Hn (120 for humans) per gram of liver. was used to determine the first order elimination constant k(min ^-1 ) (obtained from GraphPad by plotting the natural logarithm of the peak area ratio of the residual test article to the internal standard versus time).

CLint values were expressed as ml/min/g liver.

Examples 9 and 10 showed lower clearance compared to the pyridine control compounds RE11 and RE13.

(Biological Example 5: Ames test)
(Method)
The purpose of this in vitro study was to determine the potential of the test substance to induce genetic mutations in vitro in bacterial strains of Salmonella typhimurium (TA1535, TA1537, TA98, and TA100) and Escherichia coli WP2 uvrA (pKM101). was to evaluate gender. The test method was based on established procedures for bacterial mutagenicity testing. Assays were also performed in the presence and absence of an exogenous mammalian oxidative metabolism system (S9-mix).

The study was designed according to national and international guidelines and met regulatory agency requirements for toxicity testing of new drugs. The design of this study is consistent with the following study guidelines:
• ICH Guideline M3(R2) on Non-clinical Safety Studies for Conducting Human Clinical Trials and Marketing Authorization of Pharmaceutical Products (CPMP/ICH/286/95, June 2009).
• ICH Topic S2(R1) Guidance on Genotoxicity Testing and Data Interpretation of Pharmaceuticals Intended for Human Use. June 2012.

(bacterial strain)
The following bacterial strains were used:

Strains TA1535, TA100, and WP2 uvrA pKM101 detect base substitution mutations. Strains TA1537 and TA98 detect frameshift mutations.

A bacterial inoculum was used with 10 ml of nutrient broth (NB2, ampicillin in the case of S. typhirium strains TA98 and TA100, strains containing the pKM101 plasmid and E. coli WP2 uvrA (pKM101) to maintain plasmid copy number). A fresh culture medium was prepared in the medium containing Bacteria were cultured in a shaking incubator at 37±2° C. for 10-12 hours to obtain 1-2×10 ⁹ cells/mL.

Bacterial suspensions were added in a volume of 100 uL to top agar (containing trace amounts of amino acids required for auxotrophy).

(Mammalian oxidative metabolism)
The phenobarbital, 56 benzoflavone-inducible rat liver post-mitochondrial fraction (S9) from Molecular Toxicology Incorporated, USA (MolTox™) was used as an exogenous oxidative metabolic system. Batches of S9 fractions stored as aliquots were thawed immediately prior to use.The S9 mixture was added to NADP (3.15 mg/mL), glucose-6-phosphate (1.5 mg/mL), in phosphate buffer pH 7.4. and S9 (10% v/v) to a NADPH generating system containing 2% v/v saline solution containing MgCl ₂ (81.3 mg/mL) and KCl (123 mg/mL). For treatments in the presence of the mixture, the S9 mixture was used at a final volume of 500 uL/plate For treatments in the absence of the S9 mixture, an equal volume of sterile phosphate buffer pH 7.4 was substituted for the S9 mixture. was added.

陽性対照は、凍結された(約-20℃)ストック溶液から調製され、使用の間周囲温度で保管された。 (positive control formulation)
The following positive controls (supplied by MolTox™ through Trinova Biochem GmbH, Giessen, Germany and Sigma Aldrich, Milano, Italy) were used and formulated as follows:

Positive controls were prepared from frozen (approximately -20°C) stock solutions and stored at ambient temperature between uses.

ビヒクル、被験物質、及び陽性対照製剤を、100 uL/プレートの体積でプレートに添加した。 (test substance)
The study consisted of 4 replicate plates for vehicle (DMSO) control and 2 replicate plates for test articles and positive controls receiving treatment in the absence and presence of the S9 mixture. Various test article concentrations from 5ug/plate to 5000ug/plate were tested as follows:

Vehicle, test articles, and positive control formulations were added to the plates in a volume of 100 uL/plate.

(Plate treatment and incubation)
Top agar was supplemented with traces of histidine and biotin or tryptophan, aliquoted (2 ml/plate) and maintained at 46±2°C. Appropriate bacterial suspensions were added to 2 ml of top agar, followed by test article or vehicle/positive control solutions and sterile phosphate buffer pH 7.4 or S9 mixtures. This final treatment mixture was poured onto minimal agar plates (Vogel Bonner plates) and incubated at 37±2° C. for approximately 64 hours in the dark.

(Plate scoring and analysis)
At the end of the incubation period, the plates were evaluated (by visual inspection) for deposition of test article. Plates were electronically scored for bacterial colonization using a colony counter ProtoCOL3 Synbiosis. If deposition of the test article occurred, a manual bacterial colony count for each strain was performed and terminated at the lowest treatment concentration that did not interfere with manual scoring.

Scoring is followed by plating for signs of toxicity (i.e., reduced/reduced growth of background flora, presence of pin dots/pseudorevertant colonies, and/or reduced colony counts). was inspected.

Data for any treatment concentration were more than twice as high as concurrent vehicle control values for TA98, TA100, and WP2 uvrA (pKM101) and concurrent vehicle control values for TA1535 and TA1537 in relation to dose-related responses. The result should be considered positive if it shows a 3-fold or greater response. Results meeting these criteria only partially, or data for any strain showing a dose-related response but not exceeding the 2-fold or 3-fold thresholds as detailed, are equivocal. is considered.

Acceptance criteria for the following:
1. The highest concentration tested should be 5000ug/plate or limited to the solubility of the test article in the vehicle;
2. If the solubility of the test article is the limiting factor, the highest concentration selected for plate scoring is the lowest concentration at which precipitation of the test article is observed on the treatment plate at the end of the incubation period and which does not interfere with scoring. I applied what would happen.

If toxicity was the limiting factor, the highest evaluable concentration for a genetic mutation would be the lowest concentration at which signs of significant bacterial toxicity were observed within the time period of plate scoring.
(result)

Anilines associated with RE6/RE11, which have been shown to be degraded under certain conditions, were found to be mutagenic. This finding presents a risk in the future development of RE6/RE11 and also compounds that would generate related anilines (e.g., (5R)-5-ethyl-3-(6-spiro[2H-benzofuran- The risks associated with 3,1′-cyclopropane]-4-yloxy-3-pyridyl)imidazolidine-2,4-dione, RE13) are also presented. Compounds that can be distinguished on the basis of related anilines are advantageous.

The anilines for Examples 1, 9, and 10 were non-mutagenic, and this could be expected to be the case for other compounds of the invention that would produce related anilines.

(additional animal models)
Patent Applications Nos. WO2011/069951, WO2012/076877, WO2012/168710, WO2013/083994, WO2013/175215, and WO2013/182851, which describe the potential utility of the compounds. , all of which are incorporated by reference for the purpose of providing animal models for testing of the compounds), Kv3.1 in animal models of seizures, hyperactivity, sleep disorders, psychiatric disorders, hearing disorders, and bipolar disorders and demonstrate the activity of compounds that are modulators of Kv3.2.

Patent Application No. WO2013/175211 (incorporated by reference for the purpose of describing the potential utility of the compounds and providing an animal model for testing of the compounds) describes acute noise-induced deafness in chinchillas. have demonstrated the efficacy of compounds that are modulators of Kv3.1 and Kv3.2 in models of Kv3.1 and Kv3.2, and have also evaluated their efficacy in models of central auditory processing deficits and in models of tinnitus.

Glait et al. 2018, Anderson et al. 2018, and Chamber et al. 2018 demonstrate the efficacy of Kv3.1 and Kv3.2 modulators in auditory association models.

Patent Application No. WO2017/098254 (incorporated by reference for the purpose of describing the potential utility of the compounds and providing an animal model for testing of the compounds) describes neuropathic and inflammatory pain demonstrate the efficacy of compounds that are modulators of Kv3.1 and Kv3.2 in the model of.

Throughout the specification and the claims below, the word "comprises" and variations such as "comprises" and "comprising", unless the context requires otherwise means the inclusion of a stated integer, step, group of integers or group of steps, but will be understood not to exclude other integers, steps, groups of integers or groups of steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of subsequent applications. 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, without limitation, the following claims.

(式中:
R₁は、H又はメチルであり;
R₂及びR₃は双方ともメチルであるか、又はR₂及びR₃は、それらが結合している炭素原子と一緒になって、スピロシクロプロピル環であり;
R₄は、メチル又はエチルであり;
R₅は、H又はメチルであり;
或いはR₄及びR₅は、それらが結合している炭素原子と一緒になって、C₃-C₄スピロカルボシクリルを形成する)
の化合物、又はそれらの塩及び/もしくは溶媒和物及び/もしくは誘導体。
(条項2)
R₁が、Hである、条項1記載の化合物。
(条項3)
R₁が、メチルである、条項1記載の化合物。
(条項4)
R₂及びR₃が、スピロシクロプロピル環である、条項1～3のいずれか1項記載の化合物。
(条項5)
R₂が、メチルであり、かつR₃が、メチルである、条項1～3のいずれか1項記載の化合物。
(条項6)
R₄が、メチルである、条項1～5のいずれか1項記載の化合物。
(条項7)
R₄が、エチルである、条項1～5のいずれか1項記載の化合物。
(条項8)
R₅が、Hである、条項1～7のいずれか1項記載の化合物。
(条項9)
R₅が、メチルである、条項1～7のいずれか1項記載の化合物。
(条項10)
R₄及びR₅が、異なる場合、それらが、以下の立体化学配置:
を有する、条項1～9のいずれか1項記載の化合物。

(条項11)
R₄及びR₅が、異なる場合、それらが、以下の立体化学配置:
を有する、条項1～9のいずれか1項記載の化合物。

(条項12)
R₄及びR₅が、それらが結合している炭素原子と一緒になって、スピロシクロプロピルを形成する、条項1～5のいずれか1項記載の化合物。
(条項13)
R₄及びR₅が、それらが結合している炭素原子と一緒になって、スピロシクロブチルを形成する、条項1～5のいずれか1項記載の化合物。
(条項14)
以下:
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン;
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオン;
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
からなる群から選択される、条項1記載の化合物、又はそれらの塩及び/もしくは溶媒和物、並びに/又はそれらの誘導体。
(条項15)
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項16)
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項17)
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項18)
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項19)
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項20)
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項21)
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項22)
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項23)
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項24)
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項25)
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項26)
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項27)
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオンである、条項1記載の化合物。
(条項28)
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオンである、条項1記載の化合物。
(条項29)
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項30)
条項1～29のいずれか1項記載の式(I)の化合物、又はそれらの医薬として許容し得る塩及び/もしくは溶媒和物。
(条項31)
医薬品としての使用のための、条項1～30のいずれか1項記載の化合物。
(条項32)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療における使用のための、条項31記載の化合物。
(条項33)
統合失調症の予防又は治療における使用のための、条項31記載の化合物。
(条項34)
聴覚障害の予防又は治療における使用のための、条項31記載の化合物。
(条項35)
疼痛の予防又は治療における使用のための、条項31記載の化合物。
(条項36)
脆弱Xの治療における使用のための、条項31記載の化合物。
(条項37)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための方法であって、それを必要としている対象に、有効量の条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項38)
統合失調症の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項39)
聴覚障害の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項40)
疼痛の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項41)
脆弱Xの治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項42)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項43)
統合失調症の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項44)
聴覚障害の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項45)
疼痛の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項46)
脆弱Xの治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項47)
条項1～30のいずれか1項記載の化合物、及び医薬として許容し得る担体又は賦形剤を含む医薬組成物。
(条項48)
さらなる医薬として許容し得る有効成分との組み合わせでの使用のための、条項1～30のいずれか1項記載の化合物。
(条項49)
式(II)又は(XVI):

(式中、R₁、R₂、及びR₃は、条項1で定義されるとおりであり、Xは、ハロ(Brなど)である)
の化合物。
(条項50)
式(XVI):

(式中、R₁、R₂、及びR₃は、条項1で定義されるとおりである）
の化合物。
(条項51)
式(IV):

(式中、R₄及びR₅は、条項1で定義されるとおりであり、Yは、ハロ(Clなど)である)
の化合物。
(条項52)
ヒダントインの二級窒素を介してか、又はトリアゾロンの二級窒素を介して、基Lで官能基化されており、Lが、以下:
a)-PO(OH)O^-・M⁺(式中、M⁺は、医薬として許容し得る一価の対イオンである)、
b)-PO(O^-)₂・2M⁺、
c)-PO(O^-)₂・D²⁺(式中、D²⁺は、医薬として許容し得る二価の対イオンである)、
d)-CH(R^X)-PO(OH)O^-・M⁺(式中、R^Xは、水素又はC_1-3アルキルである)、
e)-CH(R^X)-PO(O^-)₂・2M⁺、
f)-CH(R^X)-PO(O^-)₂・D²⁺、
g)-SO₃ ^-・M⁺、
h)-CH(R^X)-SO₃ ^-・M⁺、及び
i)-CO-CH₂CH₂-CO₂・M⁺
からなる基から選択される、条項1～30のいずれか1項記載の式(I)の化合物の誘導体、又はそれらの塩及び/もしくは溶媒和物。
(条項53)
天然同位体形態である、条項1～36のいずれか1項記載の化合物。
(条項54)
経口投与のための、条項1～48、52又は53のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項55)
1日あたり2～400mg、例えば、1日あたり2～300mg、特に、1日あたり5～250mgでの投与のための、条項1～48又は52～54のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項56)
1日あたり1回又は2回の投与のための、条項1～48又は52～55のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項57)
1日あたり1回の投与のための、条項56記載の化合物。
(条項58)
1日あたり2回の投与のための、条項56記載の化合物。
(条項59)
少なくとも3ヶ月の期間の投与のための、条項1～48又は52～58のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項60)
ヒト対象への投与のための、条項1～48又は52～58のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項61)
ヒト成人、例えば、18～65歳のヒト成人などへの投与のための、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項62)
66歳以上の年齢のヒトへの投与のための、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項63)
4歳～17歳などの18歳未満の年齢のヒト対象への、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項64)
式(I)の化合物又はその医薬として許容し得る塩、溶媒和物、及び/もしくは誘導体が、パッチ又は留置用剤によって送達される、条項1～48、52、53、又は59～63のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。 (Clause of the invention:)
(Article 1)
Formula (I):

(in the formula:
R ₁ is H or methyl;
_R2 and _R3 are both methyl, or _R2 and _R3 together with the carbon atom to which they are attached are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
_R5 is H or methyl;
Alternatively _R4 and _R5 together with the carbon atom to which they are attached form a _C3 - _C4 spirocarbocyclyl)
or salts and/or solvates and/or derivatives thereof.
(Article 2)
2. The compound of clause ₁ , wherein R1 is H.
(Article 3)
2. The compound according to clause ₁ , wherein R1 is methyl.
(Article 4)
A compound according to any one of clauses 1-3, wherein R ₂ and R ₃ are spirocyclopropyl rings.
(Article 5)
The compound according to any one of clauses 1-3, wherein R ₂ is methyl and R ₃ is methyl.
(Article 6)
6. The compound according to any one of clauses 1-5, wherein R ₄ is methyl.
(Article 7)
6. The compound according to any one of clauses 1-5, wherein R ₄ is ethyl.
(Article 8)
8. The compound according to any one of clauses 1-7, wherein _R5 is H.
(Article 9)
8. The compound according to any one of clauses 1-7, wherein R ₅ is methyl.
(Article 10)
When R ₄ and R ₅ are different, they have the following stereochemical configurations:
A compound according to any one of clauses 1-9, having

(Article 11)
When R ₄ and R ₅ are different, they have the following stereochemical configurations:
A compound according to any one of clauses 1-9, having

(Article 12)
A compound according to any one of clauses 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclopropyl.
(Article 13)
A compound according to any one of clauses 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclobutyl.
(Article 14)
the following:
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione;
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione ;
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 ,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione ;
5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- Dione;
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione ;
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione ;
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
A compound according to clause 1, or a salt and/or solvate thereof and/or a derivative thereof, selected from the group consisting of
(Article 15)
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione , a compound according to clause 1.
(Article 16)
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione, according to clause 1 compound.
(Article 17)
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 18)
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione, according to clause 1 compound.
(Article 19)
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 2. The compound according to clause 1, which is ,4-dione.
(Article 20)
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 21)
Clause 1 which is 5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione Compound as described.
(Article 22)
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- A compound according to clause 1, which is a dione.
(Article 23)
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 24)
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione 1. The compound described in 1.
(Article 25)
is (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione 1. The compound described in 1.
(Article 26)
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione, A compound according to Clause 1.
(Article 27)
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione The compound according to clause 1, which is
(Article 28)
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione The compound according to clause 1, which is
(Article 29)
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 30)
A compound of formula (I) according to any one of clauses 1-29, or a pharmaceutically acceptable salt and/or solvate thereof.
(Article 31)
31. A compound according to any one of clauses 1-30 for use as a medicament.
(Article 32)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and 32. A compound according to clause 31 for use in preventing or treating a disease or disorder selected from the group consisting of Parkinson's disease.
(Article 33)
32. A compound according to clause 31 for use in the prevention or treatment of schizophrenia.
(Article 34)
32. A compound according to clause 31 for use in the prevention or treatment of hearing impairment.
(Article 35)
32. A compound according to clause 31 for use in the prevention or treatment of pain.
(Article 36)
32. A compound according to clause 31 for use in treating Fragile X.
(Article 37)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and A method for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 1-30. The method as described above, comprising:
(Article 38)
31. A method for the prevention or treatment of schizophrenia, comprising administering a compound according to any one of clauses 1-30 to a subject in need thereof.
(Article 39)
31. A method for the prevention or treatment of hearing impairment, said method comprising administering to a subject in need thereof a compound according to any one of clauses 1-30.
(Article 40)
31. A method for the prevention or treatment of pain, said method comprising administering a compound according to any one of clauses 1-30 to a subject in need thereof.
(Article 41)
31. A method for the treatment of fragile X comprising administering to a subject in need thereof a compound according to any one of clauses 1-30.
(Article 42)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease.
(Article 43)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of schizophrenia.
(Article 44)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of hearing impairment.
(Article 45)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of pain.
(Article 46)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the treatment of Fragile X.
(Article 47)
A pharmaceutical composition comprising a compound according to any one of clauses 1-30 and a pharmaceutically acceptable carrier or excipient.
(Article 48)
31. A compound according to any one of clauses 1-30 for use in combination with a further pharmaceutically acceptable active ingredient.
(Article 49)
Formula (II) or (XVI):

(wherein R ₁ , R ₂ and R ₃ are as defined in Clause 1 and X is halo (such as Br))
compound.
(Article 50)
Formula (XVI):

(wherein R ₁ , R ₂ and R ₃ are as defined in Clause 1)
compound.
(Article 51)
Formula (IV):

(wherein _R4 and _R5 are as defined in Clause 1 and Y is halo (such as Cl))
compound.
(Article 52)
functionalized with a group L, either through the secondary nitrogen of the hydantoin or through the secondary nitrogen of the triazolone, where L is:
a) —PO(OH)O ⁻ ·M ⁺ , where M ⁺ is a pharmaceutically acceptable monovalent counterion,
b) -PO(O ^- ) ₂ 2M ⁺ ,
c) —PO(O ⁻ ) ₂ ·D ²⁺ (wherein D ²⁺ is a pharmaceutically acceptable divalent counterion),
d) —CH(R ^x )—PO(OH)O ⁻ ·M ⁺ , wherein R ^x is hydrogen or C _1-3 alkyl,
e) —CH(R ^X )—PO(O ⁻ ) ₂ 2M ⁺ ,
f)-CH( ^Rx )-PO( ^O- ) _2.D2 ⁺ ,
g) _-SO3 ^- .M ⁺ ,
h) -CH( ^Rx ) _-SO3 ^- .M ⁺ , and
i)-CO _{- CH2CH2} - _CO2.M ⁺
A derivative of a compound of formula (I) according to any one of clauses 1-30, or a salt and/or solvate thereof, selected from the group consisting of
(Article 53)
37. A compound according to any one of clauses 1-36, in its natural isotopic form.
(Article 54)
54. A compound, method, use, composition or derivative according to any one of clauses 1-48, 52 or 53 for oral administration.
(Article 55)
A compound, method, according to any one of clauses 1-48 or 52-54, for administration at 2-400 mg per day, such as 2-300 mg per day, in particular 5-250 mg per day. Uses, Compositions or Derivatives.
(Article 56)
A compound, method, use, composition or derivative according to any one of clauses 1-48 or 52-55 for administration once or twice per day.
(Article 57)
56. A compound according to clause 56 for administration once per day.
(Article 58)
56. A compound according to clause 56 for administration twice per day.
(Article 59)
A compound, method, use, composition or derivative according to any one of Clauses 1-48 or 52-58, for administration for a period of at least 3 months.
(Article 60)
A compound, method, use, composition or derivative according to any one of Clauses 1-48 or 52-58 for administration to a human subject.
(Article 61)
A compound, method, use, composition or derivative according to clause 60 for administration to an adult human, such as an adult human aged 18-65.
(Article 62)
A compound, method, use, composition or derivative according to Clause 60 for administration to a human over the age of 66.
(Article 63)
A compound, method, use, composition or derivative according to Clause 60 for human subjects under the age of 18, such as between 4 and 17 years of age.
(Article 64)
Any of Clauses 1-48, 52, 53, or 59-63, wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is delivered by a patch or an indwelling agent. 10. A compound, method, use, composition or derivative according to claim 1.

(citation)
All publications, including but not limited to patents and patent applications, cited in this specification are hereby incorporated by reference as if each individual publication were set forth in full. are incorporated herein by reference as if specifically and individually indicated to be incorporated herein by reference.

本件出願は、以下の態様の発明を提供する。
（態様１）
式(I):
（化1）

(式中:
R ₁ は、H又はメチルであり;
R ₂ 及びR ₃ は双方ともメチルであるか、又はR ₂ 及びR ₃ は、それらが結合している炭素原子と一緒になって、スピロシクロプロピル環であり;
R ₄ は、メチル又はエチルであり;
R ₅ は、H又はメチルであり;
或いはR ₄ 及びR ₅ は、それらが結合している炭素原子と一緒になって、C ₃ -C ₄ スピロカルボシクリルを形成する)
の化合物、又はそれらの塩及び/もしくは溶媒和物及び/もしくは誘導体。
（態様２）
R ₁ が、Hである、態様1記載の化合物。
（態様３）
R ₁ が、メチルである、態様1記載の化合物。
（態様４）
R ₂ 及びR ₃ が、スピロシクロプロピルである、態様1～3のいずれか1項記載の化合物。
（態様５）
R ₂ が、メチルであり、かつR ₃ が、メチルである、態様1～3のいずれか1項記載の化合物。
（態様６）
R ₄ が、メチルである、態様1～5のいずれか1項記載の化合物。
（態様７）
R ₄ が、エチルである、態様1～5のいずれか1項記載の化合物。
（態様８）
R ₅ が、Hである、態様1～7のいずれか1項記載の化合物。
（態様９）
R ₅ が、メチルである、態様1～7のいずれか1項記載の化合物。
（態様１０）
R ₄ 及びR ₅ が、それらが結合している炭素原子と一緒になって、スピロシクロプロピルを形成する、態様1～5のいずれか1項記載の化合物。
（態様１１）
R ₄ 及びR ₅ が、それらが結合している炭素原子と一緒になって、スピロシクロブチルを形成する、態様1～5のいずれか1項記載の化合物。
（態様１２）
以下:
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン;
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオン;
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン
からなる群から選択される態様1記載の化合物、又はそれらの塩及び/もしくは溶媒和物、並びに/又はそれらの誘導体。
（態様１３）
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１４）
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１５）
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１６）
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１７）
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１８）
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様１９）
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２０）
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２１）
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２２）
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２３）
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２４）
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２５）
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオンである、態様1記載の化合物。
（態様２６）
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオンである、態様1記載の化合物。
（態様２７）
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、態様1記載の化合物。
（態様２８）
医薬品としての使用のための、態様1～27のいずれか1項記載の化合物。
（態様２９）
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療における使用のための、態様1～28のいずれか1項記載の化合物。
（態様３０）
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための医薬品の生産における、態様1～27のいずれか1項記載の化合物の使用。
（態様３１）
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための方法であって、それを必要としている対象に、有効量の態様1～27のいずれか1項記載の化合物を投与することを含む、前記方法。
（態様３２）
態様1～27のいずれか1項記載の化合物、及び医薬として許容し得る担体又は賦形剤を含む医薬組成物。
（態様３３）
前記化合物が、経口投与される、態様1～32のいずれか1項記載の化合物、使用、方法、又は組成物。
（態様３４）
前記化合物が、1日あたり2～400mg、例えば、1日あたり2～300mg、特に、1日あたり5～250mgで投与される、態様1～33のいずれか1項記載の化合物、使用、方法、又は組成物。
（態様３５）
前記化合物が、1日あたり1回又は2回投与される、態様1～34のいずれか1項記載の化合物、使用、方法、又は組成物。
（態様３６）
前記化合物が、1日あたり1回投与される、態様35記載の化合物、使用、方法、又は組成物。
（態様３７）
前記化合物が、1日あたり2回投与される、態様35記載の化合物、使用、方法、又は組成物。
（態様３８）
前記化合物が、少なくとも3ヶ月の期間投与される、態様1～37のいずれか1項記載の化合物、使用、方法、又は組成物。
（態様３９）
前記化合物が、1日あたり1回又は2回、1日あたり2～400mg、例えば、1日あたり2～300mg、特に、1日あたり5～250mgで経口投与される、態様1～32のいずれか1項記載の化合物、使用、方法、又は組成物。
（態様４０）
式(II)又は式(XVI):
（化2）

(式中、R ₁ 、R ₂ 及びR ₃ は、態様1で定義されるとおりであり、Xは、ハロ(Brなど)である)
の化合物。
（態様４１）
式(IV):
（化3）

(式中、R ₄ 及びR ₅ は、態様1で定義されるとおりであり、Yは、ハロ(Clなど)である）
の化合物。
(citation)
All publications, including but not limited to patents and patent applications, cited in this specification are hereby incorporated by reference as if each individual publication were set forth in full. are incorporated herein by reference as if specifically and individually indicated to be incorporated herein by reference.

The present application provides inventions of the following aspects.
(Aspect 1)
Formula (I):
(Chemical 1)

(in the formula:
R ₁ is H or methyl;
R2 and R3 _are both methyl, or R2 _and R3 _together with the carbon atom to _which they are attached are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
R5 is H or methyl _;
Alternatively R4 _and R5 _together with the carbon atom to which they are attached form a C3 _- C4 _{spirocarbocyclyl} )
or salts and/or solvates and/or derivatives thereof.
(Aspect 2)
A compound according to embodiment 1, wherein R ₁ is H.
(Aspect 3)
A compound according to embodiment 1, wherein R ₁ is methyl.
(Aspect 4)
A compound according to any one of embodiments 1-3, wherein R ₂ and R ₃ are spirocyclopropyl.
(Aspect 5)
The compound according to any one of embodiments 1-3 , wherein R ₂ is methyl and R ₃ is methyl.
(Aspect 6)
A compound according to any one of embodiments 1-5, wherein R ₄ is methyl.
(Aspect 7)
The compound according to any one of embodiments 1-5, wherein R ₄ is ethyl.
(Aspect 8)
A compound according to any one of embodiments 1-7, wherein R ₅ is H.
(Aspect 9)
A compound according to any one of embodiments 1-7, wherein R ₅ is methyl.
(Mode 10)
A compound according to any one of embodiments 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclopropyl.
(Aspect 11)
A compound according to any one of embodiments 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclobutyl.
(Aspect 12)
the following:
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione;
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione ;
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 ,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione ;
5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- Dione;
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione ;
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione ;
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione
A compound according to embodiment 1, or a salt and/or solvate thereof, and/or a derivative thereof, selected from the group consisting of:
(Aspect 13)
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione A compound according to embodiment 1.
(Aspect 14)
According to embodiment 1, wherein the compound.
(Aspect 15)
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione The compound according to embodiment 1, which is
(Aspect 16)
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione according to embodiment 1 compound.
(Aspect 17)
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 A compound according to embodiment 1 which is ,4-dione.
(Aspect 18)
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione The compound according to embodiment 1, which is
(Aspect 19)
Embodiment 1 which is 5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione Compound as described.
(Aspect 20)
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- A compound according to embodiment 1, which is a dione.
(Aspect 21)
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to embodiment 1, which is
(Aspect 22)
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione 1. The compound described in 1.
(Aspect 23)
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione 1. The compound described in 1.
(Aspect 24)
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione, A compound according to embodiment 1.
(Aspect 25)
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione The compound according to embodiment 1, which is
(Aspect 26)
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione The compound according to embodiment 1, which is
(Aspect 27)
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to embodiment 1, which is
(Aspect 28)
A compound according to any one of embodiments 1-27 for use as a medicament.
(Aspect 29)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and A compound according to any one of embodiments 1-28 for use in the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease.
(Aspect 30)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Use of a compound according to any one of aspects 1-27 in the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease.
(Aspect 31)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and A method for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of aspects 1-27. The method as described above, comprising:
(Aspect 32)
A pharmaceutical composition comprising a compound according to any one of aspects 1-27 and a pharmaceutically acceptable carrier or excipient.
(Aspect 33)
33. The compound, use, method or composition of any one of aspects 1-32, wherein said compound is administered orally.
(Aspect 34)
A compound, use, method according to any one of aspects 1-33, wherein said compound is administered at 2-400 mg per day, such as 2-300 mg per day, especially 5-250 mg per day, or composition.
(Aspect 35)
35. The compound, use, method or composition of any one of aspects 1-34, wherein said compound is administered once or twice per day.
(Aspect 36)
36. A compound, use, method or composition according to embodiment 35, wherein said compound is administered once per day.
(Aspect 37)
36. A compound, use, method or composition according to aspect 35, wherein said compound is administered twice per day.
(Aspect 38)
38. The compound, use, method or composition of any one of aspects 1-37, wherein said compound is administered for a period of at least 3 months.
(Aspect 39)
Any of embodiments 1-32, wherein said compound is orally administered once or twice a day at 2-400 mg per day, such as 2-300 mg per day, especially 5-250 mg per day. A compound, use, method or composition according to claim 1.
(Aspect 40)
Formula (II) or Formula (XVI):
(Chemical 2)

(wherein R ₁ , R ₂ and R ₃ are as defined in embodiment 1 and X is halo (such as Br))
compound.
(Aspect 41)
Formula (IV):
(Chemical 3)

(wherein R ₄ and R ₅ are as defined in embodiment 1 and Y is halo (such as Cl))
compound.

In one embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof is selected from the group consisting of Fragile X syndrome , Rett's disorder and Alzheimer's disease. may be useful in the treatment or prevention of diseases or disorders associated with

(式中:
R₁は、H又はメチルであり;
R₂及びR₃は双方ともメチルであるか、又はR₂及びR₃は、それらが結合している炭素原子と一緒になった、スピロシクロプロピル環であり;
R₄は、メチルもしくはエチルであり;
R₅は、Hもしくはメチルであり;
又はR₄及びR₅は、それらが結合している炭素原子と一緒になって、C₃-C₄スピロカルボシクリルを形成する)
の化合物、又はそれらの塩及び/もしくは溶媒和物及び/もしくは誘導体。
(条項2)
R₁が、Hである、条項1記載の化合物。
(条項3)
R₁が、メチルである、条項1記載の化合物。
(条項4)
R₂及びR₃が、スピロシクロプロピル環である、条項1～3のいずれか1項記載の化合物。
(条項5)
R₂が、メチルであり、かつR₃が、メチルである、条項1～3のいずれか1項記載の化合物。
(条項6)
R₄が、メチルである、条項1～5のいずれか1項記載の化合物。
(条項7)
R₄が、エチルである、条項1～5のいずれか1項記載の化合物。
(条項8)
R₅が、Hである、条項1～7のいずれか1項記載の化合物。
(条項9)
R₅が、メチルである、条項1～7のいずれか1項記載の化合物。
(条項10)
R₄及びR₅が、異なる場合、それらが、以下の立体化学配置:
を有する、条項1～9のいずれか1項記載の化合物。

(条項11)
R₄及びR₅が、異なる場合、それらが、以下の立体化学配置:
を有する、条項1～9のいずれか1項記載の化合物。

(条項12)
R₄及びR₅が、それらが結合している炭素原子と一緒になって、スピロシクロプロピルを形成する、条項1～5のいずれか1項記載の化合物。
(条項13)
R₄及びR₅が、それらが結合している炭素原子と一緒になって、スピロシクロブチルを形成する、条項1～5のいずれか1項記載の化合物。
(条項14)
以下:
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオン;
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオン;
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオン;
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオン;
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン;
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオン;
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオン;
からなる群から選択される、条項1記載の化合物、又はそれらの塩及び/もしくは溶媒和物、並びに/又はそれらの誘導体。
(条項15)
5,5-ジメチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項16)
3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5,5-ジメチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項17)
(5R)-5-エチル-5-メチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項18)
5,5-ジメチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項19)
(5R)-5-エチル-5-メチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項20)
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-5-メチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項21)
5,5-ジメチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項22)
(5R)-5-エチル-5-メチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項23)
(5R)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項24)
(5R)-5-エチル-3-(5-スピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イルオキシピラジン-2-イル)イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項25)
(5R)-3-[5-[(3,3-ジメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]-5-エチル-イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項26)
(5R)-5-エチル-3-[5-[(3,3,7-トリメチル-2H-ベンゾフラン-4-イル)オキシ]ピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項27)
7-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオンである、条項1記載の化合物。
(条項28)
6-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]-4,6-ジアザスピロ[2.4]ヘプタン-5,7-ジオンである、条項1記載の化合物。
(条項29)
(5S)-5-エチル-3-[5-(7-メチルスピロ[2H-ベンゾフラン-3,1'-シクロプロパン]-4-イル)オキシピラジン-2-イル]イミダゾリジン-2,4-ジオンである、条項1記載の化合物。
(条項30)
条項1～29のいずれか1項記載の式(I)の化合物、又はそれらの医薬として許容し得る塩及び/もしくは溶媒和物。
(条項31)
医薬品としての使用のための、条項1～30のいずれか1項記載の化合物。
(条項32)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療における使用のための、条項31記載の化合物。
(条項33)
統合失調症の予防又は治療における使用のための、条項31記載の化合物。
(条項34)
聴覚障害の予防又は治療における使用のための、条項31記載の化合物。
(条項35)
疼痛の予防又は治療における使用のための、条項31記載の化合物。
(条項36)
脆弱X症候群の治療における使用のための、条項31記載の化合物。
(条項37)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための方法であって、それを必要としている対象に、有効量の条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項38)
統合失調症の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項39)
聴覚障害の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項40)
疼痛の予防又は治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項41)
脆弱X症候群の治療のための方法であって、それを必要としている対象に、条項1～30のいずれか1項記載の化合物を投与することを含む、前記方法。
(条項42)
聴覚障害、統合失調症、うつ状態及び気分障害、双極性障害、物質乱用障害、不安障害、睡眠障害、聴覚過敏及び音量感覚障害、メニエール病、平衡障害、及び内耳の障害、衝動制御障害、パーソナリティ障害、注意欠陥多動性障害、自閉症スペクトラム障害、摂食障害、認知障害、失調症、疼痛(神経障害性疼痛、炎症性疼痛、及び種々の疼痛など)、レビー小体型認知症、並びにパーキンソン病からなる群から選択される疾患又は障害の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項43)
統合失調症の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項44)
聴覚障害の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項45)
疼痛の予防又は治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項46)
脆弱X症候群の治療のための医薬品の生産における、条項1～30のいずれか1項記載の化合物の使用。
(条項47)
条項1～30のいずれか1項記載の化合物、及び医薬として許容し得る担体又は賦形剤を含む医薬組成物。
(条項48)
さらなる医薬として許容し得る有効成分との組み合わせでの使用のための、条項1～30のいずれか1項記載の化合物。
(条項49)
式(II)又は(XVI):

(式中、R₁、R₂、及びR₃は、条項1で定義されるとおりであり、Xは、ハロ(Brなど)である)
の化合物。
(条項50)
式(XVI):

(式中、R₁、R₂、及びR₃は、条項1で定義されるとおりである）
の化合物。
(条項51)
式(IV):

(式中、R₄及びR₅は、条項1で定義されるとおりであり、Yは、ハロ(Clなど)である)
の化合物。
(条項52)
ヒダントインの二級窒素を介してか、又はトリアゾロンの二級窒素を介して、基Lで官能基化されており、Lが、以下:
a)-PO(OH)O^-・M⁺(式中、M⁺は、医薬として許容し得る一価の対イオンである)、
b)-PO(O^-)₂・2M⁺、
c)-PO(O^-)₂・D²⁺(式中、D²⁺は、医薬として許容し得る二価の対イオンである)、
d)-CH(R^X)-PO(OH)O^-・M⁺(式中、R^Xは、水素又はC_1-3アルキルである)、
e)-CH(R^X)-PO(O^-)₂・2M⁺、
f)-CH(R^X)-PO(O^-)₂・D²⁺、
g)-SO₃ ^-・M⁺、
h)-CH(R^X)-SO₃ ^-・M⁺、及び
i)-CO-CH₂CH₂-CO₂・M⁺
からなる基から選択される、条項1～30のいずれか1項記載の式(I)の化合物の誘導体、又はそれらの塩及び/もしくは溶媒和物。
(条項53)
天然同位体形態である、条項1～36のいずれか1項記載の化合物。
(条項54)
経口投与のための、条項1～48、52又は53のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項55)
1日あたり2～400mg、例えば、1日あたり2～300mg、特に、1日あたり5～250mgでの投与のための、条項1～48又は52～54のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項56)
1日あたり1回又は2回の投与のための、条項1～48又は52～55のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項57)
1日あたり1回の投与のための、条項56記載の化合物。
(条項58)
1日あたり2回の投与のための、条項56記載の化合物。
(条項59)
少なくとも3ヶ月の期間の投与のための、条項1～48又は52～58のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項60)
ヒト対象への投与のための、条項1～48又は52～58のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。
(条項61)
ヒト成人、例えば、18～65歳のヒト成人などへの投与のための、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項62)
66歳以上の年齢のヒトへの投与のための、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項63)
4歳～17歳などの18歳未満の年齢のヒト対象への、条項60記載の化合物、方法、使用、組成物、又は誘導体。
(条項64)
式(I)の化合物又はその医薬として許容し得る塩、溶媒和物、及び/もしくは誘導体が、パッチ又は留置用剤によって送達される、条項1～48、52、53、又は59～63のいずれか1項記載の化合物、方法、使用、組成物、又は誘導体。 (Clause of the invention:)
(Article 1)
Formula (I):

(in the formula:
R ₁ is H or methyl;
_R2 and _R3 are both methyl, or _R2 and _R3 , together with the carbon atom to which they are attached, are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
_R5 is H or methyl;
or _R4 and _R5 together with the carbon atom to which they are attached form a _C3 - _C4 spirocarbocyclyl)
or salts and/or solvates and/or derivatives thereof.
(Article 2)
2. The compound of clause ₁ , wherein R1 is H.
(Article 3)
2. The compound according to clause ₁ , wherein R1 is methyl.
(Article 4)
A compound according to any one of clauses 1-3, wherein R ₂ and R ₃ are spirocyclopropyl rings.
(Article 5)
The compound according to any one of clauses 1-3, wherein R ₂ is methyl and R ₃ is methyl.
(Article 6)
6. The compound according to any one of clauses 1-5, wherein R ₄ is methyl.
(Article 7)
6. The compound according to any one of clauses 1-5, wherein R ₄ is ethyl.
(Article 8)
8. The compound according to any one of clauses 1-7, wherein _R5 is H.
(Article 9)
8. The compound according to any one of clauses 1-7, wherein R ₅ is methyl.
(Article 10)
When R ₄ and R ₅ are different, they have the following stereochemical configurations:
A compound according to any one of clauses 1-9, having

(Article 11)
When R ₄ and R ₅ are different, they have the following stereochemical configurations:
A compound according to any one of clauses 1-9, having

(Article 12)
A compound according to any one of clauses 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclopropyl.
(Article 13)
A compound according to any one of clauses 1-5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclobutyl.
(Article 14)
the following:
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione;
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione ;
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 ,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione ;
5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- Dione;
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione ;
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione ;
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
A compound according to clause 1, or a salt and/or solvate thereof and/or a derivative thereof, selected from the group consisting of
(Article 15)
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione , a compound according to clause 1.
(Article 16)
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione, according to clause 1 compound.
(Article 17)
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 18)
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione, according to clause 1 compound.
(Article 19)
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 2. The compound according to clause 1, which is ,4-dione.
(Article 20)
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 21)
Clause 1 which is 5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione Compound as described.
(Article 22)
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- A compound according to clause 1, which is a dione.
(Article 23)
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 24)
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione 1. The compound described in 1.
(Article 25)
is (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione 1. The compound described in 1.
(Article 26)
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione, A compound according to Clause 1.
(Article 27)
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione The compound according to clause 1, which is
(Article 28)
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione The compound according to clause 1, which is
(Article 29)
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione The compound according to clause 1, which is
(Article 30)
A compound of formula (I) according to any one of clauses 1-29, or a pharmaceutically acceptable salt and/or solvate thereof.
(Article 31)
31. A compound according to any one of clauses 1-30 for use as a medicament.
(Article 32)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and 32. A compound according to clause 31 for use in preventing or treating a disease or disorder selected from the group consisting of Parkinson's disease.
(Article 33)
32. A compound according to clause 31 for use in the prevention or treatment of schizophrenia.
(Article 34)
32. A compound according to clause 31 for use in the prevention or treatment of hearing impairment.
(Article 35)
32. A compound according to clause 31 for use in the prevention or treatment of pain.
(Article 36)
32. A compound according to clause 31 for use in the treatment of fragile X syndrome .
(Article 37)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and A method for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 1-30. The method as described above, comprising:
(Article 38)
31. A method for the prevention or treatment of schizophrenia, comprising administering a compound according to any one of clauses 1-30 to a subject in need thereof.
(Article 39)
31. A method for the prevention or treatment of hearing impairment, said method comprising administering to a subject in need thereof a compound according to any one of clauses 1-30.
(Article 40)
31. A method for the prevention or treatment of pain, said method comprising administering a compound according to any one of clauses 1-30 to a subject in need thereof.
(Article 41)
31. A method for the treatment of Fragile X Syndrome , said method comprising administering to a subject in need thereof a compound according to any one of clauses 1-30.
(Article 42)
Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease.
(Article 43)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of schizophrenia.
(Article 44)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of hearing impairment.
(Article 45)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the prevention or treatment of pain.
(Article 46)
Use of a compound according to any one of clauses 1-30 in the manufacture of a medicament for the treatment of fragile X syndrome .
(Article 47)
A pharmaceutical composition comprising a compound according to any one of clauses 1-30 and a pharmaceutically acceptable carrier or excipient.
(Article 48)
31. A compound according to any one of clauses 1-30 for use in combination with a further pharmaceutically acceptable active ingredient.
(Article 49)
Formula (II) or (XVI):

(wherein R ₁ , R ₂ and R ₃ are as defined in Clause 1 and X is halo (such as Br))
compound.
(Article 50)
Formula (XVI):

(wherein R ₁ , R ₂ and R ₃ are as defined in Clause 1)
compound.
(Article 51)
Formula (IV):

(wherein _R4 and _R5 are as defined in Clause 1 and Y is halo (such as Cl))
compound.
(Article 52)
functionalized with a group L, either through the secondary nitrogen of the hydantoin or through the secondary nitrogen of the triazolone, where L is:
a) —PO(OH)O ⁻ ·M ⁺ , where M ⁺ is a pharmaceutically acceptable monovalent counterion,
b) -PO(O ^- ) ₂ 2M ⁺ ,
c) —PO(O ⁻ ) ₂ ·D ²⁺ (wherein D ²⁺ is a pharmaceutically acceptable divalent counterion),
d) —CH(R ^x )—PO(OH)O ⁻ ·M ⁺ , wherein R ^x is hydrogen or C _1-3 alkyl,
e) —CH(R ^X )—PO(O ⁻ ) ₂ 2M ⁺ ,
f)-CH( ^Rx )-PO( ^O- ) _2.D2 ⁺ ,
g) _-SO3 ^- .M ⁺ ,
h) -CH( ^Rx ) _-SO3 ^- .M ⁺ , and
i)-CO _{- CH2CH2} - _CO2.M ⁺
A derivative of a compound of formula (I) according to any one of clauses 1-30, or a salt and/or solvate thereof, selected from the group consisting of
(Article 53)
37. A compound according to any one of clauses 1-36, in its natural isotopic form.
(Article 54)
54. A compound, method, use, composition or derivative according to any one of clauses 1-48, 52 or 53 for oral administration.
(Article 55)
A compound, method, according to any one of clauses 1-48 or 52-54, for administration at 2-400 mg per day, such as 2-300 mg per day, in particular 5-250 mg per day. Uses, Compositions or Derivatives.
(Article 56)
A compound, method, use, composition or derivative according to any one of clauses 1-48 or 52-55 for administration once or twice per day.
(Article 57)
56. A compound according to clause 56 for administration once per day.
(Article 58)
56. A compound according to clause 56 for administration twice per day.
(Article 59)
A compound, method, use, composition or derivative according to any one of Clauses 1-48 or 52-58, for administration for a period of at least 3 months.
(Article 60)
A compound, method, use, composition or derivative according to any one of Clauses 1-48 or 52-58 for administration to a human subject.
(Article 61)
A compound, method, use, composition or derivative according to clause 60 for administration to an adult human, such as an adult human aged 18-65.
(Article 62)
A compound, method, use, composition or derivative according to Clause 60 for administration to a human over the age of 66.
(Article 63)
A compound, method, use, composition or derivative according to Clause 60 for human subjects under the age of 18, such as between 4 and 17 years of age.
(Article 64)
Any of Clauses 1-48, 52, 53, or 59-63, wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is delivered by a patch or an indwelling agent. 10. A compound, method, use, composition or derivative according to claim 1.

Claims (41)

Formula (I):

(in the formula:
R ₁ is H or methyl;
_R2 and _R3 are both methyl, or _R2 and _R3 together with the carbon atom to which they are attached are a spirocyclopropyl ring;
R ₄ is methyl or ethyl;
_R5 is H or methyl;
Alternatively _R4 and _R5 together with the carbon atom to which they are attached form a _C3 - _C4 spirocarbocyclyl)
or salts and/or solvates and/or derivatives thereof. 2. The compound of claim ₁ , wherein R1 is H. 3. The compound of claim ₁ , wherein R1 is methyl. 4. The compound of any one of claims 1-3, wherein _R2 and _R3 are spirocyclopropyl. 4. The compound of any one of claims _1-3 , wherein _R2 is methyl and R3 is methyl. 6. The compound of any one of claims 1-5, wherein _R4 is methyl. 6. The compound of any one of claims 1-5, wherein _R4 is ethyl. 8. The compound of any one of claims 1-7, wherein _R5 is H. 8. The compound of any one of claims 1-7, wherein _R5 is methyl. A compound according to any one of claims 1 to 5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclopropyl. A compound according to any one of claims 1 to 5, wherein R ₄ and R ₅ together with the carbon atom to which they are attached form spirocyclobutyl. the following:
5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1′-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione;
3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione ;
5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 ,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione ;
5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
(5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- Dione;
(5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione ;
(5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione;
(5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione;
(5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione;
7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione ;
6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione ;
(5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione 2. A compound according to claim 1, or a salt and/or solvate thereof, and/or a derivative thereof, selected from the group consisting of: 5,5-dimethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione , the compound of claim 1. 3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5,5-dimethyl-imidazolidine-2,4-dione Compound as described. (5R)-5-ethyl-5-methyl-3-(5-spiro[2H-benzofuran-3,1'-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione 2. The compound of claim 1, which is 5,5-dimethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropane]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione Compound as described. (5R)-5-ethyl-5-methyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2 2. The compound of claim 1, which is ,4-dione. (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione 2. The compound of claim 1, which is 5,5-dimethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione 1. The compound described in 1. (5R)-5-ethyl-5-methyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4- 3. The compound of claim 1, which is a dione. (5R)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione 2. The compound of claim 1, which is (5R)-5-ethyl-3-(5-spiro[2H-benzofuran-3,1′-cyclopropan]-4-yloxypyrazin-2-yl)imidazolidine-2,4-dione Item 1. The compound according to item 1. (5R)-3-[5-[(3,3-dimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]-5-ethyl-imidazolidine-2,4-dione Item 1. The compound according to item 1. (5R)-5-ethyl-3-[5-[(3,3,7-trimethyl-2H-benzofuran-4-yl)oxy]pyrazin-2-yl]imidazolidine-2,4-dione, A compound according to claim 1. 7-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-5,7-diazaspiro[3.4]octane-6,8-dione 2. The compound of claim 1, which is 6-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]-4,6-diazaspiro[2.4]heptane-5,7-dione 2. The compound of claim 1, which is (5S)-5-ethyl-3-[5-(7-methylspiro[2H-benzofuran-3,1'-cyclopropan]-4-yl)oxypyrazin-2-yl]imidazolidine-2,4-dione 2. The compound of claim 1, which is 28. A compound according to any one of claims 1-27 for use as a medicament. Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and 29. A compound according to any one of claims 1-28 for use in the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease. Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and Use of a compound according to any one of claims 1-27 in the manufacture of a medicament for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease. Hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness disorders, Meniere's disease, balance disorders and disorders of the inner ear, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain (including neuropathic pain, inflammatory pain, and various pains), dementia with Lewy bodies, and A method for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease, comprising administering an effective amount of a compound according to any one of claims 1 to 27 to a subject in need thereof. The above method, comprising: 28. A pharmaceutical composition comprising a compound according to any one of claims 1-27 and a pharmaceutically acceptable carrier or excipient. 33. The compound, use, method or composition of any one of claims 1-32, wherein said compound is administered orally. A compound, use, method according to any one of claims 1 to 33, wherein said compound is administered at 2-400 mg per day, such as 2-300 mg per day, especially 5-250 mg per day. , or composition. 35. The compound, use, method or composition of any one of claims 1-34, wherein said compound is administered once or twice per day. 36. The compound, use, method or composition of Claim 35, wherein said compound is administered once per day. 36. The compound, use, method or composition of claim 35, wherein said compound is administered twice per day. 38. The compound, use, method or composition of any one of claims 1-37, wherein said compound is administered for a period of at least 3 months. 33. Any of claims 1-32, wherein said compound is orally administered once or twice a day at 2-400 mg per day, such as 2-300 mg per day, especially 5-250 mg per day. 10. A compound, use, method or composition according to claim 1. Formula (II) or Formula (XVI):

(wherein R ₁ , R ₂ and R ₃ are as defined in claim 1 and X is halo (such as Br))
compound. Formula (IV):

(wherein _R4 and _R5 are as defined in claim 1 and Y is halo (such as Cl))
compound.