Modulators of kv3 channels to treat pain

Abstract

To provide a pharmaceutical composition for the prophylaxis or treatment of inflammatory pain and neuropathic pain.SOLUTION: The present invention provides modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels, illustrated by a formula below. Modulators for use in prophylaxis or treatment of pain include compounds of a formula (I) or a pharmaceutically acceptable salt and / or a solvate thereof and / or a derivative thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] (Technical field) The present invention relates to compounds and compositions containing such compounds for use in the prevention or treatment of pain. The present invention relates to pharmaceutical compositions comprising the compound, as well as related methods and uses. [Background technology]

[0002] BACKGROUND OF THEINVENTION The Kv3 voltage-gated potassium channel family has four members: Kv3.1, Kv3.2, and Kv3.3. The genes for each of these subtypes are expressed through alternative splicing. It may give rise to a larger number of isoforms, with different versions of the C-terminal region. To date, 13 isoforms have been identified in mammals. The currents expressed by Kv3 channels appear to be similar (Rudy et al., 2001). The channel is activated by depolarization of the plasma membrane to voltages above -20 mV. These biophysical properties allow the It was confirmed that the channels open toward the peak of the depolarization phase of the neuronal action potential, initiating repolarization. The rapid termination of action potentials mediated by Kv3 channels allows neurons to react more rapidly. They recover quickly, allowing them to reach a subthreshold membrane potential from which they can generate further action potentials. As a result, the presence of Kv3 channels in certain neurons is highly These contribute to their ability to fire at high frequency (Rudy et al. 2001). Kv3.2 channels are predominant in the central nervous system, whereas Kv3.4 channels are predominant in skeletal muscle and sympathetic neurons. The Kv3.1 to Kv3.3 channel subtypes are primarily involved in the regulation of interneuronal endothelial function (Weiser et al., 1994). Subclasses of neurons have been shown to mediate signaling in the cortical and hippocampal brain regions (e.g., Chow et al., 1999; Ma rtina et al. 1998; McDonald et al. 2006; Chang et al. 2007), and in the thalamus (e.g., in the cerebellum (Sacco et al., 2006; Puente et al., 2010) and in the auditory cortex (Kasten et al., 2007). It is differentially expressed in the brainstem nuclei of the nervous system (Li et al. 2001).

[0003] Kv3 channels are key determinants of function in the cerebellum, a brain region important for motor control (Joho et al. 2009). Characterization of mice lacking one or more of the Kv3 subtypes The absence of Kv3.1 was associated with increased locomotor activity, altered electroencephalographic activity, and fragmented It has been shown that loss of Kv3.2 leads to abnormal sleep patterns (Joho et al., 1999). , resulting in reduced seizure threshold and altered electrocortical activity (Lau et al., 2000). is associated with mild ataxia and movement disorders (McMahon et al., 2004). The deficiency is characterized by spontaneous seizures, ataxia, and increased sensitivity to the effects of ethanol. This results in a severe phenotype in the immune system (Espinosa et al. 2001; Espinosa et al. 2008).

[0004] Little is known about the pharmacology of Kv3 channels. Tetraethylammonium (TEA) has been shown to inhibit the channel at low millimolar concentrations (Rudy et al., 2001), A blood-dipogen derived from the sea anemone Anemonia sulcata The toxin BDS (BDS-defensing substance) (Diochot et al., 1998) selects Kv3 channels with high affinity. It has been shown to selectively inhibit Kv3 channels (Yeung et al. 2005). It acts directly on Kv3 channels. In addition to compounds that activate protein kinase A (PKA) and protein kinase C (PKC), Agonists of the receptors that regulate Kv3-mediated currents in specific brain regions and promote neuroprotection. It has been shown that stimulation of the cerebral cortex leads to a reduction in the ability to fire at high frequencies (Atzori et al. 2000; So These studies demonstrated that PKA and PKC act on the Kv3 channel in a neuron-specific manner. These results suggest that IL-1 can specifically phosphorylate Kv3, leading to a reduction in Kv3-mediated currents. do.

[0005] Patent applications WO2011 / 069951, WO2012 / 076877, WO2012 / 168710, WO2013 / 1752 No. 15, WO2013 / 083994, and WO2013 / 182850 describe Kv3 channels, specifically Kv3 Compounds that are modulators of Kv3 channels are disclosed. The use of such compounds in certain diseases and disorders requiring modulation is described in patent application WO 2005 / 023366. This is disclosed in WO2013 / 182851 and WO2013 / 175211.

[0006] In the broadest sense, pain can be divided into acute pain and chronic pain. is defined as pain that is self-limited and generally requires treatment for no more than a maximum of several weeks. Examples of pain that may be caused by the use of steroids include acute musculoskeletal pain such as postoperative pain or fractures (US Food and Drug Administration, 2013). 014) Chronic pain is pain that persists for more than one month after the initial injury has healed or pain that persists for more than three months. Chronic pain can be defined as either pain that continues for a long time or pain that lasts for a long time. are often absent and can lead to many other health problems, such as fatigue, depression, insomnia, and mood swings. , and reduced movement often accompany chronic pain.

[0007] Chronic pain is subdivided into the following groups: neuropathic pain, chronic musculoskeletal pain, and miscellaneous chronic pain. Neuropathic pain is usually associated with tissue injury and can be seen in amputations, strokes, Damage to the nervous system (peripheral and / or central nervous system), such as diabetes or multiple sclerosis Chronic musculoskeletal pain is caused by a variety of conditions, including osteoarthritis and chronic low back pain. It can be a symptom of any disease, including damage to muscle tissue as well as trauma to an area, e.g. For example, it can occur after fractures, sprains, and dislocations. Chronic pain of all kinds is different from that of all other types. These include non-neuropathic pain conditions such as cancer pain and fibromyalgia, as well as chronic pain conditions such as chronic pain syndromes, chronic pain syndromes, and chronic pain syndromes. as well as headaches and tendonitis.

[0008] Chronic pain is a highly heterogeneous condition that continues to be one of the most troublesome and difficult to manage clinical conditions. quality (McCarberg et al. 2008; Woolf 2010; Finnerup et al. 2015). Despite extensive research and drug development, it is effective without significant side effects or risk of addiction. There has been little progress in identifying treatments that can rival opioids. These nerve fibers have been identified as important targets for the management of specific pain indications, particularly neuropathic pain states. In addition, genetic mutations in certain ion channels have been linked to certain chronic pain disorders. Voltage-gated ion channels under investigation as pharmaceutical targets are Examples of kernels are: Sodium channels (especially NaV1.7) – Sun et al. 2014; Dib-Hajj et al. 2013 N-type calcium channels – Zamponi et al. 2015 Kv7 potassium channels – Devulder 2010; Wickenden et al. 2009 SLACK-Lu et al. 2015 Examples include:

[0009] The fundamental hypothesis underlying these approaches is that chronic pain states are mediated by peripheral sensory neurons, In particular, neurons involved in the transmission of painful sensory stimuli, e.g., C-fibers of the dorsal root ganglion and that it is associated with increased excitability and / or abnormal firing of certain circuits within the spinal cord. (Baranauskas et al., 1998; Cervero, 2009; Woolf et al., 2011; Baron et al., 2012). (2013). Animal models of chronic neuropathic and inflammatory pain have not yet demonstrated causal relationships. Although not yet fully established, this provides major support for the hypothesis (Cervero 2009).

[0010] Drugs that target hyperexcitability, such as sodium channel blockers (e.g., CNV10 14802, lamotrigine, carbamazepine, and local anesthetics), positive modulators of Kv7 (e.g. For example, flupertine and retigabine, and N-type calcium channel modules modulators (e.g., gabapentin, which interacts with the α2δ subunit of N-type calcium channels) and ziconitide, which is derived from cone snail venom, are effective in treating inflammatory pain. and / or show efficacy in models of neuropathic pain. Among drugs, clinical efficacy, e.g. efficacy and side effects on the central nervous system Evidence for balancing increased loads of cerebrospinal fluid in animal models is mixed. The discrepancy between efficacy in humans and efficacy in humans is due to a variety of factors. However, there are some limitations, particularly with regard to the drug concentrations achievable in humans (due to poor tolerability) and The heterogeneity of human pain states and of the human body's pain conditions is likely to be a major contributing factor.

[0011] A further target of interest is SLACK. Preclinical rationale suggests good potential efficacy. However, to date, no selective compounds have been developed that can This makes it difficult to determine which pain states will be most acceptable. is.

[0012] Improving the pharmacological management of pain may result in reduced side effect burden, reduced tolerance, or Good efficacy with tachyphylaxis and reduced abuse liability and / or risk of dependence The current study focuses on mechanisms that can provide

[0013] In recent years, the Kv3.4 channel has emerged as an interesting target for the treatment of chronic pain. The channel is expressed on neurons of the dorsal root ganglion (Ritter et al., 2012; Chien et al., 200 7), where Kv3.4 channels are expressed primarily on sensory C-fibers (Chien et al., 2007). ).

[0014] Kv3 channels are also expressed by specific subsets of neurons in the spinal cord. Specifically, Kv3.1b (Deuchars et al., 2001; Brooke et al., 2002), Kv3.3 (Brooke et al., 2003), 2006) and Kv3.4 subunits (Brooke et al. 2004) are consistently involved in sensory processing. Although not circuit-associated, it has been identified in the rodent spinal cord.

[0015] Recent data from animal models suggest that DRG after spinal cord injury is associated with hypersensitivity to painful stimuli. Suggesting downregulation of Kv3.4 channel surface expression in neurons (Ritter et al. 2015) Similarly, there is a downregulation of Kv3.4 expression in rodent DRGs after spinal cord ligation. This latter study also demonstrated that antisense oligonucleotides Intrathecal administration of leutidine to rats suppressed Kv3.4 expression, which reduced hypersensitivity to mechanical stimulation. They showed that inactivation of the Kv3.4 channel leads to the protein kinase C (KKC) pathway. We found that D-glucose can be affected by enzyme C-dependent phosphorylation and that this physiological mechanism This may enable RG neurons to change their firing properties in response to painful stimuli. These studies have shown that the appearance of mechanical allodynia is not This suggests a causal relationship between SC or DRG neurons and reduced Kv3.4 channel expression or function. Assessment of Kv3.1, Kv3.2, or Kv3.3 expression in mice was not performed in any of these studies. However, the expression of these three subtypes has not been explicitly demonstrated on DRG neurons. This has not been demonstrated (however, as mentioned above, these may be due to the fact that present in large quantities in

[0016] The in vivo studies reported above identify novel approaches for the treatment of certain neuropathic pain conditions. This study provides a rationale for modulating Kv3.4 as an approach to the regulation of Kv3.1 and / or Kv3.2 and / or Kv3.4. There are currently no data specifically linking the v3.3 channel subtype to pain processing. do not have.

[0017] The following desired properties: · Improved efficacy; ·Improved potency; · Easier to use dosing regimen; Reduced side effect burden; Reduced resistance or tachyphylaxis; and Reduced abuse liability and / or risk of addiction The present invention relates to a method for the prevention or treatment of pain, comprising the steps of: The need still exists.

[0018] The inventors have surprisingly found that modulation of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels We found that Kv3.1 and / or Kv4.1 are involved in pain processing and pain management. Modulation of Kv3.2 and / or Kv3.3 represents a novel approach for the prevention or treatment of pain. . Summary of the Invention

[0019] (Summary of the invention) The present invention relates to an antibody against Kv3.1 and / or Kv3.2 and / or Kv3.3 for use in the prevention or treatment of pain. Modulators of channels (referred to herein as "Kv3.1 / Kv3.2 / Kv3.3" or "Kv3.1 and / or The present invention provides a method for the preparation of a method for the preparation of a nucleic acid molecule comprising the steps of:

[0020] The present invention further relates to the use of Kv3.1 and / or Kv3. The present invention provides uses of modulators of Kv3.2 and / or Kv3.3 channels.

[0021] The present invention also provides a method for administering a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. The present invention provides a method for preventing or treating pain by administering

[0022] Suitably, the modulator is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and / or solvates and / or derivatives thereof: [ka] (In the formula: W is a (Wa), (Wb), (Wc), or (Wd) group; [ka] (In the formula: R1 is H, C 1-4 Alkyl, Halo, HaloC 1-4 Alkyl, CN, C 1-4 Alkoxy or haloC 1-4 is alkoxy; R2 is H, C 1-4 Alkyl, C 3-5 Spirocarbocyclyl, HaloC 1-4 Alkyl or halo the law of nature; R3 is H, C 1-4 Alkyl, haloC 1-4 alkyl, halo; or R3 is absent; R 13 , H, C 1-4 Alkyl, haloC 1-4 alkyl, halo; or R 13 does not exist; R 14 , H, C 1-4 Alkyl, haloC 1-4alkyl, halo; or R 14 does not exist; A is a 5- or 6-membered saturated or unsaturated heterocycle having at least one O atom; The ring is optionally fused to a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group. , when taken together with the phenyl, forms a tricyclic ring; wherein R2 and R3 may be attached to the same or different ring atoms; R2 may be attached to a fused ring atom; and wherein R 13 and R 14 are attached to the same or different ring atoms (may be); [ka] (In the formula: R 16 Halo, C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, halo-C 1-4 Alcoki SI or CN; R 17 H, halo, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; provided that R 17 But, H If yes, R 16 provided that he is not in para rank); [ka] (In the formula: R 22 is H, Cl, F, or C 1-4 is alkyl; R 23 , H, C 1-4 Alkyl, Cl, CF3, OC 1-4 alkyl, OCF3, or N(CH3)2; R 24 are H, Cl, F, and C. 1-4 Alkyl, OC 1-4alkyl, CN, OCF3, or CF3; R 25 are H, Cl, F, and OC. 1-4 Alkyl or C 1-4 is alkyl; and R 26 is H or C 1-4 is alkyl; Here, R 22 ~R 26 About C 1-4 The alkyl may be substituted by O-methyl; however: R 22 ~R 26 cannot all be H; If R4 is H, then R 23 is methyl or CF3, and R 22 , R 24 , R 25 , and R 26 All of , H; R 22 , R 24 , R 25 , or R 26 If one of is F, then R 22 ~R 26 At least one of , H or F; and R 24 If not H, then R 22 or R 23 At least one of is not H; (Provided that); X is CH or N; Y is CR 15 or N; R 15 is H or C 1-4 is alkyl; When W is a group (Wa), (Wb), or (Wc), Z is a group (Za): [ka] (In the formula: R4 is C 1-4is alkyl; R5 is H or C 1-4 is alkyl; or R4 and R5 are fused to C 3-4 capable of forming spirocarbocyclyls); When W is a (Wa), (Wb) or (Wd) group, Z is a (Zb) group: [ka] (In the formula: R4 is H or C 1-4 is alkyl).

[0023] The compounds of formula (I) can be used, inter alia, for the prevention or treatment of pain, such as neuropathic or inflammatory pain. It may also be used as a medicine for treatment.

[0024] Further provided is a method for identifying a compound as useful for the prevention or treatment of pain, comprising: The compound is determined to be a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. The method further comprises the step of determining

[0025] Also provided is a method for the manufacture of a medicament for pain, comprising: (i) a compound that binds to Kv3.1 and / or Kv3.2 and and / or a modulator of the Kv3.3 channel; and (ii) detecting said compound. The method also includes the step of manufacturing a medicament comprising the steps of: may be for therapeutic purposes. [Brief description of the drawings]

[0026] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the effect of Compound 1 on paw withdrawal threshold under mechanical pressure in a neuropathic pain model (study 1): ipsilateral paw (FIG. 1a); contralateral paw (FIG. 1b); and reversal percentage (FIG. 1c). [Diagram 2] FIG. 2 shows the effect of Compound 1 on paw withdrawal threshold to cold stimulation (10° C.) in the neuropathic pain model (Test 1): ipsilateral paw (FIG. 2a); contralateral paw (FIG. 2b); and reversal percentage (FIG. 2c). [Diagram 3] FIG. 3 shows the effect of Compound 1 on paw withdrawal threshold under mechanical pressure in the neuropathic pain model (study 2): ipsilateral paw (FIG. 3a); contralateral paw (FIG. 3b); and reversal percentage (FIG. 3c). [Figure 4] FIG. 4 shows the effect of Compound 1 on paw withdrawal threshold to cold stimulation (10° C.) in the neuropathic pain model (study 2): ipsilateral paw (FIG. 4a); contralateral paw (FIG. 4b); and reversal percentage (FIG. 4c). [Diagram 5] FIG. 5 shows the effect of Compound 1 on paw withdrawal thresholds under mechanical pressure in the inflammatory pain model: ipsilateral paw (FIG. 5a); contralateral paw (FIG. 5b); and percentage reversal (FIG. 5c). [Figure 6] FIG. 6 shows the effect of Compound 1 on paw withdrawal thresholds to cold stimulation (10° C.) in the inflammatory pain model: ipsilateral paw (FIG. 6a); contralateral paw (FIG. 6b); and percentage reversal (FIG. 6c). [Figure 7] FIG. 7 shows the effect of Compound 2 on paw withdrawal threshold under mechanical pressure in the neuropathic pain model (Test 1): ipsilateral paw (FIG. 7a); contralateral paw (FIG. 7b); and reversal percentage (FIG. 7c). [Figure 8] FIG. 8 shows the effect of Compound 2 on paw withdrawal threshold to cold stimulation (10° C.) in the neuropathic pain model (Test 1): ipsilateral paw (FIG. 8a); contralateral paw (FIG. 8b); and reversal percentage (FIG. 8c). [Figure 9] FIG. 9 shows the effect of Compound 2 on paw withdrawal threshold under mechanical pressure in the neuropathic pain model (study 2): ipsilateral paw (FIG. 9a); contralateral paw (FIG. 9b); and reversal percentage (FIG. 9c). [Figure 10]FIG. 10 shows the effect of Compound 2 on paw withdrawal threshold to cold stimulation (10° C.) in the neuropathic pain model (Test 2): ipsilateral paw (FIG. 10a); contralateral paw (FIG. 10b); and reversal percentage (FIG. 10c). [Figure 11] FIG. 11 shows the effect of Compound 2 on paw withdrawal thresholds under mechanical pressure in the inflammatory pain model: ipsilateral paw (FIG. 11a); contralateral paw (FIG. 11b); and percentage reversal (FIG. 11c). [Figure 12] FIG. 12 shows the effect of Compound 2 on paw withdrawal thresholds to cold stimulation (10° C.) in the inflammatory pain model: ipsilateral paw (FIG. 12a); contralateral paw (FIG. 12b); and percentage reversal (FIG. 12c). [Figure 23] FIG. 13 shows the effect of Compound 3 on paw withdrawal thresholds under mechanical pressure in a neuropathic pain model: ipsilateral paw (FIG. 13a); contralateral paw (FIG. 13b); and percentage reversal (FIG. 13c). [Figure 14] FIG. 14 shows the effect of Compound 3 on paw withdrawal threshold to cold stimulation (10° C.) in a neuropathic pain model: ipsilateral paw (FIG. 14a); contralateral paw (FIG. 14b); and percentage reversal (FIG. 14c). [Figure 15] FIG. 15 shows the effect of Compound 3 on paw withdrawal thresholds under mechanical pressure in the inflammatory pain model: ipsilateral paw (FIG. 15a); contralateral paw (FIG. 15b); and percentage reversal (FIG. 15c). [Figure 16] FIG. 16 shows the effect of Compound 3 on paw withdrawal thresholds to cold stimulation (10° C.) in the inflammatory pain model: ipsilateral paw (FIG. 16a); contralateral paw (FIG. 16b); and percentage reversal (FIG. 16c). [Figure 17] FIG. 17 shows the effect of Compound 4 on paw withdrawal thresholds under mechanical pressure in the inflammatory pain model: ipsilateral paw (FIG. 17a); contralateral paw (FIG. 17b); and percentage reversal (FIG. 17c). [Figure 18] FIG. 18 shows the effect of Compound 4 on paw withdrawal thresholds to cold stimulation (10° C.) in the inflammatory pain model: ipsilateral paw (FIG. 18a); contralateral paw (FIG. 18b); and percentage reversal (FIG. 18c). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Detailed Description of the Invention The present invention relates to an antibody against Kv3.1 and / or Kv3.2 and / or Kv3.3 for use in the prevention or treatment of pain. Provide a modulator for the channel.

[0028] The present invention further relates to the use of Kv3.1 and / or Kv3. The present invention provides uses of modulators of Kv3.2 and / or Kv3.3 channels.

[0029] The present invention also provides a method for administering a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. The present invention provides a method for preventing or treating pain by administering

[0030] Suitably, the modulator is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and / or solvates and / or derivatives thereof: [ka] (In the formula: W is a (Wa), (Wb), (Wc), or (Wd) group; [ka] (In the formula: R1 is H, C 1-4 Alkyl, Halo, HaloC 1-4 Alkyl, CN, C 1-4 Alkoxy or haloC 1-4 is alkoxy; R2 is H, C 1-4 Alkyl, C 3-5 Spirocarbocyclyl, HaloC 1-4 Alkyl or halo the law of nature; R3 is H, C1-4 Alkyl, haloC 1-4 alkyl, halo; or R3 is absent; R 13 , H, C 1-4 Alkyl, haloC 1-4 alkyl, halo; or R 13 does not exist; R 14 , H, C 1-4 Alkyl, haloC 1-4 alkyl, halo; or R 14 does not exist; A is a 5- or 6-membered saturated or unsaturated heterocycle having at least one O atom; The ring is optionally fused to a cyclopropyl group, or a cyclobutyl group, or a cyclopentyl group. , when taken together with the phenyl, forms a tricyclic ring; wherein R2 and R3 may be attached to the same or different ring atoms; R2 may be attached to a fused ring atom; and wherein R 13 and R 14 are attached to the same or different ring atoms (may be); [ka] (In the formula: R 16 Halo, C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, halo-C 1-4 Alcoki SI or CN; R 17 H, halo, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; provided that R 17 But, H If yes, R 16 provided that he is not in para rank); [ka] (In the formula: R 22 is H, Cl, F, or C 1-4 is alkyl; R 23 , H, C 1-4 Alkyl, Cl, CF3, OC 1-4 alkyl, OCF3, or N(CH3)2; R 24 are H, Cl, F, and C. 1-4 Alkyl, OC 1-4 alkyl, CN, OCF3, or CF3; R 25 are H, Cl, F, and OC. 1-4 Alkyl or C 1-4 is alkyl; and R 26 is H or C 1-4 is alkyl; Here, R 22 ~R 26 About C 1-4 The alkyl may be substituted by O-methyl; however: R 22 ~R 26 cannot all be H; If R4 is H, then R 23 is methyl or CF3, and R 22 , R 24 , R 25 , and R 26 All of , H; R 22 , R 24 , R 25 , or R 26 If one of is F, then R 22 ~R 26 At least one of , H or F; and R 24 If not H, then R 22 or R 23 At least one of them is not H (Provided that); X is CH or N; Y is CR15 or N; R 15 is H or C 1-4 is alkyl; When W is a group (Wa), (Wb), or (Wc), Z is a group (Za): [ka] (In the formula: R4 is C 1-4 is alkyl; R5 is H or C 1-4 is alkyl; or R4 and R5 are fused to C 3-4 Capable of forming spirocarbocyclyls; When W is a (Wa), (Wb) or (Wd) group, Z is a (Zb) group: [ka] (In the formula: R4 is H or C 1-4 is alkyl).

[0031] The compounds of formula (I) may be used, inter alia, for the prevention or treatment of pain, such as neuropathic or inflammatory pain. may be used as a drug for treatment.

[0032] In one embodiment to the present invention, the modulator is a compound of formula (IA): [ka] (In the formula, R1, R2, R3, R 13 , R 14 , A, X, Y, R4, and R5 are as defined above for compounds of formula (I). as defined above).

[0033] In one embodiment to the present invention, the modulator is a compound of formula (IB): [ka] (In the formula, R1, R2, R3, R 13 , R 14 A, X, Y, and R4 are defined above for compounds of formula (I). (As stated above.)

[0034] In one embodiment to the present invention, the modulator is a compound of formula (IC): [ka] (In the formula, R1, R2, R3, R 13 , R 14 , A, X, Y, R4, and R5 are as defined above for compounds of formula (I). as defined above).

[0035] In one embodiment to the present invention, the modulator is a compound of formula (ID): [ka] R1, R2, R3, R 13 , R 14 , A, X, Y, and R4 are as defined above for compounds of formula (I). be.

[0036] In one embodiment to the present invention, the modulator is a compound of formula (IE): [ka] (In the formula, R 16 and R 17 , X, Y, R4, and R5 are as defined above for compounds of formula (I). be).

[0037] In one embodiment to the present invention, the modulator is a compound of formula (IF): [ka] (In the formula, R 22 , R 23, R 24 , R 25 , R 26 , X, Y, and R4 are defined above for compounds of formula (I). (As stated above.)

[0038] Preferably, R1 is H, C 1-4 Alkyl, halo, or haloC 1-4 Another aspect of the present invention is In one embodiment of the invention, R1 is H or methyl. In another embodiment of the present invention, R1 is C 1-4 Alkyl, especially methyl. W is (Wa) When W is a group, preferably R1 is H. When W is a (Wb) group, preferably R1 is H or It is methyl.

[0039] When W is a (Wb) group, preferably R1 is at the para position of the phenyl ring as shown below. Located in: [ka]

[0040] Preferably, R2 is H, C 1-4 Alkyl, C 3-5 Spirocarbocyclyl or haloC 1-4 Alki In one embodiment of the present invention, R2 is C 1-4 Alkyl, especially methyl, ethyl butyl, isopropyl, tert-butyl, or cyclopropyl, in particular methyl, ethyl, isopropyl In one embodiment of the present invention, R2 is C 3-5 Spirocal In one embodiment of the present invention, R2 is C3 spirocarbocyclyl. In another embodiment of the present invention, R2 is C4 spirocarbocyclyl. In one embodiment of the present invention, R2 is C5 spirocarbocyclyl. And R2 is halo C 1-4 Alkyl, especially trifluoromethyl or 2,2,2-trifluoroethylene In one embodiment of the invention, R2 is halo, especially fluoro. In another embodiment of the invention, R2 is H.

[0041] In one embodiment of the invention, R3 is H, C 1-4 Alkyl, haloC 1-4 Alkyl or halo Alternatively, R3 is H, C 1-4 Alkyl or haloC 1-4 Preferably, R3 is alkyl. is H or C 1-4 In one embodiment of the present invention, R3 is H. In one embodiment of the present invention, R3 is H. In one embodiment, R3 is C 1-4 Alkyl, especially methyl, ethyl, isopropyl, tert -butyl, or cyclopropyl, in particular methyl or ethyl, In one embodiment of the invention, R3 is haloC 1-4 Al In one embodiment of the present invention, the aryl group is fluoromethyl or 2,2,2-trifluoroethyl. In an embodiment, R3 is halo, especially fluoro. Those skilled in the art will appreciate that the size of the A ring, the heterocycle, It will be appreciated that R3 may be absent depending on the presence of R atoms and the degree of unsaturation. Thus, in another embodiment of the invention, R3 is absent. Suitably, R3 is H , methyl, or trifluoromethyl.

[0042] In one embodiment of the invention, R2 is H, C 1-4 Alkyl, haloC 1-4 Alkyl or C3-5 Spirocarbocyclyl is preferred, R3 being H, C 1-4 Alkyl or haloC 1-4 It may be an alkyl. In certain embodiments of the invention, R2 is methyl, ethyl, isopropyl, tert-butyl. , cyclopropyl, C 3-5 Spirocarbocyclyl, trifluoromethyl, or 2,2,2-trifluoro R3 may be H, methyl, ethyl, or trifluoromethyl. In certain embodiments, R3 is H and R2 is H, methyl, ethyl, isopropyl, Or C 3-4 In a further embodiment of the invention, R3 and R2 are Both are fluoro (e.g., attached to the same ring carbon atom). R2 is C 1-4 alkyl and R3 is H, for example, R2 is methyl, ethyl, tert-butyl In one embodiment of the present invention, R2 is C 1-4 It is an alkyl , and R3 is C 1-4 alkyl, for example, R2 is methyl and R3 is methyl, R2 is R2 is ethyl and R3 is ethyl, or R2 is methyl and R3 is ethyl. In another embodiment of the invention, R2 is trifluoromethyl and R3 is methyl. .

[0043] In one embodiment of the invention, R2 and R3 are attached to the same ring atom. In an embodiment, R2 and R3 are attached to different ring atoms.

[0044] In one embodiment of the present invention, R 13 is H, F, or methyl. In R 13 is H. In another embodiment of the present invention, R 13 is C 1-4 Alkyl, In a further embodiment of the invention, R 13 is halo, especially fluoro In a further embodiment of the invention, R 13 is a halo C such as trifluoromethyl 1-4 Depending on the size of the A ring, the presence of heteroatoms, and the degree of unsaturation, one of skill in the art can determine the R 13 It will be appreciated that in some embodiments of the present invention, In R 13 does not exist.

[0045] In one embodiment of the present invention, R 14 is H, F, or methyl. Hey, R 14 is H. In another embodiment of the present invention, R 14 is C 1-4 Alkyl, especially In a further embodiment of the invention, R 14 are halo, especially fluoro. In a further embodiment of the invention, R 13 is a halo C such as trifluoromethyl 1-4 Al Those skilled in the art will appreciate that depending on the size of the A ring, the presence of heteroatoms, and the degree of unsaturation, R 14 but It will be appreciated that in some embodiments of the present invention, And R 14 does not exist.

[0046] In one embodiment of the present invention, R 13 and R 14 are attached to the same ring atom. In an embodiment, R 13 and R14 are attached to different ring atoms.

[0047] In certain embodiments of the present invention, R2, R3, R 13 , and R 14 are H and C, respectively. 1-4 Al Kill and Halo C 1-4 Alkyl, H, C 1-4 Alkyl, haloC 1-4 Alkyl and halo Preferably, R2, R3, R 13 , and R 14 are H, F, methyl, and and trifluoromethyl.

[0048] Preferably, A is a 5- or 6-membered saturated or unsaturated heterocyclic ring containing at least one O atom. the heterocycle is optionally fused to a cyclopropyl group, when considered together with the phenyl In one embodiment of the present invention, A is a 5-membered ring having at least one O atom. 1-membered saturated or unsaturated heterocycle; the heterocycle may be a cyclopropyl group, a cyclobutyl group, or optionally condensed with a cyclopentyl group to form a tricyclic ring when considered together with the phenyl group In another embodiment of the present invention, A is a 6-membered saturated or an unsaturated heterocyclic ring; the heterocyclic ring is a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; It can be optionally fused to a butyl group, forming a tricyclic ring when considered together with the phenyl.

[0049] In one embodiment of the present invention, A is a 5-membered saturated or unsaturated alkyl group having at least one O atom. The heterocycle is a fused cyclopropyl group and can be considered together with the phenyl. In another embodiment of the present invention, A is A 6-membered saturated or unsaturated heterocycle having a cyclopropyl group condensed thereto. When taken together with the phenyl, they form a tricyclic ring.

[0050] In one embodiment of the present invention, A is a 5-membered saturated or unsaturated alkyl group having at least one O atom. In one embodiment of the present invention, A is a 6-membered heterocycle having at least one O atom. It is a 3-membered saturated or unsaturated heterocycle.

[0051] In certain embodiments of the invention, ring A contains one heteroatom. In the formula, ring A contains two heteroatoms (e.g., two oxygen atoms, one oxygen atom and one nitrogen atom). or one oxygen atom and one sulfur atom), in particular two oxygen atoms or one acid It contains a nitrogen atom and one nitrogen atom.

[0052] Preferably, A is a dihydrofuran, isoxazole, dihy- drogen fused with a cyclopropyl group. dropyran, 1,3-dioxolane, 1,3-oxazine, or dihydropyran.

[0053] In one embodiment of the present invention, A is dihydrofuran. In another embodiment of the invention, A is a cyclopropyl group. , cyclobutyl, or cyclopentyl. In one embodiment of the invention, A is a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. In a further embodiment of the invention, A is a dihydropyran condensed with In yet a further embodiment of the present invention, A is a dihydrofuran condensed with a propyl group. is a dihydropyran fused with a cyclopropyl group.

[0054] In one embodiment of the invention, A is fused to a cyclopropyl group. In a further embodiment of the invention, A is fused to a cyclobutyl group. is fused to a cyclopentyl group. In one embodiment of the invention, A is It is not condensed with a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0055] In one embodiment of the invention, A is dihydrofuran, dihydropyran, furan, pyran oxazole, isoxazole, oxazine, dioxin, or 1,3-dioxalane. In another embodiment, A is dihydrofuran, dihydropyran, or 1,3-dioxadiphenylamine. It's Saran.

[0056] In one embodiment of the invention, A is: [ka] where: [ka] indicates the portion of the phenyl ring to which ring A is fused.

[0057] In another embodiment of the invention, A is: [ka] where: [ka] indicates the portion of the phenyl ring to which ring A is fused.

[0058] In a further embodiment of the invention, A is: [ka] where: [ka] indicates the portion of the phenyl ring to which ring A is fused.

[0059] When A contains a 5-membered heterocycle containing one oxygen atom, preferably the heterocycle is a dihydrofuran. It is.

[0060] When A is a 5-membered heterocycle containing one oxygen atom, preferably the oxygen atom is a phenyl ring. It is located at the benzylic position relative to

[0061] When W is a group (Wa), preferably A is a 5-membered heterocycle containing one heteroatom, It is a five-membered heterocycle in which the oxygen atom is located in the benzylic or para position relative to the phenyl ring.

[0062] When W is a (Wb) group, A is preferably a 5-membered heterocycle containing one heteroatom, It is a five-membered heterocycle in which the oxygen atom is located in the benzylic or meta position relative to the phenyl ring.

[0063] When W is a (Wa) group, in one embodiment of the invention the (Wa) group is: [ka] It is.

[0064] When W is a (Wa) group, in another embodiment of the invention the (Wa) group is: [ka] It is.

[0065] When W is a (Wb) group, in one embodiment of the invention, the (Wb) group is: [ka] It is.

[0066] When W is a (Wb) group, in another embodiment of the invention, (Wb) is: [ka] It is.

[0067] When W is a (Wb) group, in a further embodiment of the invention the (Wb) group is: [ka] It is.

[0068] When A contains a six-membered heterocycle containing one oxygen atom, preferably the heterocycle is a dihydropyran. It is.

[0069] When W is a group (Wa), preferably A is a six-membered heterocycle containing one oxygen atom, It is a six-membered heterocyclic ring in which the carbon atom is located para to the phenyl ring.

[0070] When W is a (Wb) group, preferably A is a six-membered heterocycle containing one oxygen atom, It includes six-membered heterocyclic rings in which a nitrogen atom is located meta to the phenyl ring.

[0071] When W is a (Wa) group, in one embodiment of the invention the (Wa) group is: [ka] It is.

[0072] When W is a (Wa) group, in another embodiment of the invention the (Wa) group is: [ka] It is.

[0073] When W is a (Wb) group, in one embodiment of the invention, the (Wb) group is: [ka] It is.

[0074] When W is a (Wb) group, in one embodiment of the invention, the (Wb) group is: [ka] It is.

[0075] When W is a (Wb) group, in one embodiment of the invention, the (Wb) group is: [ka] It is.

[0076] When W is a group (Wa), in one embodiment of the invention, A is: [ka] It is.

[0077] When W is a group (Wa), in one embodiment of the invention, A is: [ka] where m and p indicate the meta and para positions, respectively, of ring A relative to the phenyl ring.

[0078] When W is a group (Wa), in a further embodiment of the invention A is: [ka] is selected from the group consisting of In the formula, m and p indicate the meta and para positions, respectively, of ring A relative to the phenyl ring.

[0079] When W is a (Wb) group, in one embodiment of the invention, A is: [ka] It is.

[0080] When W is a (Wb) group, in one embodiment of the invention, A is: [ka] where m and o indicate the meta and ortho positions of ring A relative to the phenyl ring, respectively. .

[0081] When W is a (Wb) group, in one embodiment of the invention, A is: [ka] It is.

[0082] When W is a (Wb) group, in another embodiment of the invention, A is: [ka] where m and o indicate the meta and ortho positions of ring A relative to the phenyl ring, respectively. .

[0083] In one embodiment of the invention, W is a (Wc) group: [ka] It is.

[0084] In one embodiment of the present invention, R 16 is C 1-4 In another embodiment of the present invention, Hey, R 16 is methoxy. In one embodiment of the present invention, R 16 is C 1-4 Alkyl In another embodiment of the present invention, R 16 is methyl. And R 16In yet a further embodiment of the present invention, R 16 is propyl In yet a further embodiment of the invention, R 16 is butyl. In R 16 is halo. In another embodiment of the present invention, R 16 is chloro. In an embodiment, R 16 is fluoro. In one embodiment of the present invention, R 16 Halo-C 1-4 In another embodiment of the present invention, R 16 is trifluoromethyl In one embodiment of the present invention, R 16 Halo-C 1-4 The alkyl group of the present invention is In another embodiment, R 16 is trifluoromethyl. In one embodiment of the present invention , R 16 is cyano.

[0085] In one embodiment of the present invention, R 17 is H. In one embodiment of the present invention, R 17 is C 1- 4 alkyl. In another embodiment of the present invention, R 17 is methyl. In an embodiment, R 17 is halo. In another embodiment of the present invention, R 17 is chloro. In a further embodiment of the invention, R 17 is fluoro. In one embodiment of the present invention R 17 is C 1-4 In one embodiment of the present invention, R 17 is cyano.

[0086] In one embodiment of the present invention, R16 is C 1-4 Alkyl, C 1-4 Alkoxy or halo-C 1-4 Alkoxy; R 17 is H, cyano, or alkyl; X is N and Y is N or CR 15 in Yes, R4 is C 1-4 alkyl and R5 is C 1-4 alkyl or H. In this regard, R 16 is propyl, butyl, methoxy, propoxy, or trifluorometh It is kisi;R 17 is H, cyano, or methyl; X is N and Y is N or CR 15 and R4 is ethyl and R5 is methyl or H.

[0087] In one embodiment, R 16 and R 17 One of them is in para position, and the remaining R 16 or R 17 is in meta position In one embodiment, R 16 and R 17 One of them is in para position, and the remaining R 16 or R 17 is ortho position is located.

[0088] In one embodiment of the present invention, R 16 is C 1-4 Alkoxy, R 17 is C 1-4 Alkyl In one embodiment of the present invention, R 16 is methoxy and R 17 is methyl. In an embodiment, R 16 is meta-position C 1-4 Alkoxy, R 17 is a para-C 1-4 With alkyl In a further embodiment of the present invention, R 16 is a methoxy in the meta position, and R 17 Para rank R4 is C 1-4 R5 is H and R4 is in the R configuration. In a further embodiment, R 16 is a methoxy in the meta position, and R 17 is a methyl group at the para position. X is N, Y is CH, and R4 is C 1-4 alkyl, R5 is H, and the absolute chirality of the asymmetric center is In yet a further embodiment of the invention, R 16 is a methoxy group at the meta position , R 17 is methyl in the para position, X is N, Y is CH, R4 is ethyl, and R5 is H. and the absolute configuration of the asymmetric center is R.

[0089] In one embodiment of the invention, W is a (Wd) group: [ka] It is.

[0090] In one embodiment of the present invention, R 22 , R 25 , and R 26 is H. In another embodiment , R 23 is C 1-2 Alkyl, CF3, OC 1-2 Alkyl or C such as OCF3 1-4 Alkyl, Cl, CF3 , O.C. 1-4 alkyl, OCF3, or N(CH3)2, especially OCF3, and R 24 , F, C 1-2 a Rukill, CF3, OC 1-2 Alkyl, or H, Cl, F, C such as OCF3 1-4 Alkyl, OC 1-4 Alki C, CN, OCF3, especially F or methyl, and R 22 , R 25 , and R 26 is H.

[0091] Alternatively, when W is a group (Wd), suitably R 22 ~R 26 4 of the 10 are H and R 22 ~R 26 One of them, especially R 22 or R 23 is other than H. R 22 If is other than H, Preferably it is methyl. 23 When is other than H, preferably it is OCF3. .

[0092] When Z is (Za), preferably R4 is C 1-4 In one embodiment of the present invention, In another embodiment of the present invention, R4 is methyl, ethyl, isopropyl, or t-butyl. In a further embodiment of the invention, R4 is ethyl. In yet a further embodiment of the invention, R4 is propyl, such as isopropyl. In yet a further embodiment of the invention, R4 is butyl, such as t-butyl.

[0093] Suitably, R5 is H or C 1-4 In one embodiment of the invention, R5 is H. In another embodiment of the present invention, R4 is methyl, ethyl, isopropyl, or t-butyl. In another embodiment of the present invention, R4 is methyl. In yet a further embodiment of the invention, R4 is ethyl. is propyl, such as isopropyl. In yet a further embodiment of the invention, R4 is butyl, such as t-butyl.

[0094] In one embodiment of the present invention, R4 and R5 together form a C3 spiro carbocyclic ring. In one embodiment of the present invention, R4 and R5 together form a C4 spiro carbocyclic ring. In one embodiment, R4 is methyl and R5 is methyl. In another embodiment, R4 is ethyl and R5 is methyl. In further embodiments, R4 is ethyl and R5 is H.

[0095] Suitably, R4 and R5 have the following stereochemical configuration: [ka] .

[0096] When Z is (Zb), in one embodiment of the invention, R4 is H. In one embodiment, R4 is C 1-4 Alkyl, especially methyl, ethyl, isopropyl, te In one embodiment of the invention, R4 is methyl. In another embodiment of the invention, R4 is ethyl.

[0097] In one embodiment of the invention, X is CH. In another embodiment of the invention, X is It's N.

[0098] In one embodiment of the invention, Y is CR 15 In another embodiment of the present invention, Y is In a further embodiment of the invention, Y is CR 15where R 15 Is H In yet a further embodiment of the invention, Y is CR 15 where R 15 is C 1-4 Al Kill, especially methyl.

[0099] In one embodiment of the invention, X is CH and Y is CR 15 where R 15 is H. In another embodiment of the invention, X is N and Y is CR 15 where R 15 is H. In a further embodiment of the invention, X is N and Y is CR 15 where R 15 is methyl In a further embodiment of the invention, X is CH and Y is CR 15 Wherein R1 5 is methyl. In yet a further embodiment of the invention, X is N and Y is N. do.

[0100] Suitably, when Z is (Zb), an embodiment of the present invention is a compound of formula (IFa): [ka] (In the formula: R4 is CH3 or H; R 22 is H, Cl, F, or C 1-4 is alkyl; R 23 , H, C 1-4 Alkyl, Cl, CF3, OC 1-4 alkyl, OCF3, or N(CH3)2; R 24 are H, Cl, F, and C. 1-4 Alkyl, OC 1-4 alkyl, CN, OCF3, or CF3; R 25are H, Cl, F, and OC. 1-4 Alkyl or C 1-4 is alkyl; and R 26 is H or C 1-4 is alkyl; Here, C 1-4 The alkyl may be substituted by O-methyl; however: R 22 ~R 26 cannot all be H; If R4 is H, then R 23 is methyl or CF3, and R 22 , R 24 , R 25 , and R 26 It's all H can be; R 22 , R 24 , R 25 , or R 26 If one of is F, then R 22 ~R 26 It is not possible to set it to H or F. Flaw; R 24 If not H, then R 22 or R 23 At least one of them is not H (Provided that or a pharma- ceutically acceptable salt thereof.

[0101] In one embodiment of the compound of Formula (IFa), R 22 is C 1-4 In another embodiment, Hey, R 22 is methyl. In a further embodiment, R 22 is ethyl. In a further embodiment, R 22 is propyl. In one embodiment of the compound of Formula (IFa), R 22 is Cl. In one embodiment of the compound of Formula (IFa), R 22is F. In one embodiment of the compound of Formula (IFa), R 23 is H. In one embodiment of the compound of Formula (IFa), R 23 is C 1-4 The compound of formula (IFa) is In another embodiment of the product, R 23 is methyl. In one embodiment of the compound of Formula (IFa), R 23 is chloro. In one embodiment of the compound of Formula (IFa), R 23 is methoxy. Compounds of formula (IFa) In another embodiment, R 23 is ethoxy. In one embodiment of the compound of Formula (IFa), R 23 is trifluoromethyl. In one embodiment of the compound of Formula (IFa), R 23 is trifluoromethoxy. In one embodiment of the compound of Formula (IFa), R 23 is N(CH3)2. In one embodiment of the compound of Formula (IFa), R 24 is H. In one embodiment of the compound of Formula (IFa), R 24 is methyl. In one embodiment of the compound of Formula (IFa), R 24 is chloro. In one embodiment of the compound of Formula (IFa), R 24 is fluoro. In one embodiment of the compound of Formula (IFa), R 25 is H. In one embodiment of the compound of Formula (IFa), R 25 is methyl. In one embodiment of the compound of Formula (IFa), R 25 is chloro. In one embodiment of the compound of Formula (IFa), R 25is fluoro. In one embodiment of the compound of Formula (IFa), R 26 is H. In one embodiment of the compound of Formula (IFa), R 26 is methyl.

[0102] Suitably, when Z is (Zb), an embodiment of the present invention is a compound of formula (IFb): [ka] (In the formula: R4 is H or Me; R 23 is C3-C4 alkyl or OC2-C4 alkyl, and R 22 is H, or R 22 , and R 23 are both methyl; R 24 , R 25 , and R 26 is H; R 15 is H or methyl) or a pharma- ceutically acceptable salt thereof.

[0103] In one embodiment of the compound of Formula (IFb), R 4 is H. In one embodiment of the compound of Formula (IFb), R4 is methyl. In one embodiment of the compound of Formula (IFb), R 22 is H. In one embodiment of the compound of Formula (IFb), R 22 is methyl. In one embodiment of the compound of Formula (IFb), R 23 is C3-C4 alkyl. Compound of formula (IFb) In another embodiment of the product, R 23 is propyl. In one embodiment of the compound of Formula (IFb), R 23 is methyl. In one embodiment of the compound of Formula (IFb), R 23 is OC2-C4 alkyl. In another embodiment of the compound, R 23 is ethoxy. In one embodiment of the compound of Formula (IFb), R 24 is H. In one embodiment of the compound of Formula (IFb), R 25 is H. In one embodiment of the compound of Formula (IFb), R 26 is H. In one embodiment of the compound of Formula (IFb), R 15 is H. In one embodiment of the compound of Formula (IFb), R 15 is methyl.

[0104] References to "formula (I)" may refer to formula (IA), formula (IB), formula (IC), formula (ID), It should also be construed as referring to formula (IE), formula (IF), formula (IFa), and formula (IFb). be.

[0105] Suitably, the compound of formula (I) comprises a phenol group as follows: [ka] The compound may include a W group corresponding to one of:

[0106] Suitably, the compound of formula (I) comprises a phenol group as follows: [ka] The (Wa) group corresponds to one of:

[0107] Suitably, the compound of formula (I) comprises a phenol group as follows: [ka] The (Wb) group corresponds to one of:

[0108] Alternatively, the compound of formula (I) may have a phenol group as follows: [ka] In the case where the compound contains a (Wb) group corresponding to one of the following:

[0109] Alternatively, the compound of formula (I) may have a phenol group as follows: [ka] The compound may contain a (Wb) group corresponding to one of the following:

[0110] When Z is (Za) and W is a group (Wa), the compound of formula (I) is preferably selected from To be: 3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-di Methyl-imidazolidine-2,4-dione; 3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-di Methyl-imidazolidine-2,4-dione; 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl le]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl le]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 2); 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5, 5-Dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5, 5-Dimethyl-imidazolidine-2,4-dione (enantiomer 2); 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidine-5- yl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidine-5- yl]-5,5-dimethyl-imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclobutane]-5-yloxypyridine mimidin-5-yl)imidazolidine-2,4-dione; 5,5-Dimethyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclopentan]-5-yloxypyridine Rimidin-5-yl)imidazolidine-2,4-dione; 5,5-Dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl] Oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 2); 3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5,5-dimethyl Leu-imidazolidine-2,4-dione; 3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolium Dazolidine-2,4-dione; (5R)-3-[2-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5- Ethyl-5-methyl-imidazolidine-2,4-dione; (5R)-3-[2-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]pyrimidin-5-yl]-5- Ethyl-5-methyl-imidazolidine-2,4-dione; (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidine- 5-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-3-[2-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidine- 5-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-Ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran [5-phenyl]oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 1 ); (5R)-5-Ethyl-5-methyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran [5-phenyl]oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 2 ); (5R)-5-Ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidinyl din-5-yl]-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[2-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidinyl zinzyl]-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin [5-methyl-5-yl]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-3-[2-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]pyrimidin 5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-5-methyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yl Oxypyrimidin-5-yl)imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclopentane]-5-isobenzofuran Peroxypyrimidin-5-yl)imidazolidine-2,4-dione; (5R)-5-Ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran [5-phenyl]oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 1 ); (5R)-5-Ethyl-5-methyl-3-[2-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran [5-phenyl]oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 2 ); (5R)-3-[2-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]pyrimidin-5-yl]-5-ethyl 5-methyl-imidazolidine-2,4-dione; (5R)-3-[2-(4,4-dimethylisochroman-6-yl)oxypyrimidin-5-yl]-5-ethyl-5- Methyl-imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl -5-Methyl-imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl -5-Methyl-imidazolidine-2,4-dione; (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl ]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl ]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran [5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-ethyl-5-methyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran [5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-Ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl dil]-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl dil]-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl dil]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 1); (5R)-3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl diethyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-5-methyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yl Oxy-3-pyridyl)imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclopentane]-5-isobenzofuran Peroxy-3-pyridyl)imidazolidine-2,4-dione; (5R)-5-Ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran [5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-5-methyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran [5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl-5- Methyl-imidazolidine-2,4-dione; (5R)-3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5-ethyl-5-methyl- Imidazolidine-2,4-dione; 3-[6-[(3,3-diethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl- Imidazolidine-2,4-dione; 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5 -Dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5 -Dimethyl-imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 2); 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl Chil-imidazolidine-2,4-dione (enantiomer 1); 3-[6-[(3-ethyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl Chil-imidazolidine-2,4-dione (enantiomer 2); 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]- 5,5-Dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[6-[(3-cyclopropyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]- 5,5-Dimethyl-imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxy-3- Pyridyl)imidazolidine-2,4-dione; 5,5-Dimethyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclopentan]-5-yloxy-3 -pyridyl)imidazolidine-2,4-dione; 5,5-Dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl] oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[6-[[3-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl] Oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 2); 3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5,5-dimethyl-imidazolium Dazolidine-2,4-dione; 3-[6-(4,4-dimethylisochroman-6-yl)oxy-3-pyridyl]-5,5-dimethyl-imidazoline Zin-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-5-methyl-3-pyridyl] -5-ethyl-5-methyl-imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobutene [Diastereoisomeric]benzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione body 1); (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-methyl-3-(trifluoromethyl)-1H-isobutene [Diastereoisomeric]benzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione body 2); (5R)-5-ethyl-5-methyl-3-(5-methyl-6-spiro[1H-isobenzofuran-3,1'-cyclobutane 5-yloxy-3-pyridyl)imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobe [Diastereoisomeric]benzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione body 1); (5R)-5-ethyl-5-methyl-3-[5-methyl-6-[[3-(trifluoromethyl)-1,3-dihydroisobe [Diastereoisomeric]benzofuran-5-yl]oxy]-3-pyridyl]imidazolidine-2,4-dione body 2); 5,5-Dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran- 5-yl]oxy}pyridin-3-yl)imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-(5-methyl-6-{[3-(trifluoromethyl)-1,3-dihydro-2-benzofuran- 5-yl]oxy}pyridin-3-yl)imidazolidine-2,4-dione (enantiomer 2); (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl -Imidazolidine-2,4-dione; (5R)-5-Ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxy-3- Pyridyl)imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-2H-benzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl- Midazolidine-2,4-dione; (5R)-5-Ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxypyridine Rimidin-5-yl)imidazolidine-2,4-dione; (5R)-3-{4-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]phenyl}-5- Ethyl-5-methyl-2,4-imidazolidinedione; and (5R)-3-[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]-5-methyl-2,4-imidazolium Dazolidinedione; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0111] In particular, when Z is (Za) and W is a group (Wa), the compound of formula (I) is R: 5,5-Dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (enantiomer 2); (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl -5-Methyl-imidazolidine-2,4-dione; 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5 -Dimethyl-imidazolidine-2,4-dione (enantiomer 1); 3-[6-[(3-tert-butyl-1,3-dihydroisobenzofuran-5-yl)oxy]-3-pyridyl]-5,5 -Dimethyl-imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 1); 5,5-Dimethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]-3-pyridyl]imidazolidine-2,4-dione (enantiomer 2); 5,5-Dimethyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxy-3- Pyridyl)imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]-5-ethyl -Imidazolidine-2,4-dione; (5R)-5-Ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[6-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] Oxy]-3-pyridyl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-3-(6-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxy-3- Pyridyl)imidazolidine-2,4-dione; (5R)-5-Ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 1); (5R)-5-Ethyl-3-[2-[[3-methyl-3-(trifluoromethyl)-1H-isobenzofuran-5-yl] oxy]pyrimidin-5-yl]imidazolidine-2,4-dione (diastereoisomer 2); (5R)-5-ethyl-3-(2-spiro[1H-isobenzofuran-3,1'-cyclobutan]-5-yloxypyridine Rimidin-5-yl)imidazolidine-2,4-dione; (5R)-3-{4-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]phenyl}-5- Ethyl-5-methyl-2,4-imidazolidinedione; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0112] When Z is (Za) and W is a group (Wb), the compound of formula (I) is preferably Select from: (5R)-3-[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]-5-methyl-2,4-imidazolium Dazolidinedione; (5R)-5-Methyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2 ,4-Imidazolidinedione; (5R)-3-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-5-methyl Leu-2,4-imidazolidinedione; 5,5-Dimethyl-3-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-2, 4-Imidazolidinedione; (5R)-5-Ethyl-3-{6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl }-2,4-imidazolidinedione; (5R)-5-Ethyl-3-(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}- 3-pyridinyl)-2,4-imidazolidinedione; (5R)-3-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-5- Methyl-2,4-imidazolidinedione; (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl }-5-methyl-2,4-imidazolidinedione; (5R)-3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl }-5-ethyl-2,4-imidazolidinedione; (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl yl}-5-ethyl-2,4-imidazolidinedione; 7-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5,7 -diazaspiro[3.4]octane-6,8-dione; 6-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-4,6 -diazaspiro[2.4]heptane-5,7-dione; 3-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5 -Dimethyl-2,4-imidazolidinedione; (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl {ethyl}-5-(1,1-dimethylethyl)-2,4-imidazolidinedione; (5R)-5-Ethyl-3-[6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yloxy)-3- pyridinyl]-2,4-imidazolidinedione; 5,5-Dimethyl-3-[6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yloxy)-3-pyridyl Lysinyl]-2,4-imidazolidinedione; (5R)-5-ethyl-5-methyl-3-[6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yl] oxy)-3-pyridinyl]-2,4-imidazolidinedione; (5R)-5-Ethyl-3-(6-{[(3S / R)-3-methyl-1,3-dihydro-2-benzofuran-4-yl]oxy}- 3-pyridinyl)-2,4-imidazolidinedione (mixture of diastereoisomers); (5R)-5-Ethyl-3-{6-[(3-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridyl di-nyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2); (5R)-5-Ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridyl di-nyl}-2,4-imidazolidinedione (mixture of diastereoisomers); (5R)-5-Ethyl-3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridyl di-nyl}-2,4-imidazolidinedione (diastereoisomers 1 and 2); 5,5-Dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl {ru}-2,4-imidazolidinedione (racemic mixture); 5,5-Dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl {enantiomer}-2,4-imidazolidinedione (enantiomer 1 and enantiomer 2); 5,5-Dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-7-yl r)oxy]-3-pyridinyl}-2,4-imidazolidinedione; 5,5-Dimethyl-3-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-7-yl (enantiomer 1 and enantiomer 2)oxy]-3-pyridinyl}-2,4-imidazolidinedione Mar2); (5R)-5-ethyl-5-methyl-3-[6-(1H-spiro[2-benzopyran-4,1'-cyclopropane]-5-yl] [peroxy]-3-pyridinyl]-2,4-imidazolidinedione; 3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-5 ,5-Dimethyl-2,4-imidazolidinedione; (5R)-3-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl {1-methylethyl}-5-(1-methylethyl)-2,4-imidazolidinedione; (5R)-3-{6-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl }-5-ethyl-2,4-imidazolidinedione; 5,5-Dimethyl-3-[6-(1H-spiro[2-benzopyran-4,1'-cyclopropane]-5-yloxy)-3 -pyridinyl]-2,4-imidazolidinedione; (5R)-3-[2-(2,3-dihydrospiro[chromene-4,1'-cyclopropane]-5-yloxy)-5-pyridine imidinyl]-5-ethyl-5-methyl-2,4-imidazolidinedione; 5,5-Dimethyl-3-{6-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl {le}-2,4-imidazolidinedione (racemic mixture, enantiomer 1, enantiomer 2); (5R)-5-ethyl-5-methyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3 -pyridinyl}-2,4-imidazolidinedione (mixture of diastereoisomers, diastereoisomeric isomer 1, diastereoisomer 2); (5R)-5-Ethyl-5-methyl-3-[6-(1,1a,2,7b-tetrahydrocyclopropa[c]chromene-7-yl] [Diastereoisomeric Mixture, Dia(xyloxy)-3-pyridinyl]-2,4-imidazolidinedione stereoisomer 1, diastereoisomer 2); 3-{6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}-5,5-di Methyl-2,4-imidazolidinedione (racemic mixture, enantiomer 1, enantiomer 2); (5R)-5-Ethyl-5-methyl-3-[2-(4-methylchroman-5-yl)oxypyrimidin-5-yl]i Midazolidine-2,4-dione (mixture of diastereoisomers, diastereoisomer 1, diastereoisomer leioisomer 2); (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane] -4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5-ethyl-5- Methyl-imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[1H-isobenzofuran-3,1'-cyclobutane 4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl) {r)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione; (5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyridine {midinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione; (5R)-3-{2-[(2,2-difluoro-1,3-benzodioxol-4-yl)oxy]-5-pyrimidinyl} -5-ethyl-5-methyl-2,4-imidazolidinedione; (5R)-5-ethyl-5-methyl-3-{2-[(2,4,4-trimethyl-4H-3,1-benzoxazin-5-yl)oxy] ci]-5-pyrimidinyl}-2,4-imidazolidinedione; 5,5-Dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl]o xypyrimidin-5-yl]imidazolidine-2,4-dione; 3-[2-(3,3-dimethylisochroman-5-yl)oxypyrimidin-5-yl]-5,5-dimethyl-imidazolium Dazolidine-2,4-dione; 5,5-Dimethyl-3-[2-(7-methylspiro[1H-isobenzofuran-3,1'-cyclobutan]-4-yl] Oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-Ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl] Oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl] Oxy-3-pyridyl]imidazolidine-2,4-dione; (5R)-5-Ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy] -3-pyridinyl}-2,4-imidazolidinedione; (5R)-5-Ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy] -5-pyrimidinyl}-2,4-imidazolidinedione; (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane] -4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione; (5R)-3-[6-(3,3-dimethylisochroman-5-yl)oxy-3-pyridyl]-5-ethyl-5-methyl- Imidazolidine-2,4-dione; (5R)-3-[6-[(3,3-diethyl-1H-isobenzofuran-4-yl)oxy]-3-pyridyl]-5-ethyl -5-Methyl-imidazolidine-2,4-dione; (5R)-5-Ethyl-5-methyl-3-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy] -3-pyridyl]imidazolidine-2,4-dione; (5R)-3-{6-[(3,3-dimethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl }-5-ethyl-5-methyl-2,4-imidazolidinedione; 5,5-Dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl]o oxy-3-pyridyl]imidazolidine-2,4-dione; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0113] In particular, when Z is (Za) and W is (Wb) group, the compound of formula (I) is Is: (5R)-5-ethyl-5-methyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane] -4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-ethyl-5-methyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl) {r)oxy]-5-pyrimidinyl}-2,4-imidazolidinedione; (5R)-3-{2-[(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)oxy]-5-pyridine {midinyl}-5-ethyl-5-methyl-2,4-imidazolidinedione; 5,5-Dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl]o xypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-Ethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl] Oxypyrimidin-5-yl]imidazolidine-2,4-dione; (5R)-5-ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl] Oxy-3-pyridyl]imidazolidine-2,4-dione; (5R)-5-Ethyl-3-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy] -3-pyridinyl}-2,4-imidazolidinedione; (5R)-5-Ethyl-3-{2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy] -5-pyrimidinyl}-2,4-imidazolidinedione; (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane] -4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione; 5,5-Dimethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl]o oxy-3-pyridyl]imidazolidine-2,4-dione; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0114] When Z is (Za) and W is a (Wc) group, the compound of formula (I) is preferably Select from: (5R)-5-methyl-3-{4-[(3-methylphenyl)oxy]phenyl}-2,4-imidazolidinedione; (5R)-5-Methyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinyl Ngeon; (5R)-3-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-imidazolidinyl Ngeon; (5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazol Jingjiong; (5R)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazol Jingjiong; (5S)-3-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazol Jingjiong; (5R)-5-Methyl-3-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolium Dazolidinedione; (5R)-5-Methyl-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinyl Dazolidinedione; (5R)-5-Methyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinyl Zolidinedione; (5R)-5-methyl-3-[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]-2, 4-Imidazolidinedione; (5R)-3-{6-[(2,5-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinyl Ngeon; (5R)-3-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinyl Ngeon; (5R)-3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinyl Ngeon; (5R)-3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5-methyl-2,4-imidazolidinediamine on; (5R)-5-Methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; (5R)-5-Methyl-3-(6-{[2-methyl-5-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; (5R)-5-Methyl-3-(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; (5R)-5-Ethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidinyl Ngeon; (5R)-5-Ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; (5S)-5-Ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; (5R)-5-Ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinyl Zolidinedione; 5,5-Dimethyl-3-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-imidazolidine Zion; 3-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5,5-dimethyl-2,4-imidazolidinedioate hmm; 3-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinediamine on; 3-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolidinyl Ngeon; (5R)-5-(1-methylethyl)-3-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl )-2,4-Imidazolidinedione; (5R)-5-Methyl-3-(2-{[3-(1-methylethyl)phenyl]oxy}-5-pyrimidinyl)-2,4-imidazolium Dazolidinedione; (5R)-5-Ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-2 ,4-Imidazolidinedione; (5R)-5-(1,1-dimethylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3- Pyridinyl)-2,4-imidazolidinedione; (5R)-5-Ethyl-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridin Nyl)-2,4-imidazolidinedione; 7-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-5,7-diazaspiro[ 3.4]octane-6,8-dione; 6-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-4,6-diazaspiro[ 2.4]heptane-5,7-dione; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(1- (methylethyl)benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(trimethylsilyl) (trifluoromethyl)oxy]benzonitrile; 3-{6-[(4-fluoro-3-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolium Zolidinedione; 3-{6-[(4-fluoro-2-methylphenyl)oxy]-3-pyridinyl}-5,5-dimethyl-2,4-imidazolium Zolidinedione; 5,5-Dimethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4- Imidazolidinedione; (5R)-5-(1-methylethyl)-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridine di-nyl)-2,4-imidazolidinedione; 3-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5,5-dimethyl-2,4-isopropyl Midazolidinedione; 3-(2-{[2-(1,1-dimethylethyl)phenyl]oxy}-5-pyrimidinyl)-5,5-dimethyl-2,4- Imidazolidinedione; (5R)-5-Ethyl-5-methyl-3-(2-{[4-methyl-3-(methyloxy)phenyl]oxy}-5-pyrimidinyl di-nyl)-2,4-imidazolidinedione; (5R)-5-Ethyl-3-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)-5 -Methyl-2,4-imidazolidinedione; 5,5-Dimethyl-3-[6-({3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridinyl] -2,4-Imidazolidinedione; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-ethyl Benzonitrile; 2-Chloro-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy C}benzonitrile; 5,5-Dimethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridyl Lysinyl]-2,4-imidazolidinedione; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(methyl (ethyloxy)benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-methyl Benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(trimethylsilyl) (trifluoromethyl)benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-ethyl Benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-2-ene ethylbenzonitrile; 3-Cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl r]oxy}benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-3-(1,1 -Dimethylethyl)benzonitrile; 2-[(cyclopropylmethyl)oxy]-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl] nyl)-2-pyridinyl]oxy}benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-(ethyl (ethyloxy)benzonitrile; 2-Cyclopropyl-4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl r]oxy}benzonitrile; 5,5-Dimethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyridyl rimidinyl]-2,4-imidazolidinedione; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyrimidinyl]oxy}-3-(1 ,1-Dimethylethyl)benzonitrile; 4-{[5-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-pyridinyl]oxy}-2-[(1- Methylethyl)oxy]benzonitrile; 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy (1-methylethyl)oxy]benzonitrile; 3-Cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]- 2-pyridinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy (iii)-2-[(trifluoromethyl)oxy]benzonitrile; 2-Cyclopropyl-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]- 2-pyridinyl}oxy)benzonitrile; (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy]phenyl]phenyl oxy)-5-pyrimidinyl]-2,4-imidazolidinedione; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl nyl]-2-pyrimidinyl}oxy)benzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl nyl]-2-pyridinyl}oxy)benzonitrile; 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(methyloxy) (xy)benzonitrile; 4-{[4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)phenyl]oxy}-2-(ethyloxy) (xy)benzonitrile; 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(ethyl (oxy)benzonitrile; 3-Cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl nyl}oxy)benzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2- pyridinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(methyl (ethyloxy)benzonitrile; 4-({4-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]phenyl}oxy)-2-(methyl (oxy)benzonitrile; 2-[(cyclopropylmethyl)oxy]-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazol- 2-pyridinyl]-2-pyridinyl}oxy)benzonitrile; (5R)-5-Ethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3- pyridinyl]-2,4-imidazolidinedione; 2-Cyclopropyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl (nyl)oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1- (methylethyl)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1- (methylethyl)benzonitrile; (5R)-5-Ethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5- pyrimidinyl]-2,4-imidazolidinedione; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[(1 -Methylethyl)oxy]benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-3-methyl ethylbenzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-[( (trifluoromethyl)oxy]benzonitrile; 3-Ethyl-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}o (xy)benzonitrile; 4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyrimidinyl}oxy)-3- Methylbenzonitrile; 3-(1,1-dimethylethyl)-4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2- pyrimidinyl}oxy)benzonitrile; 4-({5-[(4R)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy 1-methylethyl)benzonitrile; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0115] In particular, when Z is (Za) and W is (Wc) group, the compound of formula (I) is Is: (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy]phenyl]phenyl oxy)-5-pyrimidinyl]-2,4-imidazolidinedione; (5R)-5-Ethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5- pyrimidinyl]-2,4-imidazolidinedione; 5,5-Dimethyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyridyl rimidinyl]-2,4-imidazolidinedione; (5R)-5-Ethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3- pyridinyl]-2,4-imidazolidinedione; 5,5-Dimethyl-3-[6-({4-methyl-3-[(trifluoromethyl)oxy]phenyl}oxy)-3-pyridyl Lysinyl]-2,4-imidazolidinedione; (5R)-5-Ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4 -Imidazolidinediones; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0116] When Z is (Zb) and W is (Wa), the compound of formula (I) is preferably Selected from: 4-{6-[(3,3-diethyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}-5 -Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}- 5-Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 1); 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-5-yl)oxy]pyridin-3-yl}- 5-Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (enantiomer 2); 5-Methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl enantio[yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one Mar1); 5-Methyl-4-(6-{[3-methyl-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl enantio[yl]oxy}pyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one Mar2); 5-Methyl-4-[6-(3H-spiro[2-benzofuran-1,1'-cyclobutan]-6-yloxy)pyridine -3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-[6-(3H-spiro[2-benzofuran-1,1'-cyclopentan]-6-yloxy)pyridin 3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0117] When Z is (Zb) and W is (Wb), the compound of formula (I) is preferably Selected from: 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}-5 -Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{6-[(3-tert-butyl-1,3-dihydro-2-benzofuran-4-yl)oxy]pyridin-3-yl}- 5-Methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridin lysinyl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-methylpyridine- 3-yl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-[5-methyl-6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yloxy) pyridin-3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-{5-methyl-6-[(7-methylspiro[1-benzofuran-3,1'-cyclopropane]-4-yl {aryl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-{6-[(7-methylspiro[1-benzofuran-3,1'-cyclopropane]-4-yl)oxy ]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-[6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yloxy)pyridine- 3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; and 5-Methyl-4-{2-[(7-methylspiro[1-benzofuran-3,1'-cyclopropane]-4-yl)oxy ]pyrimidin-5-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0118] In particular, when Z is (Zb) and W is a (Wb) group, the compound of formula (I) is Is: 5-Methyl-4-{6-[(7-methylspiro[1-benzofuran-3,1'-cyclopropane]-4-yl)oxy ]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-Methyl-4-[6-(spiro[1-benzofuran-3,1'-cyclopropane]-4-yloxy)pyridine- 3-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0119] When Z is (Zb) and W is (Wd), the compound of formula (I) is preferably Selected from: 5-Methyl-4-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one; 5-Methyl-4-(4-{[3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4- Triazol-3-one; 4-{4-[(3-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazo ol-3-one; 4-{4-[(2,6-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 4-(4-{[4-chloro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro- 3H-1,2,4-triazol-3-one; 4-(4-{[4-fluoro-3-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro rho-3H-1,2,4-triazol-3-one; 4-{4-[(3-chlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazo ol-3-one; 4-{4-[(3,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 4-{4-[(2,4-dichlorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 4-{4-[(3-chloro-2-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2 ,4-triazol-3-one; 4-(4-{[3-chloro-5-(methyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro- 3H-1,2,4-triazol-3-one; 5-Methyl-4-[4-({3-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]-2,4-dihydro Doro-3H-1,2,4-triazol-3-one; 4-{4-[(3-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazo ol-3-one; 5-Methyl-4-(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H- 1,2,4-Triazol-3-one; 4-{4-[(3-chloro-4-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2 ,4-triazol-3-one; 4-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2 ,4-triazol-3-one; 4-{4-[(2,3-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 5-Methyl-4-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one; 4-{4-[(3,4-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 4-{4-[(3,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 4-{4-[(2,5-dimethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-trimethyl Azol-3-one; 5-Methyl-4-{4-[(2-methylphenyl)oxy]phenyl}-2,4-dihydro-3H-1,2,4-triazo rol-3-one; 4-{4-[(2-ethylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazo rol-3-one; 5-Methyl-4-(4-{[3-(1-methylethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2, 4-Triazol-3-one; 4-(4-{[3-(dimethylamino)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2, 4-Triazol-3-one; 4-{4-[(2-fluoro-6-methylphenyl)oxy]phenyl}-5-methyl-2,4-dihydro-3H-1,2 ,4-triazol-3-one; 5-Methyl-4-(4-{[2-methyl-3-(methyloxy)phenyl]oxy}phenyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one; 4-(4-{[3-(ethyloxy)phenyl]oxy}phenyl)-5-methyl-2,4-dihydro-3H-1,2,4- Triazol-3-one; 4-{4-[(3-methylphenyl)oxy]phenyl}-2,4-dihydro-3H1,2,4-triazol-3-o hmm; 4-(4-{[3-trifluoromethyl)phenyl]oxy}phenyl)-2,4-dihydro-3H-1,2,4-trifluoromethyl Azol-3-one; 4-[4-[4-fluoro-3-(trifluoromethoxy)phenoxy]phenyl]-3-methyl-1H-1,2,4- Triazol-5-one; 5-Methyl-4-(5-methyl-6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-di Hydro-3H-1,2,4-triazol-3-one; 4-(6-{[3-(ethyloxy)phenyl]oxy}-5-methyl-3-pyridinyl)-5-methyl-2,4-dihydropyridinyl Doro-3H-1,2,4-triazol-3-one; 4-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-5-methly-2,4-dihydro -3H-1,2,4-triazol-3-one; 4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H-1,2,4-trimethylpyridinyl Riazol-3-one; 5-Methyl-4-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-dihydro-3H -1,2,4-triazol-3-one; 4-(6-{[2-(1,1-dimethylethyl)phenyl]oxy}-3-pyridinyl)-5-methyl-2,4,dihydro rho-3H-1,2,4-trazol-3-one; 5-Methyl-4-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}-2,4- Dihydro-3H-1,2,4-triazol-3-one; or a pharma- ceutical acceptable salt and / or solvate and / or derivative thereof.

[0120] Suitably, the compound of formula (I) is not a pharma- ceutically acceptable salt (or is not any salt). stomach).

[0121] Suitably the compound of formula (I) is not a solvate.

[0122] Suitably the compound of formula (I) is not a derivative.

[0123] For the specifically mentioned compounds listed above, Enantiomer 1, Enantiomer 2 The terms diastereomer 1 and diastereomer 2 refer to the original disclosure of these compounds. The specific enantiomers or diastereoisomers named and described in accordance with (The present specification is hereby incorporated by reference for the purposes of providing compounds for use in the present invention.) WO2011 / 069951, WO2012 / 076877, WO2012 / 168710, WO2013 / 175215, See WO2013 / 083994 and WO2013 / 182850).

[0124] For the avoidance of doubt, any one aspect of the compound of the present invention may be embodied as Any of the embodiments of the other features of the disclosed compounds may be combined to create further embodiments. .

[0125] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine. It means an atomic atom. Particular examples of halo are fluorine and chlorine, especially fluorine.

[0126] The compound is C 1-4 When it contains an alkyl group, it may be joined by itself to a larger group, e.g. C 1-4 a When forming part of an alkoxy group, the alkyl group may be linear, branched, cyclic, or A combination of these is also acceptable. 1-4 Examples of alkyl are methyl, ethyl, n-propyl, and isopropyl. Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, and cyclopropyl. cyclobutyl. 1-4 A particular group of alkyl groups are methyl, ethyl and n-propyl. , isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 Arco An example of an oxy is methoxy.

[0127] As used herein, "HaloC 1-4 The term "alkyl" refers to a group substituted with one or more halo atoms. and straight, branched, or cyclic alkyl groups containing 1 to 4 carbon atoms, such as fluoro. Exemplary haloC include fluoromethyl, difluoromethyl, and trifluoromethyl. 1-4 Alki A special group of alkyl groups includes alkyl groups having one to three halogen atoms, such as trifluoromethyl or 2,2,2-trifluoroethyl. and particularly methyl and ethyl groups substituted by one to three fluorine atoms.

[0128] As used herein, "HaloC 1-4 The term "alkoxy" refers to a group substituted with one or more halo atoms. alkoxy groups having 1 to 4 carbon atoms, such as linear, branched, or cyclic alkoxy groups having 1 to 4 carbon atoms. Exemplary halomethoxy include fluoromethoxy, difluoromethoxy, and trifluoromethoxy. C 1-4 A particular group of alkyl is alkyl substituted by 1 to 3 halo atoms, particularly 1 to 3 fluorine atoms. The preferred methoxy and ethoxy groups are

[0129] The term "5- or 6-membered saturated or unsaturated heterocyclic ring having at least one O atom" , for example, dihydrofuran, dihydropyran, furan, pyran, oxazole, isoxazol, The aryl group includes azoles, oxazines, dioxines, morpholines, or 1,3-dioxalanes.

[0130] For use in medicine, the salts of the compounds of formula (I) must be pharma- ceutically acceptable. It will be appreciated that suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge et al., 1977. Such pharma- ceutically acceptable salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. Acid addition salts formed with organic acids, such as succinic acid, maleic acid, nitric acid, or phosphoric acid, etc. acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methane Acid addition salts formed with sulfonic acids or naphthalenesulfonic acids. Other salts, e.g. Oxalate or formate salts may also be used, for example, in the isolation of compounds of formula (I), This is within the scope of the present invention.

[0131] Some of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. All possible stoichiometric and non-stoichiometric forms are included within the scope.

[0132] The compounds of formula (I) may be prepared in crystalline or amorphous form, and if crystalline, may be, for example, The present invention includes within its scope stoichiometric solvates. This includes compounds containing variable amounts of solvent (eg, water), as well as compounds containing hydrates (eg, hydrates).

[0133] The present invention relates to a medicament for the prevention or treatment of pain, comprising a compound of formula (I) and a method for preventing or treating pain by administering a derivative of the compound of formula (I). The present invention also includes the use of a derivative of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of pain. It will be understood that.

[0134] As used herein, a "pharmaceutical acceptable derivative" refers to a compound of formula (I) that, upon administration to a recipient, or an active metabolite or residue thereof. Any pharma- ceutically acceptable prodrug, such as an ester of the compound or a salt of such an ester. This includes

[0135] Suitably, the pharma- cetically acceptable prodrug is, for example, as shown for each Z group below: By functionalizing the secondary nitrogen of the hydantoin or triazolone with the group "L", More formed: [ka]

[0136] The compounds of formula (I) are divalent hydantoins or triazolones, with the group L being selected from the following: can be functionalized via the nitrogen atom: a) -PO(OH)O - M + (In the formula, M + is a pharma- ceutically acceptable monovalent counterion), b) -PO(O - )2·2M + , c) -PO(O - )2·D 2+ (In the formula, D 2+ is a pharma- ceutically acceptable divalent counterion), d) -CH(R X )-PO(OH)O - M + (In the formula, R X is hydrogen or C 1-3 alkyl), e)-CH(R X )-PO(O - )2·2M + , f)-CH(R X )-PO(O - )2·D 2+ g) -SO3 - M + , h)-CH(R X )-SO3 - M + , and i)-CO-CH2CH2-CO2·M + .

[0137] All of the isomers of formula (I) and their pharma- ceutically acceptable derivatives include those having geometric isomerism. This includes all isomeric, tautomeric, and optically isomeric forms, as well as mixtures thereof (e.g., racemic mixtures). Additional chiral centers are contemplated for use and methods of the present invention. When present, the present invention includes within its scope all possible diastereoisomers, The different isomeric forms can be separated one from the other by conventional methods or can be prepared by any suitable method. The specific isomers can be resolved or separated by conventional synthetic methods or by stereospecific synthesis or It can be obtained by asymmetric synthesis.

[0138] One or more atoms have an atomic mass or mass number different from the atomic mass or mass number most commonly occurring in nature. is identical to that detailed in formula (I) except for the fact that it is replaced by an atom having a mass number or an increased proportion of atoms having atomic masses or mass numbers that are not commonly found in nature. Topically labeled compounds (the latter concept is referred to as "isotopically enriched") are also within the scope of the present invention. Examples of isotopes that can be incorporated into the compounds of the invention include natural or may be a non-natural isotope; 2 H (deuterium), 3 H, 11 C. 13 C. 14 C. 18 F, 123 I, or 125 I There are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as Suitably, unless condensation is required, the isotopic content of the compounds of formula (I) is within the range commonly found in nature. Don't change what exists.

[0139] Compounds of formula (I) and pharmaceutical compositions thereof that contain the aforementioned isotopes and / or other isotopes of other atoms. Pharmaceutically acceptable salts are contemplated for use in the uses and methods of the present invention. The compounds of the present invention which have been identified, for example 3 H or 14 Those that incorporate radioactive isotopes such as C These are useful for drug and / or substrate tissue distribution assays. Nawachi 3 H isotope and carbon-14 isotope, i.e. 14 The C isotope is preferred due to its ease of preparation and detection. Particularly favorable for sex. 11 C and 18 The F isotope is particularly useful for PET (positron emission tomography). be.

[0140] Since the compounds of formula (I) are intended to be used in pharmaceutical compositions, they Each in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, preferably at least 85% pure, in particular at least 98% pure (% is weight by weight) It will be readily understood that it is preferable to provide a standard for the purity of the compound. Preparations that are not pure may be used to prepare the purer forms used in pharmaceutical compositions. It's fine.

[0141] In general, compounds of formula (I) can be prepared according to organic synthesis techniques known to those skilled in the art, as well as by the following methods: The compound can be produced by the representative method described below, the method in the Examples, or a modified method thereof.

[0142] Compounds of formula (I) in which W is a (Wa) group, as well as salts and solvates thereof, are generally described in WO2012 / 168710. They can be prepared by the general methods described above.

[0143] Compounds of formula (I) in which W is a (Wb) group, as well as salts and solvates thereof, are generally described in WO2012 / 076877. They can be prepared by the general methods described above.

[0144] Compounds of formula (I) in which W is a (Wc) group, as well as salts and solvates thereof, are generally described in WO2011 / 069951. They can be prepared by the general methods described above.

[0145] Compounds of formula (I) in which W is a (Wd) group, as well as salts and solvates thereof, are described generally in WO2013 / 175215. They can be prepared by the general methods described above.

[0146] Certain compounds of formula (I) where W is a (Wb) group may be prepared by the following method or an analogous procedure: You can also do: [ka]

[0147] Thus, the present invention relates to a novel compound: [ka] to provide.

[0148] The present invention relates to compounds of formula (I) as defined above or their pharma- ceutically acceptable salts and / or or a solvate and / or a derivative thereof, for use in the prevention or treatment of pain The present invention provides modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels.

[0149] The present invention further relates to the use of Kv3.1 and / or Kv3. The use of a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels, and / or the modulator of the Kv3.3 channel is a compound of formula (I) or The compound according to claim 1, which is a pharma- ceutically acceptable salt and / or solvate and / or derivative thereof. Provide use.

[0150] The present invention also provides a method for administering a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. A method for preventing or treating pain by administering Kv3.1 and / or Kv3.2 and / or Kv 3.3 The modulator of the channel is a compound of formula (I) or a pharmaceutical thereof, as defined above. and / or a commercially available salt and / or solvate and / or derivative thereof. Provide.

[0151] (Modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels) As used herein, a "modulator" refers to a human A small number of whole-cell currents mediated by Kv3.1 and / or human Kv3.2 and / or human Kv3.3 channels The compounds of the present invention are those having the ability to produce an enhancement of at least 20%. 1 to determine their modulatory properties. It may be determined.

[0152] In one embodiment, the modulator is a human The ability to produce at least a 20% increase in whole-cell current mediated by Kv3.1 channels Preferably, the modulator has a pEC 50 is in the range of 4 to 7 (e.g., 5 to 6.5).

[0153] In one embodiment, the modulator is a human The ability to produce at least a 20% increase in whole-cell current mediated by Kv3.2 channels Preferably, the modulator has a pEC 50 is in the range of 4 to 7 (e.g., 5 to 6.5).

[0154] In one embodiment, the modulator is a human The ability to produce at least a 20% increase in whole-cell current mediated by Kv3.3 channels Preferably, the modulator has a pEC 50 is in the range of 4 to 7 (e.g., 5 to 6.5).

[0155] In another embodiment, the modulator is a human recombinantly expressed human human Produces at least a 20% enhancement of whole-cell currents mediated by Kv3.1 and Kv3.2 channels. It has the ability to

[0156] In another embodiment, the modulator is a human recombinantly expressed human human Produces at least a 20% enhancement of whole-cell currents mediated by Kv3.1 and Kv3.3 channels. It has the ability to

[0157] In another embodiment, the modulator is a human recombinantly expressed human human Produces at least a 20% enhancement of whole-cell currents mediated by Kv3.2 and Kv3.3 channels. It has the ability to

[0158] In a further embodiment, the modulator is recombinantly expressed in a mammalian cell. At least 20% of the total cell currents mediated by human Kv3.1, Kv3.2, and Kv3.3 channels It has the ability to produce an enhancement of.

[0159] In one embodiment of the invention, the modulator (e.g., a compound of formula (I), or a pharmaceutical The compound (salts and / or solvates and / or derivatives thereof which are acceptable for use in the manufacture of Kv3.2 channels) is By "selective," it is meant that the molecule is selective for modulating Kv3.1 channels over the node. For example, the modulator is less potent for the Kv3.1 channel than for the Kv3.2 channel. It is meant that the activity of a modulator is at least 2-fold, 5-fold, or 10-fold greater than that of a modulator. Preferably, EC 50 It is quantified by its potency, which is indicated by a value.

[0160] In another embodiment of the present invention, the modulator (e.g., a compound of formula (I), The compound (or its pharma- ceutically acceptable salts and / or solvates and / or derivatives) is a compound that inhibits Kv3.1 channel modulation. 1. Selective for modulating Kv3.2 channels over Kv3.2. The modulator may have, for example, a smaller affinity for the Kv3.2 channel than for the Kv3.1 channel. It is meant that W is Wb and R1 is H and exhibits at least 2, 5, or 10 times the activity. Certain compounds of formula (I) or their pharma- ceutically acceptable salts and / or solvates are It may show greater activity against Kv3.2 channels than against Kv3.1 channels. Disclosed Example 15 is a compound of the invention that exhibits selectivity for the Kv3.2 channel. .

[0161] In one embodiment of the invention, the modulator (e.g., a compound of formula (I), or a pharmaceutical The compound (salts and / or solvates and / or derivatives thereof which are acceptable for use in the manufacture of Kv3.3 channels) is used in the manufacture of Kv3.3 channels. By "selective" we mean that the modulator is selective for modulating Kv3.1 channels over the The inhibitor is, for example, at least twice as potent for Kv3.1 channels as for Kv3.3 channels. , 5-fold, or 10-fold greater activity. The activity of a modulator is preferably measured by E C 50It is quantified by its potency, which is indicated by a value.

[0162] In another embodiment of the present invention, the modulator (e.g., a compound of formula (I), The compound (or its pharma- ceutically acceptable salts and / or solvates and / or derivatives) is a compound that inhibits Kv3.1 channel modulation. 3.3 channels. The modulator may have, for example, a smaller affinity for the Kv3.3 channel than for the Kv3.1 channel. It is meant that the activity of a modulator is at least 2-fold, 5-fold, or 10-fold greater than that of a modulator. Preferably, EC 50 It is quantified by its potency, which is indicated by a value.

[0163] In one embodiment of the invention, the modulator (e.g., a compound of formula (I), or a pharmaceutical The compound (salts and / or solvates and / or derivatives thereof which are acceptable for use in the manufacture of Kv3.3 channels) is used in the manufacture of Kv3.3 channels. By "selective" it is meant that the modulator is selective for modulating Kv3.2 channels over the The inhibitor has a higher affinity for the Kv3.2 channel than for the Kv3.3 channel, e.g., at least 2 It is meant that the activity of a modulator is preferably greater than or equal to 10 fold, 5 fold, or 10 fold. , E.C. 50 It is quantified by its potency, which is indicated by a value.

[0164] In another embodiment of the present invention, the modulator (e.g., a compound of formula (I), The present invention relates to a method for treating Kv3.2 channel. It is more selective for modulation of Kv3.3 channels than for modulation of Kv3.3 channels. Again, by "selective" the modulator has a stronger affinity for the Kv3.3 channel than for the Kv3.2 channel, e.g. It is meant to show at least 2-fold, 5-fold, or 10-fold greater activity. , preferably EC 50 It is quantified by its potency, which is indicated by a value.

[0165] In a further embodiment of the invention, the modulator (e.g. a compound of formula (I), or (or a pharma- ceutical acceptable salt and / or solvate and / or derivative) is a compound that inhibits Kv3.1 and Kv 3. The activity of the two channels is comparable. For example, the activity of one channel is W is less than twice that for the other channel, for example, less than 1.5 or 1.2 times. and R1 is C 1-4 Compounds of formula (I) or the like in which the alkyl is methyl, especially in the para position The pharma- ceutically acceptable salts and / or solvates thereof are useful for modulating Kv3.1 and Kv3.2 channels. Compound 3 exhibits comparable activity between the modulation of Kv3.1 and Kv3.2 channels. The activity of the modulator is preferably measured by measuring the EC 50 By value It is quantified by its potency as indicated.

[0166] In a further embodiment of the invention, the modulator (e.g. a compound of formula (I), or (or a pharma- ceutical acceptable salt and / or solvate and / or derivative) is a compound that inhibits Kv3.1 and Kv 3. The activity of the three channels is comparable. For example, the activity of one channel is It is less than twice that for the other channel, for example less than 1.5 or less than 1.2. The activity of the modulator is preferably 50Quantified by its potency, as indicated by the value will be done.

[0167] In a further embodiment of the invention, the modulator (e.g. a compound of formula (I), or (or a pharma- ceutical acceptable salt and / or solvate and / or derivative) is a compound that inhibits Kv3.2 and Kv 3. The activity of the three channels is comparable. For example, the activity of one channel is It is less than twice that for the other channel, for example less than 1.5 or less than 1.2. The activity of the modulator is preferably 50 Quantified by its potency, as indicated by the value will be done.

[0168] Suitably, the modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 is a modulator of pain-related It is more selective for Kv3.1 and / or other channels that are known to be The modulator of Kv3.2 and / or Kv3.3 is 50 micromolar N-cyclohexyl-N-[(7,8- Observation using dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N'-phenylurea and capable of providing an increase in whole cell current of at least 20%, on average, of the increase observed in On the other hand, the modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 is Kv3.4, Kv7.2 / 7.3, and / or Nav1.7 currents. The examples herein show that Kv3.1, Kv3. 2. Provides suitable methods for testing Kv3.3, Kv3.4, Kv7.2 / 7.3, and Nav1.7 currents.

[0169] In one embodiment, the modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 is v3.4. That is, the Kv3.1 and / or Kv3.2 and / or Kv3.3 are more selective than the Kv3. The modulator was 50 micromolar N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2 The increase observed with N-dihydro-3-quinolinyl)methyl-N'-phenylurea was the ability to provide an increase in Kv3.1 and / or Kv3.2 and / or Kv3.3 whole cell currents of at least 20% potent but provides less than a 10% increase in Kv3.4 current at the same concentration (e.g., 10 uM) (e.g., less than 5%, in particular less than 1%, or preferably no increase).

[0170] In one embodiment, the modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 is v7.2 / 7.3, i.e., the Kv3.1 and / or Kv3.2 and / or Kv3. The modulator of 3 was 50 micromolar N-cyclohexyl-N-[(7,8-dimethyl-2-oxo- The average increase observed with 1,2-dihydro-3-quinolinyl)methyl-N'-phenylurea On average, the method provides an increase in Kv3.1 and / or Kv3.2 and / or Kv3.3 whole cell currents of at least 20%. but at the same concentration (e.g., 10 uM), provides less than a 10% increase in Kv7.2 / 7.3 current. (eg less than 5%, in particular less than 1%, or preferably no increase).

[0171] In one embodiment, said modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 is More selective than av1.7. That is, the Kv3.1 and / or Kv3.2 and / or Kv3.3 The modulator was 50 micromolar N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1 ,2-dihydro-3-quinolinyl)methyl]-N'-phenylurea, provides an increase in Kv3.1 and / or Kv3.2 and / or Kv3.3 whole cell currents of at least 20% However, at the same concentration (e.g., 10 uM), it provides less than a 10% increase in Nav1.7 current (e.g., For example, less than 5%, in particular less than 1%, or preferably no increase).

[0172] (pain symptoms) As used herein, the term "treatment" or "treating" refers to the treatment of a disease state or This includes managing, alleviating, reducing, or regulating symptoms.

[0173] The term "prevention" refers to preventing symptoms of a disease or disorder in a subject or preventing the onset of the disease or disorder in a subject. As used herein, the term "prevention" refers to preventing the recurrence of symptoms of a disease or disorder in a subject. Its use is not limited to complete prevention of disease.

[0174] In one embodiment of the invention, the modules of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels are In another embodiment of the present invention, the pain that can be mediated by a modulator is chronic pain. The pain is acute pain.

[0175] In an embodiment of the invention, the modularization of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels is Pain symptoms that can be mediated by the neurotransmitter include nociceptive pain, neuropathic pain, inflammatory pain, Or various types of pain.

[0176] Nociceptive pain is pain caused by the sensation of pain in tissues, such as skin, muscle, internal organs, joints, tendons, or bones. Examples of nociceptive pain that form part of the present invention Somatic pain: musculoskeletal (joint pain, myofascial pain) or cutaneous (which is often pain, which is highly localized in some cases; or visceral pain, which may involve hollow organs or smooth muscles.

[0177] Neuropathic pain is initiated or mediated by a primary lesion or disease in the somatosensory nervous system. Paresthesia is a loss of sensation that is perceived as abnormal sensation (numbness). These range from hypersensitivity (hyperalgesia or allodynia) and dysesthesia (tingling and other sensations). Examples of neuropathic pain that form part of the These include, but are not limited to, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain. Other causes of neuropathic pain include trauma, chemotherapy, and heavy metal exposure. do.

[0178] Inflammatory pain is a nociceptive pain caused by various mediators released at the site of tissue inflammation. It occurs as a result of activation and sensitization of pain pathways. The mediators that have been implicated as the cause of the inflammatory response are infiltrating leukocytes, vascular endothelial cells, or tissue Pro-inflammatory cytokines, such as IL-1-alpha, released by resident mast cells , 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 the present invention Examples include appendicitis, rheumatoid arthritis, inflammatory bowel disease, and shingles.

[0179] Pain disorders refer to pain conditions or disorders that cannot be easily classified. Although the therapies are well known, current understanding of their underlying mechanisms is still rudimentary. Various types of pain include cancer pain, migraine and other primary headaches, and fibromyalgia. These include widespread pain of any type.

[0180] Preferably, mediated by a modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. Particular pain indications that may be treated are neuropathic pain and / or inflammatory pain.

[0181] may be improved by modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels Neuropathic pain may be central or peripheral neuropathic pain. Central neuropathic pain is to the central nervous system (CNS), including, but not limited to, the brain, brain stem, and spinal cord Peripheral neuropathic pain is caused by damage to or dysfunction of sensory nerves, motor Injury or injury to the peripheral nervous system, including but not limited to the nervous and autonomic nervous systems In one embodiment, the neuropathic pain is caused by a dysfunction of the In another embodiment, the neuropathic pain is peripheral neuropathy. It is sexual pain.

[0182] Pain is a subjective state and, in clinical practice, is measured by the patient's self-assessment. Therefore, pain thresholds can be difficult to measure and quantify. For chronic pain, a subjective 11-point rating scale is typically used, where 0 is no pain and 1 is no pain. A is pain with 10 being the worst pain imaginable. Subjects are generally asked to Patients will record their worst pain during the period of pain relief. The minimum mean baseline score will also be recorded. The response to is measured relative to a baseline, e.g., a baseline score In some cases, a reduction in pain of at least 10%, 20%, 30%, 40%, or 50% from the initial dose may be observed. do.

[0183] Because individual drug responses may vary, all individuals will experience a change in their baseline score. Therefore, preferably, the reduction is not a result of the test. At least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or all of the individuals It is observed in

[0184] Thus, in one embodiment of the invention, a reduction of at least 10% from the baseline score is achieved. , 20%, 30%, 40%, or 50% reduction in pain to a subject in need thereof. Kv3.2 / Kv3.3 modulators, for example compounds of formula (I) or a pharma- ceutically acceptable salt thereof; This has been observed upon administration of solvates and / or derivatives.

[0185] Administration of a Kv3.1 / Kv3.2 / Kv3.3 modulator may occur prior to the anticipated onset of pain or immediately following the onset of pain. The progression of the disease or disorder may lead to increased pain experienced by the subject. If it is expected that Kv3.1 / Kv3.2 / Kv3.3 modulators, such as compounds of formula (I) or Pharmaceutically acceptable salts, solvates, and / or derivatives may be administered. If the subject is already suffering from pain, a Kv3.1 / Kv3.2 / Kv3.3 modulator, such as a compound of formula (I) The compound or its pharma- ceutically acceptable salts, solvates, and / or derivatives may be administered to It may be administered to a subject in need thereof.

[0186] Treatment of a subject in need thereof may be continued for as long as treatment is needed, e.g., for a day, a week, or the like. , 2 weeks, 3 weeks, 1 month, 6 months, 1 year, more than 1 year, more than 2 years, more than 5 years, or more than 10 years. Thus, in one embodiment of the invention, a therapeutically effective amount of Kv3.1 / Kv3.2 / Kv3.3 modulator is administered. a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, and / or the like The derivatives are administered to subjects in need for 1 day to 1 month, 1 week to 3 months, or 1 month to 6 months. , for 3 months to 1 year or more.

[0187] The reduction in pain in a subject can be achieved by the initiation of pain treatment using an external stimulus, e.g., a mechanical or thermal stimulus (e.g., a cold stimulus). by assessing the response to (as described in the Experimental Section) The reduction can be calculated by the percentage of reversal (the percentage of affected pain sites along with unaffected pain sites). The thresholds for the pre- and post-administration of the site are calculated, e.g., as described in the Experimental Section. (as described in more detail in the data analysis section of this paper) or as affected pain This can be examined by either measuring the withdrawal threshold of the site. The inversion percentage calculation is used.

[0188] Thus, in one embodiment of the invention, pain (e.g., neuropathic pain or inflammatory pain) is Sensitivity to pain) is increased by a therapeutically effective amount of a Kv3.1 / Kv3.2 / Kv3.3 modulator, e.g., a compound of formula (I) or a pharma- ceutically acceptable salt, solvate, and / or derivative thereof, , more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% reversed. Preferably, pain sensitivity is reversed by more than 80%, or more than 90%.

[0189] Subjects receiving Kv3.1 / Kv3.2 / Kv3.3 modulators may experience secondary benefits, e.g., improved function. experience one or more of the following: improved performance, mood, sleep, quality of life, and reduced time off work There are times when I do.

[0190] Preferably, the prevention or treatment of pain includes prevention or treatment of sleep disorders caused by neuropathic pain. Preferably, the prevention or treatment of pain does not include treatment of a sleep disorder caused by pain. It does not include prevention or treatment.

[0191] (Administration) For use in therapy, the modulators are typically administered as pharmaceutical compositions. The invention also relates to modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 (e.g., compounds of formula (I) or a pharma- ceutically acceptable salt and / or solvate and / or derivative thereof), and a pharma- ceutical composition comprising the compound of formula (I) and a pharma- ceutical acceptable carrier.

[0192] The modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 may be administered by any convenient method, For example, it can be administered orally, parenterally, buccal, sublingually, intranasally, rectally, intrathecally, or transdermally. In such cases, the pharmaceutical composition will be adapted accordingly.

[0193] Modulators of Kv3.1 and / or Kv3.2 and / or Kv3.3 that are active when administered orally can be administered as a liquid or solid, for example, as a syrup, suspension, emulsion, tablet, capsule, or It can be formulated as a lozenge.

[0194] Liquid formulations generally contain a suitable liquid carrier(s), such as water, ethanol, or is an aqueous solvent such as glycerin, or a non-aqueous solvent such as polyethylene glycol or oil. The formulation consists of a suspension or solution of the active ingredient in water. The formulation may also contain suspending agents, preservatives, flavoring agents, and / or colorants.

[0195] The composition in tablet form contains magnesium stearate, starch, lactose, sucrose, and glycerol. Any suitable pharmaceutical agent routinely used in the manufacture of solid formulations, such as cellulose, cellulose acetate, and the like. It can be prepared using a carrier(s).

[0196] A composition in the form of a capsule can be prepared utilizing routine encapsulation procedures, e.g., Pellets containing the active ingredient can be prepared using standard carriers and then placed in a hard gelatin capsule. Alternatively, the dispersion or suspension can be loaded into any suitable pharmaceutical carrier(s), e.g. For example, the dispersion may be prepared using an aqueous gum, cellulose, silicate, or oil, and then the dispersion or The suspension can be filled into a soft gelatin capsule.

[0197] Typical parenteral compositions include a sterile aqueous carrier or a parenterally acceptable oil, such as a polyethylene glycol. Active ingredients in ethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil Alternatively, the solution may be lyophilized and then mixed with a suitable solution or suspension immediately prior to administration. It can be reconstituted with a solvent.

[0198] Compositions for intranasal administration are conveniently presented as aerosols, drops, gels, and powders. Aerosol formulations can typically be formulated in pharma- ceutically acceptable aqueous or non-aqueous solutions. It comprises a solution or fine suspension of the active ingredient in an aqueous solvent, usually for use with a nebulizer device. In single or multi-dose sterile form in a sealed container which may be in the form of a cartridge or refill Alternatively, the sealed container may be a single dose intranasal inhaler or an aerosol dispenser equipped with a metering valve. The dosage form may be a disposable dispensing device such as an aerosol dispenser. If it contains a gas, it may be a compressed gas, such as air, or a fluorochlorohydrocarbon or hydride. The propellant may be an organic propellant such as a fluorocarbon. The sol dosage form may also take the form of a pump atomizer.

[0199] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, which contain the active ingredient with a carrier such as sugar and gum arabic, tragacanth, or gelatin and glycerin. It is formulated.

[0200] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. This is an attitude.

[0201] Compositions suitable for transdermal administration include ointments, gels, and patches. In some cases, the composition is in unit dosage form, such as a tablet, capsule, or ampoule.

[0202] The compositions may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active ingredient, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 4% by weight, depending on the method of administration. The composition may contain 0% to 90% of a carrier. The composition may be administered in an amount of 0.05 mg to 1000 mg, depending on the method of administration. For example, the composition may contain from 1.0 mg to 500 mg of active substance. The composition may contain a carrier in an amount of from 100 mg to 1000 mg, for example from 100 mg to 400 mg. The dosage of the compound administered will usually vary depending on the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guideline, a suitable unit dose is between 0.05 and 1000 mg, more preferably Suitably, the unit dose may be 1.0 to 500 mg, and such a unit dose may be administered two or more times a day, for example, twice or three times a day. Such therapy may continue for several weeks or months.

[0203] In one embodiment of the invention, the modulator of Kv3.1 and / or Kv3.2 and / or Kv3.3 The modulator is used in combination with one or more additional therapeutic agents. When used in combination with other therapeutic agents, the compounds may be administered sequentially by any convenient route. Alternatively, the compounds may be administered separately. stomach.

[0204] The above-mentioned combinations are conveniently presented for use in the form of pharmaceutical formulations. However, the individual components of such combinations may be The individual components of the combination may be administered either sequentially or simultaneously in the same pharmaceutical formulation. They may also be administered separately, by the same or different routes.

[0205] Therapeutic agents that may be used in combination with the present invention include NSAIDs (e.g., aspirin, nasal Proxen, Ibuprofen, Parecoxib, Diclofenac), Paracetamol, Pre Gabalin, gabapentin, or opioids (e.g., fentanyl, sufentanil, These include xycodone, morphine, tramadol, and codeine.

[0206] Examples of therapeutic agents that may be used in combination with neuropathic pain include pregabalin, dutasteride, and cefotaxime. These include loxetine and capsaicin.

[0207] The appropriate dosage will be readily appreciated by those skilled in the art. modulators, such as compounds of formula (I) or pharma- ceutically acceptable salts, solvates, and / or the like Alternatively, the derivative preferably achieves a desired medical outcome without undue adverse effects. The therapeutic agent will be administered at a dosage level that satisfies the therapeutic objective - that is, at a dosage that is both safe and effective. can range from 10 mg to 3 g per day, for example, from 200 mg to 1.5 g per day.

[0208] The pharmaceutical compositions of the present invention may be prepared by mixing at ambient temperature and atmospheric pressure. Usually, they are suitable for oral, parenteral or rectal administration and therefore come in the form of tablets, capsules, oral liquids, etc. Mixtures, powders, granules, lozenges, powders for reconstitution, liquids for injection or infusion or The formulation may be in the form of a suspension, or suppository. Orally administered compositions are generally preferred. EXAMPLES

[0209] (Example) The invention is illustrated by the compounds depicted below:

[0210] (Compound 1) 5,5-Dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl] Oxypyrimidin-5-yl]imidazolidine-2,4-dione - Example 58 of WO2012 / 076877 [ka]

[0211] (Compound 2) (5R)-5-ethyl-5-methyl-3-[2-({4-methyl-3-[(trifluoromethyl)oxy]phenyl} oxy)-5-pyrimidinyl]-2,4-imidazolidinedione - Example 64 of WO2011 / 069951 [ka]

[0212] (Compound 3) 5-Methyl-4-{6-[(7-methylspiro[1-benzofuran-3,1'-cyclopropane]-4-yl)oxy 3H-1,2,4-triazol-3-one Example 14 [ka]

[0213] (Compound 4) (5R)-5-Ethyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl )Oxy-3-pyridyl]imidazolidine-2,4-dione - Example 6 of WO2013 / 083994 [ka]

[0214] Example 1: Measurement of Kv3 channel regulation The compounds of the present invention regulate the voltage-gated potassium channel subtypes Kv3.3 / Kv3.2 / Kv3.1. The ability of the compounds of the invention to bind to the IL-1 receptor can be determined using the following assay. The ability of the agent to modulate other channel subtypes can be examined.

[0215] (Cell Biology) To evaluate the effect of compounds on human Kv3.3 channels (hKv3.3), A stable cell line expressing the nucleic acid was generated by transfecting Chinese hamster ovary (CHO)-K1 cells with pBacMi The cells were transfected with the re_KCNC-3 vector. DMEM / supplemented with non-essential amino acids (Invitrogen) and 400 μg / mL of geneticin (G418) F12 (Gibco). Cells were grown and maintained at 37°C in a humidified atmosphere containing 5% CO2 in air. did.

[0216] To evaluate the effect of compounds on human Kv3.2 channels (hKv3.2), A stable cell line expressing the human keratinocyte kinase (hKv3.2) was generated by transfecting CHO-K1 cells with the pCIH5-hKv3.2 vector. The cells were cultured in 10% fetal bovine serum, 1x non-essential amino acids (Invitrogen). and cultured in DMEM / F12 medium supplemented with 100 μg / ml hygromycin-B (Invitrogen). Cells were grown and maintained at 37°C in a humidified atmosphere containing 5% CO2 in air.

[0217] To evaluate the effect of compounds on human Kv3.1 channels (hKv3.1), Lone 22, also known as CGE22 cells, were transduced using hKv3.1 BacMam reagent. This cell line is Improved CHO-K1 for increased recombinant protein expression compared to wild-type CHO-K1 The cell line was designed to express the adenovirus-Gam1 protein. Transduction of CHO-K1 cells with BacMam virus and selection with geneticin-G418 A stable cell line, CHO / Gam-A3, was subsequently generated. CHO / Gam-A3 cells were transfected with pCDNA3-E1A-Hyg ro, followed by hygromycin-B selection and FACS sorting. Then, single cell clones were obtained. Then, BacMam-Luciferase and BacMam-GFP viruses were transiently transfected into the cells. Used in transduction studies to determine the best BacMam transduction and recombinant protein expression. Clones were selected based on the addition of 300 μg / ml hygromycin-B and 300 μg / ml G418. CGE22 cells were cultured in the same medium used for the hKv3.2 CHO-K1 stable cell line. All conditions were the same as those for hKv3.2 CHO-K1 cells. The day before the experiment, 10 million CGE22 cells were The cells were plated in a T175 culture flask and hKv3.1 BacMam reagent (pFBM / human Kv3.1) was added (MOI 50). The transfected cells were used 24 hours later.

[0218] (Cell preparation for IonWorks Quattro™ experiments) On the day of the experiment, the cells were removed from the incubator and the medium was removed. The cells were washed with 5 ml of Dulbecco's PBS (DPBS) without calcium and magnesium, and then with 3 ml of Versene (Invitrogen, Italy) was added, followed by a short incubation at 37°C for 5 min. The flask was gently tapped to dislodge the cells, and calcium and magnesium were then added. The cell suspension was then prepared by adding 10 ml of DPBS containing 10 ml of sodium chloride. The mixture was placed in a centrifuge tube and centrifuged at 1200 rpm for 2 minutes. After centrifugation, the supernatant was removed and the cell pellet was The pellet was resuspended in 4 ml of DPBS containing calcium and magnesium using a 5 ml pipette. The cell suspension volume was then corrected and 1 ml was added for the assay. A cell concentration of approximately 3 million cells was obtained.

[0219] All solutions added to the cells were pre-warmed to 37°C.

[0220] (Electrophysiology) Experiments were performed at room temperature using an IonWorks Quattro™ planar array with a PatchPlate™ PPC. The stimulation protocol and The measurements and data acquisition were performed using a microcomputer (Dell Pentium 4). The planar electrode hole resistance (Rp) is a 10 mV voltage switch between each well. These measurements were performed before the addition of cells. After the formation of the filter, a seal test was performed by applying a voltage step from -80mV to -70mV for 160ms. After this, amphotericin-B solution was added to the inner surface of the cell of the electrode to measure its intracellular access. The cells were maintained at -70 mV. A 50 ms hyperpolarizing (10 mV) prepulse was applied to obtain leak current. currents were evoked by a 20 ms period at the holding potential followed by a test pulse. For hKv3.2 and hKv3.1 assays, a leak subtraction of −70 mV was performed. From the holding potential, a first test pulse to -15 mV was applied for 100 ms, followed by a further test pulse at -70 mV for an additional 100 ms. Afterwards, a second pulse to 40 mV was applied for 50 ms. The cells were then held at -100 mV for an additional 100 ms. A voltage ramp from -100 mV to 40 mV was then applied for 200 ms. From a holding potential of -70 mV, a first test pulse to 0 mV was applied for 500 ms, followed by a further 100 ms at -70 mV. Afterwards, a second pulse to 40 mV was applied for 200 ms. These longer test pulses were It was used to test the inactivation of cells.

[0221] The test pulse protocol consisted of pulses administered in the absence (pre-read) and presence (post-read) of the test compound. Pre-read and post-read can be performed by adding compound followed by 3 min of incubation. The separation can be achieved by incubation.

[0222] (Solutions and Drugs) The intracellular solution contained (mM): potassium gluconate 100, KCl 54, MgCl2 3.2, HEPE S 5, pH adjusted to 7.3 with KOH. Amphotericin-B solution was prepared from a stock solution of 50 mg / ml in DMSO. The external solution was prepared as a 0.1 mg / ml final working concentration in Dulbecco's solution. The dilute phosphate-buffered saline (DPBS) contained (in mM): CaCl2 0.90, KCl 2.67, KH2PO4 1. 47, MgCl.6H2O 0.493, NaCl 136.9, Na3PO48.06, pH is 7.4.

[0223] The compound of use in the present invention (or N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2 (Reference compounds such as)-N'-dihydro-3-quinolinyl)methyl-N'-phenylurea were added to 10 mM These solutions were then transferred to a Biomek FX (Beck Each dilution solution (1 μL) was further diluted with DMSO in a 384-compound plate using a 1 μL dilution kit (manufactured by Coulter). ) was transferred to another compound plate, and an external solution (66 μL) containing 0.05% pluronic acid was added. Add 3.5 μL from each plate containing compound and monitor the cells for the duration of the IonWorks Quattro™ experiment. The final assay dilution was 200, and the final compound concentrations were 50 μM to 50 μM. The concentrations were in the nM range.

[0224] (Data Analysis) Seal resistance (>20 MΩ) and peak current amplitude (>500 pA, voltage of 40 mV) in the absence of compound Analyze and filter the recordings using both the In the hKv3.2 and hKv3.1 assays, drug responses measured at a -15 mV voltage step were excluded from the analysis. Paired comparisons of evoked currents before and after addition were used to assess the positive modulatory effects of each compound. The outward current mediated by Kv3 channels was measured at the end of the -15 mV voltage pulse. The average intensity of the current over 10 ms was calculated by subtracting the average at -70 mV over the 10 ms period immediately preceding the -15 mV step. The average baseline current was then subtracted to determine the Kv3 currents after addition of the test compound. Channel currents were compared to currents recorded before compound addition. Data were compared to currents recorded before compound addition. Micro M N-cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl) methyl-N'-phenylurea) and standardized to the effect of vehicle control (0.5% DMSO). Standardized data were analyzed using ActivityBase or Excel software. The concentration of compound required to increase the current by 50% of the maximum increase produced by the reference compound (EC50 ) is a method to calculate concentration-response data using a four-parameter logistic function in ActivityBase. In the hKv3.3 assay, the time course between pre- and post-drug addition was determined by fitting. A paired comparison of the measured currents was performed as the peak current and the decrease in current over the duration of the 0mv test pulse (500ms). Measurements were made in 0 mV steps to take into account decay (inactivation).

[0225] N-Cyclohexyl-N-[(7,8-dimethyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-N '-Phenylurea was obtained from ASINEX (registration number: 552311-06-5).

[0226] All of the compounds of the examples were used to measure the potentiation of Kv3.1 or Kv3.2 or Kv3.1 and Kv3.2. The hKv3.1 and hKv3.2 assays described above were used to test positive modulators of Kv3.1 and / or Kv3.2. In the above assay, 50 micromolar N-cyclohexyl-N-[(7,8-dimethyl-2- The average increase seen in oxo-1,2-dihydro-3-quinolinyl)methyl-N'-phenylurea was It produces an increase in whole cell current of at least 20%.

[0227] Compound 1 was found to have a pEC50 of 5.17 against Kv3.3. Compound 2 was found to have a pEC50 of 5.17 against Kv3.3. Compound 3 was found to have a pEC50 of 4.76 against Kv3.3. I found out that...

[0228] Compound 2 at 12.5 micromolar produced an average 113% increase in human Kv3.3 peak current at 0 mV. Compound 1 at 12.5 micromolar increased human Kv3.3 peak currents by an average of 192% at 0 mV. This resulted in an increase in the number of stimuli (n=2).

[0229] Compound 4 at 12.5 micromolar produced an average 365% increase in human Kv3.3 peak current at 0 mV. (n=2).

[0230] Secondary analyses of data from the hKv3.1, hKv3.2, and hKv3.3 assays described in Example 1 The effect of compounds on the rate of rise of the current from the onset of the depolarizing voltage pulse was measured. The magnitude of the effect of the compound can be investigated by measuring the activity of Kv3.1, Kv3. 2, and the Kv3.3 current onset is obtained from a nonlinear fit using the following equation: Time constant (Tau act ) can be determined. 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).

[0231] Similarly, closure of channels at the end of a -15 mV depolarizing voltage pulse was associated with Kv3.1, Kv3.2, or Kv3 .3 The effect of a compound on the time it takes for the current to decay can also be investigated. In this latter case, The magnitude of the effect of the compound on channel closure was measured by the decrease in current immediately after the end of the depolarizing voltage pulse. The time constant (Tau) of the nonlinear fit of the decay ("tail current") deact ) can be determined.

[0232] Kv3.1, Kv3.2, and Kv3.3 channels enable neurons to fire action potentials at high frequency. It must be activated and inactivated very quickly so that it can be 001). Slowing of activation likely delays the onset of action potential repolarization. This reduces the excitability of the neuron and the time it takes for the neuron to fire further action potentials. These may generate hyperpolarizing currents that slow down the time course of channel activation and inactivation. The combined effects of these two slowing factors work together to enhance the ability of neurons to fire at high frequency. Therefore, Kv3.1 and / or Kv3.2 and / or Kv3.3 seem to result in a decrease in Compounds that have this slowing effect on the channel lead to a slowing of neuronal firing. , would effectively act as a negative modulator of the channel. This latter effect , which has been shown for some of the compounds disclosed in WO2011 / 069951, in vitro Using electrophysiological techniques, 'fast-firing' interneurons in the rat brain cortex From the records made by act A significant increase in the 300 Hz frequency can be observed. It reduces the ability of neurons to fire in response to a train of depolarizing pulses.

[0233] Thus, certain compounds are positively labeled in the recombinant cell assay of Example 1. It can be identified as acting as a deuterator, but Tau act These significantly increase the value of The compound can reduce the ability of neurons in native tissue to fire at high frequency. do.

[0234] Example 2: Mechanical stimulation and pain in models of neuropathic and inflammatory pain in rats Evaluation of the effects of Kv3.1 / Kv3.2 channel modulators on the sensitivity to cold stimulation The efficacy of compounds 1, 2, 3, and 4 was assessed in patients with neuropathic pain and / or persistent inflammatory pain. This was investigated using a rat model.

[0235] Materials and Methods Subjects included 6 male Wistar Hanover rats per group (Compound 1 Test and Compound in the test for compound 2, 225 ± 2 g; in the test for compound 3, 214 ± 1 g; in the test for compound 4, 236 ± 1 g).

[0236] Vehicle (12% Captisol®; 0.5% w / v HPMC, and 0.1% w / v Tween-80; i.p. 5ml / kg depending on route) using deionized water autoclaved within one week prior to use. It was prepared as follows.

[0237] Details of the tests performed are outlined in Table 1.

[0238] [Table 1]

[0239] The control for the neuropathic pain model was ramosetron administered at 30 mg / kg by oral delivery. The control for the inflammatory pain model was trigine administered at 30 mg / kg by oral delivery. Statistical analysis was performed using one-way analysis of variance and Tukey's H Comparisons with time-matched vehicle groups were performed using SD tests, where *p<0.05, **p<0 .01, ***p<0.001.

[0240] (Experimental Protocol) All experimental procedures were conducted after review by the Institutional Review Board for the Use of Animals in Research. Approved and regulated by the UK Home Office Animal Procedures Act (1986) It was carried out.

[0241] Treatment groups were randomized and blinded. Groups of 6 rats were used.

[0242] (Neuropathic pain) Neuropathic pain was induced by partial ligation of the sciatic nerve. The patient was anesthetized (isoflurane / O2 inhalation) and the left sciatic nerve was exposed through a small incision at mid-thigh level. The wound was then surgically incised and 1 / 3 to 1 / 2 of the nerve thickness was tightly ligated with 7.0 silk suture. The incision was closed with surgical glue. Animals were allowed to recover and were examined 12-15 days after surgery.

[0243] The ipsilateral (ligated) paw and Withdrawal thresholds or latencies were measured for both contralateral (unligated) paws.

[0244] Pre-treatment behavioral measurements were performed 14 days after nerve ligation; paw withdrawal was measured before the start of drug treatment. Following treatment, further readings were obtained at 1, 3, 6, and 24 hours post-dose.

[0245] (inflammatory pain) Mechanical hyperalgesia was investigated in a tonic inflammatory pain model. The vaccination was induced by intraplantar injection (25 μl) of complete adjuvant (FCA) into the left hind paw.

[0246] To assess the effects of the test compounds, the ipsilateral (FCA-injected) and contralateral (non-injected) paws were ) both paws before FCA injection (untreated) and 24 hours after FCA injection (pre-administration), and Paw withdrawal thresholds or latencies were measured 1, 3, 6, and 24 hours after administration of drug or vehicle.

[0247] (Behavioral Tests) Mechanical hyperalgesia was measured using a wedge-shaped probe (area 1.75 mm 2 Analgesia meter (Analgesy meter) was attached to the The rats were then subjected to increasing force applied to the dorsal surface of the paw using a tachometer (Ugo-Basile, Milan). Modeling neuropathic pain by measuring paw withdrawal threshold (PWT) to mechanical force The cutoff was set at 250 g and the end point was the withdrawal of the hind paw. Both ipsilateral and contralateral paw withdrawal readings were obtained.

[0248] Cold sensitivity was evaluated using a commercially available cold plate (Ugo Basile, Milan). The cold plate was allowed to stabilize at the set temperature for 5 min before testing. Paw withdrawal latency (PWL) was calculated as: The temperature was determined using a cold plate set at 10°C. The animals were lightly restrained and each hind paw was rotated in turn. The rat was placed on the surface of a cold plate. The endpoint was paw withdrawal, and the ipsilateral paw and Contralateral paw withdrawal latency was recorded. A maximum cutoff of 30 seconds was used for each paw. .

[0249] (General Observations) In addition to behavioral pain readouts, each rat was monitored for changes in general behavior throughout the study. and observed.

[0250] (Data Analysis) (Neuropathic pain) Data were expressed as withdrawal threshold (g) or withdrawal latency (s) and expressed using the following formula:

number

[0251] (inflammatory pain) Data were expressed as withdrawal threshold (g) or withdrawal latency (s) and expressed using the following formula:

number

[0252] Statistical analysis was performed using analysis of variance with repeated measures followed by Tukey's HSD test. Threshold readings were performed and the statistical significance level was set at p<0.05.

[0253] (result) (Compound 1) (Neuropathic Pain Study 1) Partial ligation of the sciatic nerve reduces the withdrawal threshold to mechanical stimulation of the affected paw and This resulted in a significant reduction in withdrawal latency to cold stimulation. A pre-dose threshold reading of 66 ± 1 g was measured in the ipsilateral paw compared with 106 ± 1 g in the The cold latency was 7.0 ± 0.2 s in the same paw compared with 10.9 ± 0.2 s in the contralateral paw (Fig. 1a,b). Measurements were taken in both paws (Figures 2a and 2b).

[0254] Compound 1 exhibits mechanistic efficacy with rapid onset of action and good dose separation. This resulted in reversal of both sensitivity (Figures 1a and 1c) and cold sensitivity (Figures 2a and 2c).

[0255] A peak reversal of mechanical sensitivity was seen 3 hours after dosing (51% at 30 mg / kg and 60 mg / kg). Cold sensitivity was 52% and 68% at 30 and 60 mg / kg, respectively, 3 hours after administration. The lower dose of the compound reversed the effect of mechanical hyperalgesia by 125%. At 60 mg / kg, the compound was still effective 6 hours after administration. Lamotrigine, which is a 65% (3 hours after administration) and 58% (1 hour after administration) reduction in mechanical and cold responses, respectively, was observed. This gave a peak inversion after 1 h.

[0256] At 60 mg / kg of Compound 1, there was a significant change in contralateral paw withdrawal and latency; Treated rats were slightly relaxed at 1 and 3 hours post-dose (both doses).

[0257] (Neuropathic Pain Study 2) Partial ligation of the sciatic nerve reduces the withdrawal threshold to mechanical stimulation of the affected paw and This resulted in a significant reduction in withdrawal latency to cold stimulation. A pre-dose threshold reading of 66 ± 1 g was measured in the ipsilateral paw compared with 104 ± 1 g in the The cold latency was 6.8 ± 0.1 s in the same paw compared with 10.8 ± 0.2 s in the contralateral paw (Fig. 3a,b). Measurements were taken in both paws (Figures 4a and 4b).

[0258] Compound 1 inhibited mechanosensitivity (Figure 3a, Figure 3c) and hypothermia with rapid onset and long duration of action. This produced a dose-related reversal of sensitivity (FIGS. 4a, 4c).

[0259] Peak reversal of mechanical sensitivity was seen 3 hours after administration (31% at 10 mg / kg, 73% at 30 mg / kg, Cold sensitivity was significantly increased at 3 hours after administration at 10, 30, and 60 mg / kg. The positive control, lamotrigine, reversed the inflammatory bowel movement by 39%, 68%, and 76%, respectively. After a period of time, the mechanical and cryogenic conditions gave peak reversals of 67% and 67%, respectively.

[0260] Compound 1, which achieved significance at just 3 hours for mechanical thresholds, reduced contralateral paw withdrawal and There were small changes in the latency and duration of the reaction, and some mild changes in some of the rats treated with Compound 1. Some degree of relaxation was observed (1 / 6 at 30 mg / kg and 2 / 6 at 60 mg / kg).

[0261] (Inflammatory Pain Test) Intraplantar injection of FCA increased the withdrawal threshold to mechanical stimuli and the cold temperature of the affected paw. This resulted in a significant reduction in withdrawal latency to the stimulus. The mean untreated threshold reading was 10 5±1 g. 24 hours after FCA injection, 65±1.0 g compared with 104±1.0 g in the contralateral paw. Pre-treatment threshold readings were measured in the ipsilateral paw (Figure 5a, b). The mean time reading was 11.8 ± 0.2 s. Twenty-four hours after FCA injection, the mean time reading in the contralateral paw was 11.5 ± 0.2 s. A pre-administration threshold reading of 7.3 ± 0.1 s was measured in the ipsilateral paw compared with 1.0 ± 0.1 s ( Fig. 6 a , Figure 6b).

[0262] Compound 1 significantly improved mechanical sensitivity ( 5a, 5c) and cold sensitivity (Fig. 6a, 6b). Peak reversal of efficacy was seen 1 hour after dosing at 30 mg / kg and 60 mg / kg (74% and 92%, respectively). The peak reversal of cold sensitivity was seen 3 hours after dosing at 10 mg / kg (64% reversal). At 30 mg / kg and 3 hours after administration (45% and 65%, respectively), the incidence was higher at 1 hour after administration at 60 mg / kg. The reversal was long-lasting, with significant activity still present 6 hours after administration. This was clearly seen: both mechanical and cold sensitivity were reversed by 45% at 60 mg / kg. The control, diclofenac, showed significantly improved mechanical (1 hour after administration) and cold (3 hours after administration) responses, respectively. Peak reversals of 64% and 79% were given.

[0263] At 60 mg / kg Compound 1, a significant increase in contralateral paw withdrawal / latency was observed. These changes varied as indicated by the error bars, with only 3 / 6 animals showing the effect. Marked relaxation was also observed in 2 / 6 rats at 30 mg / kg and 4 / 6 rats at 60 mg / kg. (1 to 6 hours after administration).

[0264] (Compound 2) (Neuropathic Pain Study 1) Partial ligation of the sciatic nerve reduces the withdrawal threshold to mechanical stimulation of the affected paw and This resulted in a significant reduction in withdrawal latency to cold stimulation. A pre-dose threshold reading of 67 ± 1 g was measured in the ipsilateral paw compared with 106 ± 1 g in the The cold latency was 7.0 ± 0.2 s in the same paw compared with 11.3 ± 0.3 s in the contralateral paw (Fig. 7a,b). Measurements were taken in both paws (Figures 8a and 8b).

[0265] Compound 2 exhibits rapid onset of action and lamotrigine-like efficacy, and exhibits mechanical sensitivity. This resulted in reversal of both the sex (Fig. 7a, c) and cold sensitivity (Fig. 8a, c).

[0266] There was little difference in efficacy between the two doses of the compound. Peak reversal of low was seen 1 hour after dosing (53% with 30 mg / kg and 47% with 60 mg / kg). Temperature sensitivity was reversed by 42% and 71% at 1 hour after administration at 30 mg / kg and 60 mg / kg, respectively. However, at 30 mg / kg, a peak reversal was observed 3 hours after administration (55% reversal). The dose was effective 3 hours after administration, but not until 6 hours after administration. The control, lamotrigine, reduced mechanical and cold symptoms by 54% and 55%, respectively, 3 hours after administration. A peak reversal of 8% was given.

[0267] There were no obvious behavioral changes in the rats.

[0268] (Neuropathic Pain Study 2) Partial ligation of the sciatic nerve reduces the withdrawal threshold to mechanical stimulation of the affected paw and This resulted in a significant reduction in withdrawal latency to cold stimulation. A pre-dose threshold reading of 66 ± 1 g was measured in the ipsilateral paw compared with 104 ± 1 g in the (Fig. 9a,b). The cold latency was 6.8 ± 0.1 s in the same paw compared with 10.8 ± 0.2 s in the contralateral paw. Measurements were taken in both paws (Fig. 10a, b).

[0269] Compound 2 exhibited rapid onset of action and reduced mechanical sensitivity (Figure 9a, Figure 9c) and cold sensitivity (Figure 10). a, FIG. 10c), resulting in a dose-related reversal of

[0270] Peak reversal of mechanical sensitivity was seen 3 hours after dosing (31% at 10 mg / kg and 72% at 30 mg / kg). Cold sensitivity was significantly increased at 3 hours after administration at 10, 30, and 60 mg / kg. The positive control, lamotrigine, reversed the effect by 35%, 70%, and 95%, respectively. Three hours after administration, mechanical and cold responses were at a peak of 67% and 67%, respectively. .

[0271] Compound 2, which achieved mechanical significance at just 3 hours, reduced contralateral paw withdrawal and latency. There was little change in

[0272] There were no obvious behavioral changes in the rats.

[0273] (Inflammatory Pain Test) Intraplantar injection of FCA increased the withdrawal threshold to mechanical stimuli and the cold temperature of the affected paw. This resulted in a significant reduction in withdrawal latency to the stimulus. The mean untreated threshold reading was 10 6±1 g. 24 hours after FCA injection, 67±1.0 g compared with 106±1.0 g in the contralateral paw. Pre-treatment threshold readings were measured in the ipsilateral paw (Figure 11a, Figure 11b). The latency reading was 11.1±0.2 s. Twenty-four hours after FCA injection, the latency reading was 10.7±0.0 s in the contralateral paw. A pre-administration threshold reading of 7.9 ± 0.2 s was measured in the ipsilateral paw compared with 0.2 s (Figure 12a , Figure 12b).

[0274] Compound 2 inhibited mechanical sensitivity with a rapid onset of action and peak reversal 1-3 hours after administration. 11a, 11c) and cold sensitivity (Fig. 12a, 12c).

[0275] Peak reversal of mechanical sensitivity was seen 3 hours after dosing (46% at 10 mg / kg and 67% at 60 mg / kg). Peak reversal of cold sensitivity was seen 1 hour after dosing (96% at 60 mg / kg) and 30 mg / kg (97% at 30 mg / kg). The compound at 60 mg / kg was still effective 3 hours after dosing. (81% reversal).

[0276] In this study, cold sensitivity was particularly good. At 24 hours after FCA, paw swelling was In many cases, this results in variable cold withdrawal latencies. Although varying, there was a fairly consistent withdrawal latency to cold.

[0277] The positive control, diclofenac, showed 3-hour mechanical and cold responses, respectively. , giving peak reversals of 66% and 69%.

[0278] No changes in contralateral paw withdrawal or latency were seen with Compound 2.

[0279] There were no obvious behavioral changes in the rats.

[0280] (Compound 3) (Neuropathic Pain Test) Partial ligation of the sciatic nerve reduces the withdrawal threshold to mechanical stimulation of the affected paw and This resulted in a significant reduction in withdrawal latency to cold stimulation. A pre-dose threshold reading of 64 ± 1 g was measured in the ipsilateral paw compared with 104 ± 1 g in the (Fig. 13a,b). The cold latency was 7.0 ± 0.2 s compared with 11.2 ± 0.2 s in the contralateral paw. Measurements were taken in the ipsilateral paw (Figures 14a and 14b).

[0281] Compound 3 had a slow onset of action and reduced mechanical sensitivity (Figure 13a, Figure 13c) and cold sensitivity (Figure 14). a, FIG. 14c) produced a dose-related reversal of both.

[0282] A peak reversal of mechanical sensitivity was seen 3 hours after administration (46% at 60 mg / kg), after which it The cold sensitivity was decreased at 3 h after administration at 60 mg / kg. The 60 mg / kg dose level produced a consistent effect on mechanical and cold hyperalgesia, which was reversed by 52% after 24 hours. The positive control, lamotrigine, achieved statistical significance 3 hours after administration. The peak inversions at low and high temperatures were 61% and 74%, respectively.

[0283] There were no significant changes in contralateral paw withdrawal / latency following treatment with Compound 3, and no behavioral changes were observed. I couldn't.

[0284] (Inflammatory Pain Test) Intraplantar injection of FCA increased the withdrawal threshold to mechanical stimuli and the cold temperature of the affected paw. This resulted in a significant reduction in withdrawal latency to the stimulus.

[0285] Only the highest dose of Example Compound 3 significantly reduced mechanical sensitivity (Figures 15a, 15c) or cold sensitivity (Figure 16 The compound produced a reversal of either the 1-h administration or 2-h administration of the 1 ... After a short time, there was little obvious inversion. The peak inversion was due to mechanical sensitivity and low temperature sensitivity. The activity was observed in both sexes 3 hours after administration, then decreased, but was still present 6 hours after administration. was still evident (significant for mechanical thresholds).

[0286] Three hours after administration, mechanical sensitivity was reversed by 67% and cold sensitivity was reversed by 51%. Both doses were 60 mg / kg. The positive control, diclofenac, showed The mechanical and cryogenic conditions gave peak inversions of 60% and 45%, respectively.

[0287] There were no significant changes in contralateral paw withdrawal / latency following treatment with Example Compound 3 ( 15b and 16b). The only behavioral observation was in 4 / 6 rats in the 30 mg / kg group and 1 / 6 rat in the 60 mg / kg group. Six rats appeared to be more alert and vocal than their cage mates. (1 to 6 hours after administration).

[0288] (Compound 4) (Inflammatory Pain Test) Intraplantar injection of FCA increased the withdrawal threshold to mechanical stimuli and the cold temperature of the affected paw. This resulted in a significant reduction in withdrawal latency to the stimulus. The mean untreated threshold reading was 10 4±1 g. 24 hours after FCA injection, 64±1.0 g compared with 104±1.0 g in the contralateral paw. Pre-treatment threshold readings were measured in the ipsilateral paw (Figure 17a, Figure 17b). The latency reading was 11.1±0.1 s. Twenty-four hours after FCA injection, the latency reading was 11.0±0 A pre-administration threshold reading of 6.6 ± 0.2 s was measured in the ipsilateral paw compared with 0.2 s (Figure 18a , Figure 18b).

[0289] Compound 4 induced mechanical hyperalgesia (Figures 17a, 17c) and cold hyperalgesia (Figures 17b, 17c) that were largely dose-related. The compound produced a reversal of hypersensitivity (Fig. 18a, Fig. 18c). The compound produced a peak reversal 1 to 3 hours after administration. This subsequently decreased, although significant activity was still evident 6 hours after administration. .

[0290] At 30 mg / kg, mechanical sensitivity was reversed by 50% and cold sensitivity was reversed by 55%. The antimicrobial control, diclofenac, showed 49% and 50% reversal in mechanical and cold conditions, respectively. At 30 mg / kg, the compound had efficacy and potency similar to diclofenac. had the following characteristics:

[0291] Following treatment with Compound 4, there were no significant changes in contralateral paw withdrawal / latency, and no behavioral changes were observed. It was not allowed.

[0292] (Conclusion) In rat models of neuropathic and inflammatory pain, Kv3.1 and / or Kv3.2 and / or Compounds 1, 2, and 3 are structurally diverse and selective modulators of the Kv3.3 channel. When administered acutely, it was effective in reversing behavioral measures of pain but had no effect on normal behavior. Furthermore, in a rat model of inflammatory pain, Kv3.1 and Compound 4, a selective modulator of Kv3.2 and / or Kv3.3 channels, is administered acutely When administered, it was effective in reversing behavioral measures of pain but did not cause significant changes in normal behavior. These data did not result in the induction of Kv3.1 and / or Kv3.2 and / or Kv3.3 channels. These results strongly support the proposition that modulation of the agonist's receptors holds promise in the treatment of pain.

[0293] Example 3: Specificity of compounds as enhancers of Kv3.1 and / or 3.2 and / or 3.3 The utility of compounds 1, 2, 3, and 4 is that they inhibit Kv3.1 and / or 3.2 and / or 3.3 channels. To confirm that the ability to enhance activity stems from the compound's ability to enhance other pain-related targets, We investigated the ability to do so.

[0294] (method) (Kv3.4 Assay 1) The human cloned Kv3.4 channel was stably expressed in the HEK293 cell line (HEK293 call line). The effects of compounds on the cellular functions were measured using an automated parallel patch clamp system, QPatch HT (registered trademark) (Sop The compounds were evaluated at room temperature using a 30-μg / mL ELISA kit (Hion Bioscience A / S, Denmark). Exposure time to each test article concentration was 5 minutes.

[0295] In preparation for the recording session, intracellular solution is placed into the intracellular compartment of the QPlate and the cell suspension is After the whole-cell configuration was established, membrane currents were measured using a QPatch Recordings were made using up to 48 parallel patch clamp amplifiers on the HT® system. Current records were sampled at 2000 Hz and low-pass Bessel filtered at 400 Hz. .

[0296] A valid whole-cell recording meets the following criteria: 1.Seal resistance(Rseal)≧200MΩ. 2.Leakage current ≤ 25% channel current.

[0297] (Kv3.4 Assay 2) Human Kv3.4 channels were stably expressed in HEK293 cell lines. The cells were incubated for 1-4 hours after cell preparation. The internal and external physiological solutions were prepared freshly prior to the assay. Continuous recording was performed using an automated patch clamp platform (QPatch, Sophion Biosciences). The extracellular solution was 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HE PES, and 10 mM glucose; pH was adjusted to 7.4 with NaOH, and osmolality was was measured at 313 mOsm / L. 135.6 mM CsCl, 5.37 mM CaCl2, 1.75 mM MgCl2, 10 mM EGTA, A low potassium intracellular solution containing 15.6 mM KOH, 4 mM Na2ATP, and 10 mM HEPES was used; pH was 0.5. The sOH was adjusted to 7.2 and the osmolality was measured to be 303 mOsm / L.

[0298] The voltage dependence of inactivation of homomeric hKv3.4 channels was determined by a train of two rectangular voltage pulses. The protocol consisted of: Pulse 1 (P1 = prepulse) was 1000 ms long; It was immediately followed by a second pulse (P2 = test pulse) of 500 ms duration. Pulse 1 was the hold The potential was varied between -60 mV and +40 mV, and pulse 2 was at -60 before returning to a holding potential of -60 mV. The voltage was stepped from the holding potential to ~+40 mV. G / Gmax was calculated as a single Steady-state voltage activation and inactivation curves were fitted with a Boltzmann function. V 50 teeth , represents the half-activation or inactivation voltage.

[0299] The time constant of the inactivation phase of the hKv3.4 current was the mono( τ) or double (τ1 and τ2) standard exponential fits.

[0300] The time course of the compound's effect on the hKv3.4 potassium channel was measured by a 500-fold increase in potential up to +40 mV every 5 s. Measurements were made using repeated voltage pulses from a holding potential of -60 mV, with pulses of ms duration.

[0301] One concentration (10 uM) of test compound was assessed during the activation, inactivation, and peak pulse protocols. The protocol was applied with the addition of physiological solution (control period) and 10 uM of test compound. and 10 mM of the standard blocker TEA.

[0302] Data are expressed as baseline current control values ​​(maximum current; 1.0) as the top of the curve, and the The zero potassium current (minimum current; 0.0) was used as the bottom of the curve.

[0303] Series resistance and seal quality were monitored throughout the experiment. The analysis was carried out using the software (version 5.2).

[0304] A stock solution of the standard blocker TEA (10 mM) was prepared for analysis by the e-phys automated platform. Freshly prepared in physiological solution prior to testing. Test compounds were prepared in 10 mM DMSO stocks. and then diluted 1:1000 in physiological solution.

[0305] (Kv3.4 Assay 3) Microarray of in vitro transcribed mRNA (mMessage mMachine kit, Ambion, Austin, TX) After cloning, hKv3.4 channels were transfected into Xenopus oocytes (Xenopus laevis oocytes). Whole oocyte currents were measured 1–4 days after microinjection. Recordings were made under two-electrode voltage clamp conditions (OC-725C, Warner, Hamden, CT) at room temperature (21–23°C). ND-96, and ND-96 and test compounds were delivered using a gravity-driven perfusion system.

[0306] Whole oocyte currents mediated by hKv3.4 channels were measured in the absence and after the test compound. In the presence of α-aminobutyric acid, a 400 ms depolarizing step from -40 to 60 mV in 10 mV increments from a holding potential of -100 mV was administered. The voltage conductance curves show the peaks evoked by each voltage step. The peak currents were generated and the data were fitted to the Boltzmann equation.

[0307] Data acquisition, leak subtraction, and initial analysis were performed using pClamp 9.2 / 10.3 (Molecular Devices, S The macroscopic currents were low-pass filtered at 0.5–1 kHz. The leakage and capacitance currents were measured on the basis of a p / 4 subtraction scheme. Xenopus laevis was used in a protocol approved by the IACUC. The matter was handled in accordance with the rules and regulations.

[0308] (Kv7.2 / 7.3) Human Kv7.2 / 7.3 heteromeric channels were stably expressed in the HEK293 cell line. , plated on 13 mm plastic dishes and incubated in 5% CO2 for conventional whole-cell patch clamp experiments. The mice were incubated in a 20-well incubator for 1–3 days. Electrophysiological recordings were performed using an automated patch The procedure was carried out using a clamp platform (QPatch, Sophion Biosciences). The solution consisted of: potassium aspartate (130), KCl (15), MgCl2 (5.5), Na2ATP (5), K2PCr (5 ), EGTA (20), HEPES (10) (mM), pH adjusted to 7.25 with KOH. The cells were then supplemented with: NaCl (140), KCl (4), CaCl2 (2), MgCl2 (1), glucose (100), and 100 mM NaCl. The mice were perfused at room temperature with a standard physiological solution containing (mM) 10 sucrose and 10 HEPES, pH adjusted to 7.35 with NaOH. It was flushed.

[0309] Patch pipettes were pulled from borosilicate glass and filled with the above solutions. The tip resistance was 2-4 MW at 100 Hz. The capacitive transient response was electronically compensated for from the recording. However, the voltage drop across the series resistor and the liquid junction potential are not compensated for. Generally, it is less than 10 MG (n=5 cells) and the average cell capacitance is 25±5 pF.

[0310] In some cases, manual patch clamp was performed using an Axon 200B amplifier (Axon Instruments). The experiment was carried out using the software program pClamp (version 10) from Axon Instruments. ) and electrical activity was recorded using GraphPad Prism (version 5) software. The data was analyzed using.

[0311] To activate Kv7.2 / 7.3 currents, a steady-state voltage pulse (1 s) was applied from a holding potential of -80 mV. +60 mV in 10 mV steps was applied every 10 s. After a control period of at least 3 min, The cells were perfused for at least 3 min. Compounds were dissolved (at 10 mM) in 100% DMSO, followed by 10 The solution was diluted in physiological solution at a final concentration of no more than 0.1% DMSO in μM. The fully activated hKv7.2 / 7.3 channels generally remain stable during typical whole-cell recordings. The treatment did not have a significant effect on the amplitude of the peaks.

[0312] Perfusion of test compound was performed until cells stopped functioning by less than 10% during two complete IV control protocols. Cells that showed a higher run-down rate were initiated for further division. After perfusion of the test compound, the agonist retigabine (obtained from Alomone Labs) was administered. The blocker TEA (obtained from Sigma) was tested on the same cells. and TEA were prepared as 10 mM and 100 mM stock solutions in DMSO and water, respectively. The solutions were then diluted in physiological solution to final concentrations of 10 μM and 10 mM, respectively.

[0313] In this study, due to the limited number of experiments, a two-tailed paired t-test was used only when N=3. Statistical analysis was applied.

[0314] (Nav1.7) Human Nav1.7 channels were stably expressed in HEK293 cell lines. Electrophysiological recordings were performed in vitro. At room temperature, the specimens were recorded using a dynamic patch clamp platform (QPatch, Sophion Biosciences). went.

[0315] The QPatch assay was performed at room temperature using the QPatch platform (Sophion). On the day of the experiment, cells were cultured using standard cell preparations for QPatch. Internal and external physiological solutions were The standard extracellular solution was prepared freshly before the assay. 10 mM MgCl, 10 mM HEPES, and 10 mM glucose; pH was adjusted to 7.4 with NaOH. The osmolality was measured to be 314 mOsm / L. The standard intracellular solution was 140 mM CsF, 10 mM NaCl , 5 mM CsOH, 1 mM EGTA, 10 mM HEPES; pH was adjusted to 7.25 with CsOH, molar Osmolality was measured to be 293 mOsm / L.

[0316] A series of 40 voltage pulses (2.4 ms duration, from -120 mV to 0 mV, at 117 Hz) were delivered every 60 s to the control (2x), compound (5x), standard blocker (2x), and washout (2x). % Inhibition The values ​​are normalized to the first pulse (P1) and the 40th pulse vs. the first pulse The series resistance and the quality of the seal were calculated by calculating the ratio between the 40 and 100 Ω of the series resistance and the seal quality. All graphs were analyzed using Sophion QPatch Assay Software 5.0. 10 μM of test compound was applied, followed by 1 μM TTX (standard blocker), This was followed by saline (rinse). Compounds were administered at up to 0.1% DMSO as required. The samples were diluted in physiological solution to the concentration required for the assay.

[0317] (BK) Cloned human BK (hKCa1.1 / β1) potassium channel (mediated by human KCNMA1 and KCNMB1 genes) The effect of the compound on the chromosome 111 of ... hBK current initiation and steady-state were investigated in a CHO cell line using the Sigma-Aldrich (S) assay. State inhibition was assessed by administering depolarizing test pulses (+100 mV amplitude, 200 ms duration) spaced 10 s apart from a holding potential of -80 mV. For each test pulse, a delayed outward voltage was measured. The peak amplitude of current was measured. Compounds were administered three times after 3 min of compound application. The steady-state inhibition produced by each compound was calculated.

[0318] (result) (hNav1.7) Compounds 1, 2, and 3 were tested at 10 μM concentration in the Nav1.7 assay (N=3). No significant effect on mediated currents was observed.

[0319] (hBK) Compounds 1, 2, and 3 were tested at 10 μM concentration in the BK assay (N=3). Channel current No significant effect on was observed.

[0320] (hKv7.2 / 7.3) Compounds 1 and 2 were tested at 10 μM concentration in the Kv7.2 / 7.3 assay (N=3). The compound was also found to have no significant effect on Kv7.2 / 7.3-mediated currents.

[0321] (hKv3.4) Compound 2 was tested at 10 μM concentration in Kv3.4 assay 1 (N=2). The results showed that the current flowing through the endothelial cells was not enhanced by the endothelial cells.

[0322] Compounds 1, 2, 3, and 4 were tested at 10 μM concentration in Kv3.4 assay 2 (N≧2). The compound did not enhance the observed currents and showed a notable change in the voltage dependence of activation of Kv3.4 currents. However, in both cases the compound did not produce any significant shifts. , was associated with a reduction in peak Kv3.4 currents (compound 1: 40 ± 5%; compound 2: 45.4 ± 4%; compound 3: Compound 4: 36 ± 3%; Compound 5: 50.0 ± 4%), but these peak currents remained constant even after compound washout. did not recover to baseline levels.

[0323] Compound 1 was administered in a Kv3.4 assay3 (manual patch assay using transiently transfected oocytes). The drug was tested at a concentration of 10 μM in 100 μg / mL (N=6). No significant effects on Kv3.4-mediated channel currents were observed. , and Compound 1 did not significantly shift the voltage / conductance curve of hK3.4. It was.

[0324] All publications, including but not limited to patents and patent applications, cited in this specification. are incorporated by reference herein as if each individual publication were fully set forth. All such disclosures are incorporated herein by reference as if specifically and individually indicated to be incorporated by reference.

[0325] Throughout the specification and the claims that follow, unless the context requires to the contrary, " The words "comprise" and "comprises" and "comprising" Variations such as "a" or "b" refer to the inclusion of a stated integer, step, group of integers, or group of steps. It will be understood that this does not exclude other integers, steps, groups of integers, or groups of steps. This application, of which the specification and claims form part, serves as a basis for priority of any subsequent application. The claims of such subsequent application may be used as though they were made in whole or in part to any of the features or aspects described herein. may be directed to a combination of features. They may be directed to a product, composition of matter, process, or These claims may take the form of use claims, including, by way of example and without limitation, the following claims: It may include.

[0326] (References) [ka] TIFF2025003958000064.tif248170TIFF2025003958000065.tif240170TIFF2025003958000066.tif147170

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.

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