Anticonvulsant compounds and uses thereof

Abstract

The present invention relates to a composition of cannabinoid compounds having a structural formula I as defined herein. The invention also relates to compositions comprising these compounds, to processes for preparing these compounds, to intermediates useful for preparing these compounds and to the use of these compounds as medicaments, in particular for the treatment of conditions associated with epileptic seizures, such as epilepsy.

Description

Related Applications

[0001] This application is related to GB2307065.9, filed on 12 May 2023 (2023.05.12), and claims the benefit of GB2307065.9, the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0002] The present invention relates to a group of synthetic cannabinoid compounds and the use of these compounds as research tools and medicines, in particular for the treatment of conditions associated with seizures such as epilepsy. BACKGROUND

[0003] Epilepsy is a disabling neurological disorder characterized by a susceptibility to epileptic seizures caused by abnormal, excessive, or synchronous neuronal activity in the brain. Patients with epilepsy can experience a significant impairment in quality of life due to seizures, co-morbid mood and psychiatric disorders, cognitive deficits, and side effects of antiepileptic drugs [Devinsky et al., 2018]. Furthermore, seizures can be fatal either directly due to effects on autonomic and arousal functions, or indirectly due to accidents such as drowning or motor vehicle accidents.

[0004] Epilepsy is reported to affect 650 million people worldwide [Devinsky et al., 2018] with a lifetime prevalence of 7.6 / 1,000 people [Fiest et al., 2017]. Although prevalence shows no variation by age group or sex, the prevalence and incidence of epilepsy is higher in low- and middle-income countries [Fiest et al., 2017].

[0005] Causes of epilepsy include acquired structural changes to the brain (e.g. due to traumatic brain injury, brain tumour or stroke), infectious diseases (e.g. viral or bacterial disorders) and genetic mutations.

[0006] The International League Against Epilepsy (ILAE) classification framework starts with the diagnosis of the type of epileptic seizure and assumes that non-epileptic events have been excluded. The classification proposes a three-level classification approach for patients presenting with epileptic seizures, where the first level is the seizure type, the second level is the epilepsy type, and the third level is the epilepsy syndrome diagnosis [Scheffer et al., 2017].

[0007] Seizure type classification begins with determining whether the initial presentation of a seizure is focal in origin or generalized in origin. If the origin is missed or is ambiguous, the seizure is classified as unknown origin [Fisher et al., 2017]. Focal origin seizures can be further defined according to the level of consciousness, and all three seizure types (focal, generalized, and unknown) can be further characterized as either motor or non-motor in origin.

[0008] Seizure type classification is divided into focal seizures, generalized seizures, combined generalized and focal seizures, and unknown seizures. Focal seizures include single and multiple foci disorders and seizures involving one hemisphere. For diagnosis of generalized seizures, patients typically show generalized spike activity on EEG. Individuals with generalized seizures can have a range of seizure types, including absence seizures, myoclonic seizures, atonic seizures, tonic seizures, and tonic-clonic seizures. Combined generalized and focal seizures encompass patients who have both generalized and focal seizures, while unknown seizures encompass cases where the patient has epilepsy but the clinician is unable to determine whether the seizure type is focal or generalized due to insufficient information [Scheffer et al. ，

[0009] Epilepsy syndromes refer to a group of characteristic clinical and EEG features, often supported by specific etiologic findings (structural, genetic, metabolic, immune, and infectious) [Wirrell et al., 2022]. The group of epilepsy syndromes includes syndromes that onset in the neonatal and infantile period (up to 24 months of age); syndromes that onset in childhood; syndromes that onset at different ages; and idiopathic generalized epilepsy syndromes (IGE). The group of syndromes can also include self-limited epilepsy, developmental and epileptic encephalopathy (DEE), and etiology-specific syndromes.

[0010] Examples of neonatal and infantile epilepsy syndromes include self-limited neonatal seizures, infantile spasms syndrome, Dravet syndrome, glucose transporter 1 deficiency syndrome, and Sturge Weber syndrome [Zuberi et al., 2022].

[0011] Examples of childhood-onset syndromes include childhood occipital visual epilepsy (COVE), Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic atonic seizures (previously known as Doose syndrome), and epilepsy with eyelid myoclonia (previously known as Jeavons syndrome) [Specchio et al., 2022].

[0012] ​Examples of syndromes with onset at different ages include sleep-related hypermotor epilepsy / excessive movement epilepsy (SHE), progressive myoclonic epilepsy (PME), fever-induced seizure syndrome (FIRES), and Rasmussen syndrome [Riney et al., 2022].

[0013] Idiopathic generalized epilepsy syndromes (IGE) include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with isolated generalized tonic-clonic seizures (GTCA) [Hirsch et al., 2022].

[0014] In the management of epilepsy, options include anti-seizure drugs (ASDs), dietary therapies, neurostimulation, and surgery. ASDs are the mainstay of therapy for epilepsy and are intended to reduce the incidence and severity of seizures. Over 20 ASDs have been approved, however, full seizure control often requires multiple drugs. It is also important for patients to adhere strictly to their ASD treatment regimen, as ASDs must be taken once and between four times daily, and a single missed dose can lead to seizure recurrence [Devinsky et al., 2018].

[0015] Cannabidiol (CBD) is one such ASD. In 2018, CBD (Epidiolex®) was approved in the United States for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in children and adults over 2 years of age. CBD is a naturally occurring cannabinoid compound derived from Cannabis species, such as industrial hemp plants ( Cannabis sativa ) Unlike other cannabinoids, such as tetrahydrocannabinol (THC), CBD does not bind to (or its binding to receptors is negligible in terms of inducing pharmacological effects) CB1 or CB2 receptors and does not induce psychotropic effects associated with Cannabis.

[0016] Despite the wide variety of ASDs available, approximately one-third of patients do not achieve seizure control, regardless of how many ASDs are tried, using single or combination drug regimens [Devinsky et al., 2018]. Drug-resistant or treatment-resistant epilepsy is associated with increased risk of injury and death, greater medication burden and adverse effects, and reduced quality of life. For these patients, surgery offers the greatest chance of achieving long-term seizure control, but only a small number of patients are good candidates for surgery. Clearly, alternative treatment options for seizures are desirable.

[0017] The present invention was designed in light of the above considerations. SUMMARY

[0018] Most generally, the present invention relates to synthetic cannabinoid compounds. These synthetic cannabinoid compounds have exhibited anticonvulsant activity in one or more rodent seizure models, and therefore the compounds may be used to treat or prevent medical conditions such as epilepsy.

[0019] In a first aspect of the invention, a compound of formula (I) or a salt thereof is provided:

[0020] (I) in, R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl or halogen.

[0021] In a second aspect of the invention, a pharmaceutical composition is provided comprising the compound of the first aspect or a pharmaceutically acceptable salt thereof, together with one or more ingredients selected from: carriers, diluents, excipients, excipients, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners.

[0022] In a third aspect of the invention, a compound of the first aspect or a pharmaceutical composition of the second aspect is provided for use in a treatment method.

[0023] In the third aspect of the implementation, a compound of the first aspect or a pharmaceutical composition of the second aspect is provided for use in treating conditions associated with epileptic seizures.

[0024] In a fourth aspect of the invention, a treatment method is provided, comprising administering to a subject requiring treatment a therapeutically effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect.

[0025] In the implementation of the fourth aspect, treatment includes treating conditions associated with epileptic seizures.

[0026] In a fifth aspect of the invention, a method for preparing the compound of the first aspect is provided, the method comprising: (1a) React the compound of formula (II) with the compound of formula (III) to give the compound of formula (IV):

[0027] in: R 1 R 2 R 3 R 4 and R 5 As defined in this article; X is chlorine, bromine, iodine, or trifluoromethanesulfonate; R 6 and R 7 It is hydrogen, alkyl, or phenyl; or R 6 and R 7 Linked to form cyclic boronic esters (such as pinacol boronic acid ester, neopentyl boronic acid ester, or catechol boronic acid ester); and R 8 and R 9 Suitable protecting groups, such as methyl or benzyl; and (1b) Convert the compound of formula (IV) into the compound of formula (I).

[0028] In a sixth aspect of the invention, an intermediate is provided for use in preparing the compound of the first aspect, wherein the intermediate is a compound of formula (II) or (IV):

[0029] Where R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; X is chlorine, bromine, iodine, or trifluoromethanesulfonate; R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 8 and R 9 It is a suitable protecting group, such as methyl or benzyl.

[0030] These and other aspects of the invention, as well as embodiments thereof, are described in more detail below. Detailed description of the invention

[0031] This invention relates to synthetic cannabinoid compounds that are biologically active and therefore can be used to treat diseases.

[0032] The compound is structurally related to the naturally occurring cannabinoid cannabidiol (CBD), a non-psychoactive cannabinoid that has been used to treat a variety of diseases and disorders. While such treatments remain promising, there is still a need in the field for more effective treatments, and this has been achieved through novel synthetic cannabinoid compounds.

[0033] synthetic cannabinoids Natural cannabidiol (CBD) has the following formula:

[0034] compound of formula (I) In one aspect, the present invention provides a compound of formula (I) or a salt thereof:

[0035] (I) in, R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl or halogen.

[0036] In the implementation plan, R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups or halogens. In the embodiments, R... 1 It is hydrogen, methyl, CF3, fluorine, or chlorine. In the implementation scheme, R... 1 It is hydrogen, methyl, CF3, or chlorine. In the implementation scheme, R... 1 It is hydrogen or methyl. In a more convenient implementation, R 1 It is hydrogen.

[0037] In the implementation plan, R 2 It is hydrogen, C 1-3 Alkyl or halogen. In the embodiment, R 2 It is hydrogen, methyl, fluorine, or chlorine. In the implementation scheme, R... 2 It is hydrogen, methyl, or chlorine. In the implementation scheme, R... 2 It is hydrogen or methyl. In a more convenient implementation, R 2 It is hydrogen.

[0038] In the implementation plan, R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or halogen. In the embodiment, R 3 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine. In a more convenient embodiment, R 3 It is hydrogen, fluorine, or chlorine. In yet another, more convenient implementation, R 3 It is chlorine.

[0039] In the implementation plan, R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or halogen. In the embodiment, R4 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine. In a more convenient embodiment, R 4 It is methyl, CF3, cyclopropyl, fluorine, or chlorine. In yet another, more convenient embodiment, R 4 It is a methyl group.

[0040] In the implementation plan, R 5 It is C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl or halogen. In the embodiment, R 5 It is hydrogen, C 3-6 Alkyl, C 3-6 Haloalkyl, C 3-6 Cycloalkyl or halogen. In the embodiment, R 5 It is C 3-6 Alkyl, C 3-6 Haloalkyl, C 3-6 Cycloalkyl or halogen. In the embodiment, R 5 It is C 3-6 Alkyl, C 3-6 Haloalkyl, C 3-6 Cycloalkyl or chlorinated. In the embodiments, R 5 It is C 1-10 Alkyl, C 1-10 Halogenated alkyl or C 3-6 Cycloalkyl. In the embodiment, R 5 It is C 3-6 Alkyl, C 3-6 Halogenated alkyl or C 3-6 Cycloalkyl. In the embodiment, R 5 It is hydrogen, C 3-5 Alkyl, C 3-5 Halogenated alkyl, cyclopentyl, or chlorinated. In the embodiments, R... 5 It is C 3-5 Alkyl, C 3-5 Halogenated alkyl, cyclopentyl, or chlorinated. In a more convenient embodiment, R 5 It is hydrogen, propyl, pentyl, 1,1-dimethylpropyl (tert-pentyl), 3,3,3-trifluoropropyl, cyclopentyl, or chlorine. In a more convenient embodiment, R 5 It is propyl, pentyl, 1,1-dimethylpropyl (tert-pentyl), 3,3,3-trifluoropropyl, cyclopentyl, or chlorine. In yet another, more convenient embodiment, R 5 It is C 1-10 Alkyl groups, such as C 3-6 Alkyl or C 3-5 Alkyl group. In the most convenient embodiment, R 5 It is propyl or pentyl. In the most convenient embodiment, R 5It is propyl. In the most convenient implementation, R 5 It is pentyl.

[0041] In a convenient embodiment, the compound of formula I has one of the structural formulas IA to IF (a substructure of formula I) or a salt thereof: , Where R 1 R 2 R 3 R 4 and R 5 As defined in any of the above implementation schemes.

[0042] In the embodiments, compounds of formula (IC) or salts thereof are provided, wherein R 3 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine; and R 5 It is hydrogen, C 3-6 Alkyl, C 3-6 Haloalkyl, C 3-6 Cycloalkyl or halogen. In embodiments, compounds of formula (IC) or salts thereof are provided, wherein R 3 It is hydrogen, fluorine, or chlorine; and R 5 It is C 3-6 Alkyl or C 3-6 Halogenated alkyl groups. In embodiments, compounds of formula (IC) or salts thereof are provided, wherein R 3 It is hydrogen, fluorine, or chlorine; and R 5 It is C 3-6 Alkyl groups (such as propyl groups).

[0043] In the embodiments, a compound of formula (IF) or a salt thereof is provided, wherein R 3 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine. In the embodiments, a compound of formula (IF) or a salt thereof is provided, wherein R... 3 It is hydrogen, fluorine, or chlorine.

[0044] In the embodiments, the compounds of formula (I) are selected from the following compounds and their salts: 2-(imidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(2,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-trifluoromethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Clomidazolo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Fluorimidazolo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(3,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Cyclopropylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(3-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(2-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-pentylphenyl-1,3-diol; 5-Cyclopentyl-2-(7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(2-trifluoromethyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-Cyclopropyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-trifluoromethyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-pentylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-(tert-amyl)phenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-(tert-amyl)phenyl-1,3-diol; 5-Chloro-2-(6-Chloro-7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-(3,3,3-trifluoropropyl)benzene-1,3-diol; and 2-(6-chloroimidazolo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol.

[0045] In the embodiments, the compounds of formula (I) are selected from the following compounds and their salts: 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; and 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol.

[0046] salt In some implementations, the compound of formula (I) is provided in the form of a free base.

[0047] Alternatively, the preparation, purification, and / or treatment of the corresponding salt of the compound, such as a pharmaceutically acceptable salt, may be convenient or desirable. Examples of pharmaceutically acceptable salts are discussed in “Pharmaceutical Salts: Properties, Selection, and Use”, 2nd edition, 2002, Stahl and Wermuth (eds.), Wiley-VCH, Weinheim, Germany.

[0048] Therefore, in some embodiments, the compound of formula (I) is provided as a salt, for example, in a protonated form together with a suitable counter anion.

[0049] Suitable counter anions include both organic and inorganic anions. Examples of suitable inorganic anions include those derived from inorganic acids, including chloride ions (Cl-). - ), bromide ions (Br) - ), iodide ions (I) - ), sulfate (SO4 2- ), sulfite (SO3) 2- ), nitrate (NO3) - ), nitrite (NO2) - ), phosphate (PO4) 3- ) and phosphate (PO3) 3-Examples of suitable organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, benzenesulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartrate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannins and carboxymethyl cellulose. In embodiments, the counter anion is chloride or formate, such as formate.

[0050] Alternatively, in some embodiments, the compound of formula (I) is provided as a salt, for example, in a deprotonated form together with a suitable countercation.

[0051] Suitable counter cations include both organic and inorganic cations. Examples of suitable inorganic cations include alkali metal ions such as Na+. + and K + Alkaline earth metal cations such as Ca 2+ and Mg 2+ Other cations such as Al 3+ Examples of suitable organic cations include ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Examples of substituted ammonium ions include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. + .

[0052] In a preferred embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0053] solvate In some embodiments, the compound of formula (I) is provided in a desolvated form, such as in a dehydrated form.

[0054] Alternatively, it may be convenient or desirable to prepare, purify and / or treat the corresponding solvate of the compound.

[0055] Therefore, in some embodiments, the compound of formula (I) is provided as a solvate (a complex of a solute (e.g., a compound, a salt of a compound) and a solvent). Examples of solvates include hydrates, such as monohydrates, dihydrates, and trihydrates.

[0056] N-oxide The compound of formula (I) contains sp 2 Nitrogen atoms (─N=), for example, those containing sp in heteroaryl groups. 2 In the case of nitrogen atoms (─N=), the preparation, purification, and / or treatment of the corresponding N oxides (─N(→O)=) (also represented as (─N) + (O - =)) might be convenient.

[0057] Therefore, in some embodiments, certain compounds of formula (I) are provided in the form of N-oxides. For example, pyridine can be substituted to give pyridine N-oxides.

[0058] certain isomers Some compounds of formula (I) may exist in one or more specific optical forms, enantiomeric forms, diastereomeric forms, epimeric forms, stereoisomeric forms, tautomeric forms, or conformational forms, including but not limited to D and L forms; d and l forms; (+) and (-) forms; cis and trans forms; axial and equatorial forms; boat, chair, torsion boat, envelope, and half-chair forms; and combinations thereof, hereinafter collectively referred to as “isomers” or “isomeric forms”.

[0059] Excluded from the term "isomer" as used herein are structural (or compositional) isomers (i.e., isomers that differ in the bonding between atoms rather than merely in their spatial positions). For example, a reference to the methoxy group -OCH3 should not be interpreted as a reference to its structural isomer, the hydroxymethyl group -CH2OH. Similarly, a reference to 2-pyridyl should not be interpreted as a reference to its structural isomer, 3-pyridyl.

[0060] The above exclusions do not apply to tautomer forms, such as ketone, enol, and enol salt forms, for example, in the following tautomer pairs: ketone / enol, imine / enamine, amide / imino alcohol, nitroso / oxime, and lactam / lactim.

[0061] The term "isomer" includes compounds having one or more isotopic substitutions. For example, H can be in any isotopic form, including... 1 H, 2 H(D) and3 H(T); C can exist in any isotopic form, including 12 C 13 C and 14 C and O can exist in any isotopic form, including 16 O and 8 O; etc.

[0062] Unless otherwise stated, references to a particular compound include all such isomers, including (in whole or in part) racemic mixtures and other mixtures thereof.

[0063] synthesis method Methods for synthesizing specific example compounds within the range of formula (I) are set forth in the working examples.

[0064] This invention provides a first method for preparing a compound of formula (I), the method comprising: (1a) React the compound of formula (II) with the compound of formula (III) to give the compound of formula (IV):

[0065] in: R 1 R 2 R 3 R 4 and R 5 As defined in this article; X is chlorine, bromine, iodine, or trifluoromethanesulfonate; R 6 and R 7 It is hydrogen, alkyl, or phenyl; or R 6 and R 7 Linked to form cyclic boronic esters (such as pinacol boronic acid ester, neopentyl boronic acid ester, or catechol boronic acid ester); and R 8 and R 9 Suitable protecting groups, such as methyl or benzyl; and (1b) Convert the compound of formula (IV) into the compound of formula (I).

[0066] In a preferred embodiment, X is bromine or iodine. Most preferably, X is bromine.

[0067] In the preferred embodiment, R 6 and R 7 Together they form -C(Me)2C(Me)2-(pinacolborate). In a preferred embodiment, R 6 and R 7 Both are hydrogen.

[0068] In the implementation plan, R 8 and R 9 It is an alcohol protecting group selected from methyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, and 4-methoxybenzyl. In a preferred embodiment, R 8 and R 9 Both are methyl groups. In a preferred embodiment, R 8 and R 9 All are benzyl groups.

[0069] Preferably, step (1a) includes reacting the compound of formula (II) with the compound of formula (III) and a palladium catalyst. Suitable palladium catalysts include Pd(dppf)Cl2, X-Phos-Pd-G3((2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate), SPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), cataCXium®PdG3([(di(1-adamantyl)-butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II)), APhos-Pd-G3([4-(di-tert-butylphosphino)- N,N -dimethylaniline-2-(2'-aminobiphenyl)]palladium(II)methanesulfonate and PEPPSI-IPENT (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). Preferred palladium catalysts include Pd(dppf)Cl2 and SPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

[0070] Preferably, step (1a) further includes reacting the compound of formula (II) with the compound of formula (III) and a base. Suitable bases include sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3).

[0071] Typically, step (1a) is carried out in a solvent. Suitable solvents include dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane (DME), dimethylacetamide (DMA), toluene, ethanol, propanol, isopropanol, butan-1-ol, butan-2-ol, pentanol, water, and mixtures thereof. Preferred solvents include dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), cyclopentyl methyl ether (CPME), water, and mixtures thereof.

[0072] Optionally, certain additives may be used in step (1a). Suitable additives include cesium fluoride (CsF).

[0073] Step (1a) is typically carried out at an elevated temperature (above ambient temperature; about 20°C). Methods for providing heat during the reaction are known and include, for example, the use of a reaction vessel with an external heating jacket or the use of microwave heating.

[0074] Typically, step (1a) involves reacting the compound of formula (II) with the compound of formula (III) at a temperature from 60°C to 140°C, preferably from 80°C to 140°C, and more preferably from 80°C to 120°C.

[0075] Step (1a) can be carried out for a sufficient time to allow the desired amount of coupling product to form. Typically, step (1a) is carried out until substantially all of the compound of formula (II) has been consumed.

[0076] Typically, step (1a) involves reacting the compound of formula (II) with the compound of formula (III) for 1 hour to 24 hours.

[0077] Step (1b) involves subjecting the compound of formula (IV) to a process suitable for removing R. 8 and R 9 The reaction occurs under the condition of a protecting group. Technicians will be able to determine the reaction based on R... 8 and R 9 The properties of the protecting group determine the appropriate deprotection conditions, and are guided by the examples described below.

[0078] In the preferred embodiment, R 8 and R 9 All are methyl groups, and step (1b) involves reacting the compound of formula (IV) with a Lewis acid such as BBr3, AlCl3, BeCl2, trimethylsilyl iodide, or pyridine hydrochloride. Preferably, R 8 and R 9All are methyl groups, and step (1b) involves reacting the compound of formula (IV) with BBr3. Typically, step (1b) is carried out in a solvent. Suitable solvents include dichloromethane (DCM). Typically, step (1b) is carried out at a temperature from 0°C to 30°C, preferably from 0°C to 20°C.

[0079] In the preferred embodiment, R 8 and R 9 All are benzyl groups, and step (1b) involves reacting the compound of formula (IV) with hydrogen in the presence of a suitable catalyst (such as carbon-supported palladium or carbon-supported platinum) and a suitable solvent (such as methanol, ethanol, acetonitrile or tetrahydrofuran (THF)).

[0080] The present invention also provides compounds that are obtained or obtainable by the methods described in paragraphs

[0059] to

[0073] above.

[0081] intermediate This invention provides intermediates that can be used to prepare compounds of formula (I). The intermediates of this invention are compounds of formula (II):

[0082] (II) Where R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; and X is chlorine, bromine, iodine, or trifluoromethanesulfonate.

[0083] In the implementation scheme, a compound of formula (II) is provided, wherein R 1 It is hydrogen, methyl, CF3, or chlorine. In the embodiments, compounds of formula (II) are provided, wherein R... 2It is hydrogen, methyl, or chlorine. In the embodiments, compounds of formula (II) are provided, wherein R... 3 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine. In the embodiments, compounds of formula (II) are provided, wherein R... 4 It is methyl, CF3, cyclopropyl, fluorine, or chlorine. In the embodiments, a compound of formula (II) is provided, wherein X is bromine.

[0084] In the implementation scheme, compounds selected from the following formula (II) are provided: 8-Bromo-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-6-chloro-7-methylimidazo[1,2-a]pyridine; 8-Chloro-7-(trifluoromethyl)imidazo[1,2-a]pyridine; 8-Bromo-6,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-7-fluoroimidazole[1,2-a]pyridine; 8-Bromo-3,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-7-cyclopropylimidazo[1,2-a]pyridine; 8-Bromo-3-chloro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-6-fluoro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2-chloro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2-(trifluoromethyl)-7-methylimidazo[1,2-a]pyridine; and 8-Bromo-6-(trifluoromethyl)-7-methylimidazo[1,2-a]pyridine.

[0085] Another intermediate of the present invention is a compound of formula (IV):

[0086] (IV) Where R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 8 and R 9 It is a suitable protecting group, such as methyl or benzyl.

[0087] In the implementation scheme, a compound of formula (IV) is provided, wherein R 1 It is hydrogen, methyl, CF3, or chlorine. In the embodiments, compounds of formula (IV) are provided, wherein R... 2 It is hydrogen, methyl, or chlorine. In the embodiments, compounds of formula (IV) are provided, wherein R... 3 It is hydrogen, methyl, CF3, cyclopropyl, fluorine, or chlorine. In the embodiments, compounds of formula (IV) are provided, wherein R... 4 It is methyl, CF3, cyclopropyl, fluorine, or chlorine. In the embodiments, compounds of formula (IV) are provided, wherein R... 5 It is hydrogen, C 3-5 Alkyl, C 3-5 Halogenated alkyl, cyclopentyl, or chlorinated. In embodiments, compounds of formula (IV) are provided, wherein R... 5 It is hydrogen, propyl, pentyl, 1,1-dimethylpropyl (tert-pentyl), 3,3,3-trifluoropropyl, cyclopentyl, or chlorine. In embodiments, compounds of formula (IV) are provided, wherein R... 8 and R 9 It is methyl. In the embodiments, compounds of formula (IV) are provided, wherein R 8 and R 9 It is benzyl.

[0088] In the implementation scheme, compounds selected from the following formula (IV) are provided: 8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-2,7-dimethylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-trifluoromethylimidazo[1,2-a]pyridine; 7-Chloro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-6,7-dimethylimidazo[1,2-a]pyridine; 7-Fluoro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-3,7-dimethylimidazo[1,2-a]pyridine; 3-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Fluoro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 2-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-pentylphenyl)7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-2-trifluoromethyl-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-6-trifluoromethyl-7-methylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-cyclopropylimidazo[1,2-a]pyridine; 6-Chloro-8-(4-Chloro-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-tert-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-tert-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(4-cyclopentyl-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Cyclopropyl-8-(2,6-Dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-6-fluoro-7-methylimidazo[1,2-a]pyridine; and 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine.

[0089] pharmaceutical composition While the compound of formula (I) may be administered alone, it is preferred to administer a pharmaceutical composition (e.g., formulation, article, or drug) comprising the compound of formula (I) and one or more other pharmaceutically acceptable ingredients.

[0090] Therefore, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, and one or more pharmaceutically acceptable ingredients.

[0091] Suitable pharmaceutically acceptable ingredients (such as carriers, diluents, excipients, etc.) can be found in standard pharmacy textbooks, such as Remington: The Science and Practice of Pharmacy, 20th edition, published in 2000, by Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, published in 2020, Pharmaceutical Press.

[0092] Examples of suitable pharmaceutically acceptable ingredients include pharmaceutically acceptable carriers, diluents, excipients, excipients, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners.

[0093] Pharmaceutical compositions may be in any suitable form. Examples of suitable forms include liquids, solutions (e.g., aqueous and non-aqueous), suspensions (e.g., aqueous and non-aqueous), emulsions (e.g., oil-in-water and water-in-oil), syrups, granules, mouthwashes, drops, tablets (including, for example, coated tablets), granules, powders, lozenges, soft lozenges, capsules (including, for example, hard gelatin capsules and soft gelatin capsules), flat capsules, pills, ampoules, large pills, suppositories, vaginal suppositories, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0094] medical treatment The inventors have discovered that compounds of formula (I) possess biological activity. Working examples demonstrate that compounds of formula (I) exhibit anticonvulsant activity in a rodent model of generalized epilepsy. Therefore, compounds of formula (I) and their salts, as well as pharmaceutical compositions comprising compounds of formula (I) or their salts, are suitable for medical treatment.

[0095] Therefore, the present invention provides a compound of formula (I) or a salt thereof for use in treatment methods, such as methods for treating the human or animal body by therapy (i.e., therapeutic methods).

[0096] The present invention also provides compounds of formula (I) or salts thereof for use as pharmaceuticals.

[0097] The present invention also provides a treatment method comprising administering to a subject requiring treatment a therapeutically effective amount of a compound of formula (I) or a salt thereof.

[0098] The present invention also provides the use of compounds of formula (I) or salts thereof for the preparation of pharmaceuticals.

[0099] The present invention also provides the use of compounds of formula (I) or salts thereof as pharmaceuticals.

[0100] The present invention also provides the use of compounds of formula (I) or salts thereof in therapeutic methods.

[0101] condition being treated The inventors have discovered that compounds of formula (I) exhibit anticonvulsant activity in rodent models of generalized epileptic seizures. Therefore, compounds of formula (I) or salts thereof, as well as pharmaceutical compositions comprising compounds of formula (I) or salts thereof, could be used to treat certain conditions associated with epileptic seizures.

[0102] Similarly, compounds of formula (I) or salts thereof, as well as pharmaceutical compositions comprising compounds of formula (I) or salts thereof, may be used as medicaments for treating certain conditions associated with seizures (and may be used to prepare medicaments for treating certain conditions associated with seizures).

[0103] seizure type In the implementation plan, the condition associated with seizures is selected from focal seizures, generalized seizures, and seizures of unknown origin.

[0104] Focal-origin seizures can be further characterized by a level of consciousness. In one implementation, a focal-origin seizure is a focal-origin seizure with consciousness. In another implementation, a focal-origin seizure is a focal-origin seizure with impaired consciousness (having impairment).

[0105] Focal-origin seizures can be further characterized by motor or non-motor origin features. In one implementation, a focal-origin seizure is a focal-origin seizure with motor origin features, such as motor origin features selected from automatisms, atonicity, clonicity, epileptic spasms, hyperkinesis, myoclonus, and tonicity. In another implementation, a focal-origin seizure is a focal-origin seizure with non-motor origin features, such as non-motor origin features selected from voluntary, behavioral cessation, cognitive, emotional, and sensory characteristics.

[0106] Focal-origin epilepsy can also manifest as focal progression to bilateral tonic-clonic seizures. In the implementation plan, a focal-origin epileptic seizure is a focal progression to bilateral tonic-clonic seizure.

[0107] Generalized-origin seizures can be further characterized by motor or non-motor (absence) features. In one implementation, a generalized-origin seizure is a generalized-origin seizure with motor features, such as those selected from tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, and epileptic spasms. In another implementation, a generalized-origin seizure is a generalized-origin seizure with non-motor (absence) features, such as those selected from typical, atypical, myoclonic, and eyelid myoclonic features.

[0108] Seizures of unknown origin can be characterized by motor or non-motor features. In one embodiment, a seizure of unknown origin is one with motor features, such as motor features selected from tonic-clonic and epileptic spasms. In another embodiment, a seizure of unknown origin is one with non-motor (absence) features (such as behavioral arrest).

[0109] In the implementation plan, the condition associated with seizures is a type of seizure that may exist as one or more of focal-origin seizures, generalized-origin seizures, or seizures of unknown origin, such as seizure types selected from the following: typical absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic-clonic seizures, tonic-clonic seizures, febrile seizures, focal seizures progressing to bilateral tonic-clonic seizures, laughing and crying seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, and epileptic (or infantile) spasms.

[0110] type of epilepsy and epilepsy syndrome In the implementation plan, the condition associated with epileptic seizures is epilepsy, such as epilepsy selected from focal epilepsy, generalized epilepsy, and epilepsy that combines generalized and focal epilepsy.

[0111] In the implementation plan, the condition associated with epileptic seizures is an epileptic syndrome, such as a syndrome selected from neonatal and infancy syndromes, childhood syndromes, syndromes with onset at different ages, and idiopathic generalized epilepsy syndrome (IGE).

[0112] In the implementation plan, the condition associated with seizures is a neonatal and infancy-onset epilepsy syndrome, such as selected from the following neonatal and infancy-onset epilepsy syndromes: self-limiting epilepsy (such as self-limiting neonatal epilepsy, self-limiting familial neonatal-infant epilepsy, self-limiting infantile epilepsy, hereditary epilepsy with febrile seizures, or infantile myoclonic epilepsy), developmental and epileptic encephalopathy-DEE (such as early infantile developmental and epileptic encephalopathy (EIDEE), infantile epilepsy with migratory focal seizures (EIMF), infantile epileptic spasm syndrome (West syndrome), or Dravet syndrome) and etiology-specific syndromes (such as KCNQ2-DEE, pyridoxine-dependent DEE, pyridoxine 5'-phosphate deficiency DEE, CDKL5-DEE, PCDH19 clustering epilepsy, glucose transporter 1 deficiency syndrome, gelastic seizures with hypothalamic hamartoma, or Sturge Weber syndrome) - more information is provided in the etiology section below.

[0113] In the implementation plan, the condition associated with seizures is a childhood-onset epilepsy syndrome, such as selected from the following childhood-onset epilepsy syndromes: childhood self-limiting focal epilepsy (such as childhood occipital visual epilepsy (COVE), self-limiting epilepsy with autonomous seizures, self-limiting epilepsy with centrotemporal spikes or photosensitive occipital lobe epilepsy (POLE)), childhood-onset DEE (such as epilepsy with myoclonic atonic seizures, Lennox-Gastaut syndrome, febrile infection-associated epilepsy syndrome (FIRES), hemiconvulsion-hemiplegia-epilepsy syndrome, developmental and epileptic encephalopathy with sleep spike activation (DEE-SWAS), epileptic encephalopathy with sleep spike activation (EE-SWAS) or Landau-Kleffner syndrome), and childhood hereditary generalized epilepsy (such as epilepsy with eyelid myoclonus or epilepsy with myoclonic absence).

[0114] In the implementation plan, the condition associated with seizures is an epilepsy syndrome with onset at different ages, such as the following epilepsy syndromes with onset at different ages: juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), epilepsy with isolated generalized tonic-clonic seizures (GTCA), childhood occipital visual epilepsy (COVE), photosensitive occipital lobe epilepsy (POLE), familial medial temporal lobe epilepsy (FMTLE), epilepsy with auditory features (EAF), medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), sleep-related hyperkinetic / hyperdynamic epilepsy (SHE), familial focal epilepsy with variable lesions (FFEVF), epilepsy with reading-induced seizures (EwRIS), progressive myoclonic epilepsy (PME), febrile infection-associated epilepsy syndrome (FIRES), and Rasmussen syndrome.

[0115] In the implementation plan, the condition associated with epileptic seizures is idiopathic generalized epilepsy syndrome (IGE), such as IGE selected from childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with isolated generalized tonic-clonic seizures (GTCA).

[0116] etiology In the implementation plan, the condition associated with seizures is epilepsy defined by etiology (cause), such as epilepsy with etiologies selected from structural, genetic, infectious, metabolic, and autoimmune factors.

[0117] In the implementation plan, the condition associated with seizures is epilepsy with a structural etiology (“structural epilepsy”), such as structural etiologies selected from the following: focal cortical dysplasia (FCD), hypothalamic hamartoma (HH), hypoxic-ischemic encephalopathy (HIE), incontinence pigmentosa (IP), medial temporal lobe sclerosis (MTS), neurofibromatosis type 1, multiple sclerosis (MS), Sturge Weber syndrome (SWS), traumatic brain injury (TBI), periventricular nodular heterotopia (PVNH), polymicrogyri (PMG), tuberous sclerosis complex (TSC), and brain tumors.

[0118] In the implementation plan, the condition associated with seizures is epilepsy with a genetic cause (“hereditary epilepsy”), such as the following genetic causes: Happy Puppet syndrome, PCDH19 mutation, RC20 syndrome, CACNA1A mutation, CDKL5 deficiency disorder, GRIN2A mutation, SCN8A mutation, SLC2A1 (Glut1 deficiency syndrome), TBCK mutation, Rett syndrome (MECP2 mutation), SYNGAP1 mutation, KCNQ2 mutation, STXBP1 mutation, SCN1A mutation, CHD2 mutation, PRRT2 mutation, SLC6A1 mutation, and GATOR1-associated epilepsy.

[0119] In the implementation plan, the condition associated with seizures is epilepsy with an infectious cause (“infectious epilepsy”), such as infectious causes selected from the following: neurocysticercosis, cerebral malaria, TORCH infection (toxoplasmosis, other agents, rubella / rubella, cytomegalovirus and herpes simplex), bacterial meningitis, viral encephalitis, tuberculosis and human immunodeficiency virus (HIV).

[0120] In the implementation plan, the condition associated with seizures is epilepsy with a metabolic etiology (“metabolic epilepsy”), which includes metabolic etiologies such as glucose transporter type 1 (Glut1) deficiency syndrome (SLC2A1), vitamin-dependent metabolic disorders (such as pyridoxine, P5P or leucovorin-dependent disorders), creatine transporter disorders, mitochondrial disorders and storage disorders.

[0121] In the implementation scheme, the condition associated with seizures is epilepsy with an autoimmune etiology (“autoimmune epilepsy”), such as autoimmune etiologies selected from the following: Rasmussen syndrome, anti-NMDA receptor encephalitis, limbic encephalitis (e.g., limbic encephalitis associated with LGI1 antibody or CASPR2 antibody), and GAD65 antibody-associated epilepsy.

[0122] subject / patient Treatment typically involves administering a compound of formula (I) or a salt thereof to a subject or patient.

[0123] Subjects / patients may be chordates, vertebrates, mammals, placental mammals, marsupials (e.g., kangaroos, wombats), rodents (e.g., guinea pigs, hamsters, rats, mice), mice (e.g., mice), lagomorphs (e.g., rabbits), birds (e.g., birds), canids (e.g., dogs), felines (e.g., cats), equines (e.g., horses), suidae (e.g., pigs), sheep (e.g., sheep), bovids (e.g., cattle), primates, apes (e.g., monkeys or apes), monkeys (e.g., marmosets, baboons), apes (e.g., gorillas, chimpanzees, orangutans, gibbons), or humans.

[0124] The subject / patient can be in any stage of development; for example, the subject / patient can be a newborn, an infant, a child, or an adult.

[0125] In a preferred embodiment, the subject / patient is a human, more preferably an adult human.

[0126] Subjects / patients can also be non-human mammals used in laboratory studies, such as rodents. Rodents include rats, mice, guinea pigs, and chinchillas.

[0127] route of administration Treatment methods may include administering a compound of formula (I) or a salt thereof to a subject via any convenient route of administration, whether systemic / peripheral or topical (i.e., at the desired site of action).

[0128] Routes of administration may be oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by using, for example, via aerosols, such as inhalation or blowing therapy through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, for example, by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intrasacral, subsacral, orbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; or by implantation of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0129] dose Treatment methods typically involve administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to the subject.

[0130] The appropriate dosage of compounds of formula (I), their salts, and pharmaceutical compositions comprising compounds of formula (I) or their salts may vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any risks or harmful side effects. The chosen dosage level will depend on a variety of factors, including but not limited to the activity of the specific compound of formula (I), route of administration, time of administration, rate of excretion of the compound, duration of treatment, other active agents, compounds and / or materials used in combination, severity of condition, and the patient's species, sex, age, weight, condition, general health, and medical history. The dosage and route of administration will ultimately be determined by the clinician, although the dosage will generally be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or deleterious side effects.

[0131] Throughout the treatment course, it can be administered as a single dose, continuously, or intermittently (e.g., in doses at appropriate intervals). It can be administered as a single or multiple doses, with the dosage level and pattern chosen by the treating clinician. other aspects and embodiments

[0132] This document explicitly discloses each and every compatible combination of the implementation schemes described above, as if each and every combination were described individually and explicitly.

[0133] In view of this disclosure, various other aspects and embodiments of the invention will be apparent to those skilled in the art.

[0134] In use, "and / or" will be regarded as a specific disclosure of each individual related component or feature, as well as a specific disclosure of the combination of components or features. For example, "A and / or B" will be regarded as a specific disclosure of each of i) A, ii) B, and iii) A and B, as if each were stated separately.

[0135] When used, “selected from” a list of members should be treated as the specific public content of each individual related member. For example, “selected from A, B, and C” should be treated as the specific public content of each of i)A, ii)B, and iii)C, as if each were described separately.

[0136] When used, “selected from one or more of the members” should be regarded as the specific public content of the individual related members and the specific public content of the combination of members. For example, “selected from one or more of A, B and C” should be regarded as the specific public content of each of i) A, ii) B, iii) C, iv) A and B, v) A and C, vi) B and C, and vi) A and B and C, as if each were described separately.

[0137] Unless the context otherwise indicates, the description and definition of the features set forth above are not limited to any particular aspect or embodiment of the invention, and are equally applicable to all aspects and embodiments described.

[0138] definitions To aid in understanding this invention, the following definitions are provided.

[0139] An alkyl group is a monovalent saturated hydrocarbon group. The alkyl group can be C10 or C20. 1-6 Alkyl groups, such as C 1-4 C 1-3 Or C 1-2 Alkyl groups. In this case, the prefix (e.g., C) 1-6 The ) indicates the number of carbon atoms in the hydrocarbon backbone. Alkyl groups can be straight-chain or branched.

[0140] C 1-6 Examples of straight-chain alkyl groups include methyl (-Me), ethyl (-Et), n-propyl (-nPr), n-butyl (-nBu), n-pentyl (-Amyl), and n-hexyl.

[0141] C 1-6 Examples of branched alkyl groups include isopropyl (-iPr), isobutyl (-iBu), sec-butyl (-sBu), tert-butyl (-tBu), isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, and neohexyl.

[0142] The term "alkoxy" includes both straight-chain alkyl groups and branched-chain alkyl groups bonded to oxygen single bonds. For example, "C 1-3 "Alkoxy" includes methoxy, ethoxy, and isopropoxy.

[0143] The term "halogenated alkyl" is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g., fluorine) atoms. 1-3 Examples of haloalkyl groups include fluoroalkyl groups such as -CHF2, -CH2CF3 and perfluoroalkyl groups such as -CF3 or -CF2CF3.

[0144] "Cycloalkyl" refers to a hydrocarbon consisting of a single or double ring containing a carbon atom. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0145] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0146] Epilepsy is considered a brain disorder defined by any of the following: (1) at least two unexplained (or reflexive) seizures occurring at intervals >24 h; (2) one unexplained (or reflexive) seizure and the probability of further seizures occurring within the next 10 years with a similar risk of recurrence (at least 60%) as after two unexplained seizures; (3) a diagnosis of an epilepsy syndrome (International League Against Epilepsy (ILAE) Practical Clinical Definition of Epilepsy, 2014).

[0147] The term “generalized seizure” (“generalized origin seizure”) refers to a seizure that is conceptualized as originating from a few points in the brain and rapidly occupies a bilaterally distributed network (ILAE Business Classification of Seizure Types, 2017).

[0148] The term "focal seizure" ("focal-origin seizure") refers to a seizure originating within a network confined to one hemisphere of the brain. These may be discrete and localized, or more widely distributed. Focal seizures can originate from subcortical structures (ILAE Business Classification of Seizure Types, 2017). When a subject remains awake and conscious during a seizure, this is called a focal aware seizure. When a subject feels confused or their consciousness is impaired in some way during a focal seizure, this is called a focal impaired awareness seizure.

[0149] The term “seizure with unknown origin” (“unknown onset seizures”) refers to seizures whose origin is missed (e.g., because the subject was asleep or alone) or is ambiguous. When more information becomes available, these seizures may subsequently be classified as focal or generalized origin (ILAE Business Classification of Seizure Types, 2017).

[0150] The term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that, to a reasonable degree of medical judgment, are suitable for use in contact with the tissues of the subject in question (e.g., humans) without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio. Each ingredient (e.g., carrier, diluent, excipient, etc.) must also be "acceptable" in the sense of compatibility with other components of the composition.

[0151] The term "therapeutic effective amount" refers to an amount of a compound or a material, composition or dosage form containing the compound that, when administered according to the desired treatment regimen, effectively produces some of the desired therapeutic effect commensurate with a reasonable benefit / risk ratio.

[0152] "Tonic-clonic seizures" occur in two phases: a tonic phase, which typically involves muscle rigidity and loss of consciousness, and a clonic phase, which typically involves rhythmic twitching of the limbs. Working Example

[0153] Certain aspects and embodiments of the invention will be shown by way of example and with reference to the accompanying drawings described above.

[0154] analytical method NMR Bruker Avance 400 MHz, 5 mm QNP probe (H, C, F, P), single Z-gradient, dual-channel instrument, running TopSpin 2.1 Bruker Avance III 400 MHz, 5 mm BBFO Plus probe, single Z-gradient, dual-channel instrument, running TopSpin 3.1.

[0155] LCMS

[0156]

[0157] abbreviations

[0158] Example 1 : Synthesis of compounds Typically, the compounds of the present invention can be prepared by reacting a suitably protected dihydroxyphenylboronic acid with a suitable 8-halo-imidazo[1,2-a]pyridine via a Suzuki reaction, followed by deprotection of the resulting intermediate.

[0159]

[0160] The aryl halides and boric acid precursors can be purchased from commercial sources and prepared according to literature procedures or synthesized according to one of the following methods.

[0161] Synthesis of intermediates General procedure A The synthesis of intermediate 1 is used to illustrate general method A.

[0162] Intermediate 1 : (2,6-dimethoxy-4-propyl-phenyl)boronic acid

[0163] 1,3-Dimethoxy-5-propylbenzene (10.00 g, 55.5 mmol) was stirred in tetrahydrofuran (230 mL) at 0 °C under a nitrogen atmosphere, and a solution of n-butyllithium (2.5 M, 27 mL, 66.6 mmol in hexane) was added over 10 min. The reaction mixture was stirred at 0 °C for 1 h, then cooled to -78 °C, treated with trimethyl borate (19 mL, 166 mmol), and allowed to warm to room temperature over 150 min. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (150 mL), and ethyl acetate (200 mL) was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under vacuum. 。 The residue was purified by column chromatography on silica gel eluted with 0%–50% ethyl acetate in dichloromethane to give the title compound (10.1 g, 81%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 7.17 (s, 2H), 6.45 (s, 2H), 3.90 (s, 6H), 2.59 (t, J=7.7 Hz, 2H), 1.72 - 1.62 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

[0164] Alternatively, using general method A, with a suitable dimethoxy aromatic hydrocarbon, the following intermediates are produced: Intermediate 2: (2,6-dimethoxy-4-pentylphenyl)boronic acid

[0165] 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 2H), 6.45 (s, 2H), 3.90 (s, 6H), 2.60 (t, J=7.8 Hz, 2H), 1.68 - 1.58 (m, 2H), 1.39 - 1.30 (m, 4H), 0.91 (t, J=6.9 Hz, 3H).

[0166] General procedure B The synthesis of intermediate 3 is used to illustrate general method B.

[0167] Intermediate 3: (4-(tert-pentyl)-2,6-dimethoxyphenyl)boronic acid

[0168] Step 1: 1,3-Dimethoxy-5-(tert-amyl)benzene Dichloromethane (30 mL) was cooled under nitrogen in a dry ice / acetonitrile bath until the internal temperature was below -40 °C. Titanium chloride (IV) solution (1 M, 12.9 mL, 12.9 mmol in dichloromethane) was added dropwise, followed by dimethyl zinc solution (1 M, 12.9 mL, 12.9 mmol in heptane), maintaining the temperature below -45 °C. A solution of 1-(3,5-dimethoxyphenyl)prop-1-one (1000 mg, 5.15 mmol) in dichloromethane (5 mL) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by adding water (10 mL), poured into water (100 mL), and extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried (on phase separation paper) and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–50% diethyl ether in cyclohexane to give the title compound (699 mg, 65%) as a colorless oil. 1 H NMR(400 MHz, CDCl3) δ 6.49 (d, J=2.0 Hz, 2H), 6.30 (t, J=2.2 Hz, 1H), 3.80 (s,6H), 1.61 (q, J=7.3 Hz, 2H), 1.25 (s, 6H), 0.69 (t, J=7.3 Hz, 3H).

[0169] Step 2: (4-(tert-pentyl)-2,6-dimethoxyphenyl)boronic acid 1-Terpentyl-3,5-dimethoxybenzene was borated according to general method A to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ7.18 (s, 2H), 6.58 (s, 2H), 3.92 (s, 6H), 1.65 (q, J=7.4 Hz, 2H), 1.29 (s, 6H), 0.71 (t, J=7.5 Hz, 3H).

[0170] Intermediate 4: (2,6-bis(benzyloxy)-4-propylphenyl)boronic acid

[0171] Step 1: 2-Bromo-5-propylbenzene-1,3-diol 1,3-Dibenzyloxy5-propylbenzene-1,3-diol (22.05 g, 0.145 mol) in methanol (450 mL) was cooled and stirred in an ice / water bath. It was added in batches over 1 hour. N- Bromosuccinimide (77.36 g, 0.435 mol) was added while maintaining an internal temperature below 10 °C. After complete addition, the reaction was stirred at room temperature for 20 h. The reaction was cooled in an ice-salt bath, and a solution of sodium sulfite (40.2 g, 318 mmol) and NaOH (12.7 g, 317 mmol) in water (600 mL) was added in portions over 10 min. The reaction mixture was stirred for 2 h, then acidified with 1 M hydrochloric acid aqueous solution (220 mL) and extracted with ethyl acetate (2 × 600 mL). The combined organic layers were dried (magnesium sulfate), and the residue was purified by column chromatography on silica gel eluted with 0%–30% ethyl acetate in cyclohexane to give the title compound (28.4 g, 84%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 6.45 (s, 2H), 5.25 (s, 2H), 2.48 (t,J=7.6 Hz, 2H), 1.61 - 1.57 (m, 2H), 0.95 - 0.90 (t, J=7.2 Hz, 3H).

[0172] Step 2: (((2-bromo-5-propyl-1,3-phenylene)bis(oxy))bis(methylene))diphenyl exist N , N 2-Bromo-5-propylphenyl-1,3-diol (28.40 g, 0.123 mol) in dimethylformamide (400 mL) was treated with potassium carbonate (84.93 g, 0.614 mol) and then with benzyl bromide (32 mL, 0.270 mol). The reaction mixture was stirred for 90 min, then concentrated under vacuum and the residue was partitioned between water (1 L) and diethyl ether (1 L). The layers were separated, and the aqueous layer was extracted with diethyl ether (3 × 400 mL). The combined organic layers were washed with 4% LiCl (300 mL), dried (magnesium sulfate), and concentrated under vacuum. The residue was ground with n-pentane (500 mL) to give the title compound (46.4 g, 92%) as a pink solid. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J=7.3 Hz, 4H),7.41 - 7.31 (m, 6H), 6.45 (s, 2H), 5.15 (s, 4H), 2.50 (t, J=7.6 Hz, 2H), 1.63- 1.53 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).

[0173] Step 3: (2,6-bis(benzyloxy)-4-propylphenyl)boronic acid (2-bromo-5-propyl-1,3-phenylene)bis(oxy)bis(methylene))diphenyl (20.0 g, 48.6 mmol) in tetrahydrofuran (750 mL) was cooled in a dry ice / acetone bath and treated with 2.5 M n-butyllithium solution (29 mL, 72.9 mmol). After 5 minutes, trimethyl borate (16 mL, 0.146 mol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (300 mL), poured into water (1 L), and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under vacuum. 。 The residue was purified by column chromatography on silica gel eluted with 5%–30% ethyl acetate in cyclohexane to give the title compound (11.36 g, 42%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.42 - 7.36 (m, 10H), 7.14 (s,2H), 6.54 (s, 2H), 5.13 (s, 4H), 2.57 (t, J=7.6 Hz, 2H), 1.69 - 1.59 (m, 2H),0.93 (t, J=7.3 Hz, 3H).

[0174] Intermediate 5: (4-(cyclopent-1 -en-1 -yl)-2,6-dimethoxyphenyl)boronic acid

[0175] Step 1: 1-(cyclopent-1-en-1-yl)-3,5-dimethoxybenzene A mixture of 1-bromo-3,5-dimethoxybenzene (1.50 g, 6.91 mmol), cyclopenten-1-ylboronic acid (928 mg, 8.29 mmol), and potassium carbonate (2.87 g, 20.7 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was degassed with nitrogen and treated with SPhos Pd G2 (249 mg, 0.346 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 30 min, then diluted with ethyl acetate (100 mL), washed with water (2 × 100 mL), dried (on phase separation paper), and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–30% diethyl ether in cyclohexane to give 1-(cyclopenten-1-yl)-3,5-dimethoxybenzene (1.23 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.60 (d, J=2.3 Hz, 2H), 6.35 (t, J=2.3 Hz, 1H), 6.19 -6.15 (m, 1H), 3.80 (s, 6H), 2.72 - 2.65 (m, 2H), 2.55 - 2.48 (m, 2H), 2.05 -1.97 (m, 2H).

[0176] Step 2: (4-(cyclopent-1-en-1-yl)-2,6-dimethoxyphenyl)boronic acid The title compound was given as a white solid by acidification of 1-(cyclopenten-1-yl)-3,5-dimethoxyphenylboronic acid using general method A. 1 ¹H NMR (400 MHz, DMSO) δ 7.80 (s, 2H), 6.63 (s, 2H), 6.32 -6.28 (m, 1H), 3.73 (s, 6H), 2.72 - 2.66 (m, 2H), 2.51 - 2.46 (m, 2H, partially obscured by DMSO peaks), 2.02 - 1.92 (m, 2H).

[0177] Intermediate 6: 8-bromo-2,7-dimethylimidazo[1,2-a]pyridine

[0178] 3-Bromo-4-methylpyridin-2-amine (400 mg, 2.14 mmol) and 1-bromoprop-2-one (439 mg, 3.21 mmol) were stirred in ethanol (8 mL) at 70 °C for 2 hours and then cooled to room temperature. A saturated aqueous solution of sodium bicarbonate (20 mL), ethyl acetate (20 mL), and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were filtered through a hydrophobic glass frit and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with ethyl acetate:ethanol (3:1) in cyclohexane to give the title compound (348 mg, 72%) as a light pink solid. 1 H NMR (400 MHz, DMSO) δ 8.42 (d, J=6.8 Hz, 1H) 7.78-7.76 (m, 1H), 6.85 (d, J=6.8,1H), 2.56 (s, 3H), 2.38-2.36 (m, 3H).

[0179] General procedure C The synthesis of intermediate 7 is used to illustrate general method C.

[0180] Intermediate 7: 8-bromo-6-chloro-7-methylimidazo[1,2-a]pyridine

[0181] A solution of chloroacetaldehyde (50 wt% in water, 0.17 mL, 1.35 mmol) was added to a solution of 3-bromo-5-chloro-4-methylpyridin-2-amine (200 mg, 0.903 mmol) in ethanol (3.6 mL), and the reaction mixture was stirred at 70 °C for 1 day. The reaction mixture was cooled to room temperature, and ethyl acetate (3 mL) was added, followed by the slow and careful addition of a saturated aqueous solution of sodium bicarbonate (3 mL), resulting in the precipitation of a colorless solid. Ethyl acetate (10 mL) and water (10 mL) were added, and the organic phase was separated, with the aqueous phase extracted with ethyl acetate (10 mL). The combined organic phases were filtered through a hydrophobic glass frit, and the solvent was concentrated under vacuum to give the title compound (224 mg, quantified) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 2.60 (s, 3H).

[0182] Using general method C, with appropriate aminopyridine, the following intermediate is produced.

[0183] Intermediate 8: 8-bromo-7-methylimidazo[1,2-a]pyridine

[0184] 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J=6.8 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 6.67 (d, J=6.9 Hz, 1H), 2.49 (s, 3H).

[0185] Intermediate 9: 8-chloro-7-(trifluoromethyl)imidazo[1,2-a]pyridine

[0186] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J=7.1 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.07 (d, J=7.1 Hz, 1H).

[0187] Intermediate 10: 8-bromo-6,7-dimethylimidazo[1,2-a]pyridine

[0188] 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.59 (d, J=1.1 Hz, 1H), 7.52 (d, J=0.9 Hz, 1H), 2.46 (s, 3H), 2.30 (s, 3H).

[0189] Intermediate 11 : 8-bromo-7-fluoroimidazo[1,2-a]pyridine

[0190] 1 H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=5.0, 7.3 Hz, 1H), 7.68 (d, J=1.2Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 6.76 (t, J=7.1 Hz, 1H).

[0191] Intermediate 12: 8-bromo-6-fluoro-7-methylimidazo[1,2-a]pyridine

[0192] 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J=4.1 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 2.47 (d, J=2.3 Hz, 3H).

[0193] Intermediate 13: 8-bromo-7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridine

[0194] A suspension of 3-bromo-4-methylpyridin-2-amine (400 mg, 2.14 mmol), 3-bromo-1,1,1-trifluoroprop-2-one (0.44 mL, 4.28 mmol), and potassium carbonate (443 mg, 3.21 mmol) in ethanol (20 mL) was heated under reflux overnight. The cooled reaction mixture was filtered and concentrated under vacuum. The residue was partitioned between diluted aqueous sodium bicarbonate solution and dichloromethane. The organic phase (hydrophobic glass frit) was separated and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–100% ethanol / ethyl acetate in cyclohexane to give the title compound (275 mg, 46%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=6.8 Hz, 1H), 7.90 (s,1H), 6.79 (1H, d, J=6.8 Hz, 1H), 2.52 (3H, s).

[0195] Intermediate 14: 8-bromo-3,7-dimethylimidazo[1,2-a]pyridine

[0196] 3-Bromo-4-methylpyridin-2-amine (500 mg, 2.67 mmol) in ethanol (5.0 mL) was treated with hydrobromic acid (48%, 0.45 mL, 3.98 mmol) and 2-bromo-1,1-dimethoxy-propane (1.1 mL, 7.98 mmol). The mixture was stirred at 80 °C for 3 days, then treated with 0.5 M sodium carbonate aqueous solution (10 mL) and extracted with dichloromethane (2 × 15 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under vacuum. 。 The residue was purified by column chromatography on silica gel eluted with a 3:1 mixture of 0%-60% ethyl acetate and ethanol in cyclohexane to give the title compound (222 mg, 35%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J=7.1 Hz, 1H), 7.39 (s, 1H), 6.70 (d, J=8.1 Hz, 1H), 2.50 (s, 3H), 2.45 (s, 3H).

[0197] Intermediate 15: 8-bromo-2-chloro-7-methylimidazo[1,2-a]pyridine

[0198] Step 1: 3-Bromo-1-(2-ethoxy-2-oxoethyl)-4-methylpyridine-1-onium bromide 3-Bromo-4-methylpyridin-2-amine (500 mg, 2.67 mmol) was suspended in ethyl bromoacetate (1.2 mL, 10.7 mmol) and stirred at room temperature for 1 day. The resulting solid was flowed with diethyl ether (4 mL), collected by filtration, washed with additional diethyl ether (2 × 5 mL), and dried under vacuum to give the title compound (869 mg, 92%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 2H), 8.06 (d, J=6.9 Hz, 1H), 7.07 (d,J=6.9 Hz, 1H), 5.27 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).

[0199] Step 2: 8-Bromo-2-chloro-7-methylimidazo[1,2-a]pyridine 3-Bromo-1-(2-ethoxy-2-oxoethyl)-4-methylpyridin-1-onium bromide (869 mg, 2.45 mmol) was suspended in phosphorus oxychloride (V) (2.3 mL, 24.5 mmol) and heated at 100 °C for 90 min, during which time the material dissolved. The reaction mixture was poured into ice water (100 mL), neutralized with solid sodium carbonate, and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried (on phase-separating paper) and concentrated under vacuum to give the title compound (580 mg, 96%) as a pink solid. 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J=6.7 Hz, 1H), 7.51 (s, 1H), 6.72 (d, J=6.8 Hz, 1H), 2.49 (s, 3H).

[0200] Intermediate 16: 8-bromo-3-chloro-7-methylimidazo[1,2-a]pyridine

[0201] In N,N 8-Bromo-7-methylimidazo[1,2-a]pyridine (250 mg, 1.18 mmol) in dimethylformamide (5 mL) was used N 1,30 mmol of chlorosuccinimide (174 mg) was treated and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3 × 50 mL), dried (on phase separation paper), and concentrated under vacuum to give the title compound (243 mg, 84%) as a pale brown solid, which was used in subsequent reactions without further purification. 1 HNMR (400 MHz, CDCl3) δ 7.96 (d, J=6.8 Hz, 1H), 7.57 (s, 1H), 6.82 (d, J=6.8Hz, 1H), 2.52 (s, 3H).

[0202] Intermediate 17: 8-bromo-7-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine

[0203] Step 1: N -(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine 2-Chloro-4-methyl-5-(trifluoromethyl)pyridine (550 mg, 2.81 mmol) in 1-methyl-2-pyrrolidone (10 mL) was treated with 4-methoxybenzylamine (1.5 mL, 11.2 mmol) and heated in a microwave reactor at 140 °C for 60 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3 × 25 mL), dried (on phase separation paper), and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–50% ethyl acetate in cyclohexane to give the title compound (555 mg, 67%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.28(s, 1H), 7.26 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.22 (s, 1H), 5.02(s, 1H), 4.46 (d, J=4.3 Hz, 2H), 3.81 (s, 3H), 2.34 (s, 3H).

[0204] Step 2: 4-Methyl-5-(trifluoromethyl)pyridine-2-amine The N-[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (735 mg, 2.48 mmol) was stirred overnight in trifluoroacetic acid (40 mL). The reaction mixture was concentrated under vacuum and partitioned between a semi-saturated aqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was washed with ethyl acetate (2 × 50 mL), and the combined organic layers were dried (on phase separation paper) and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–50% ethyl acetate in cyclohexane to give the title compound (407 mg, 93%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 6.35 (q, J=0.8 Hz, 1H), 4.65 (s, 2H), 2.37 - 2.35 (m, 3H).

[0205] Step 3: 3-Bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine 4-Methyl-5-(trifluoromethyl)pyridine-2-amine (387 mg, 2.20 mmol) in tetrahydrofuran (20 mL) was then... N 1,3-bromosuccinimide (469 mg, 2.64 mmol) was treated and stirred at room temperature for 90 min. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with a semi-saturated aqueous solution of sodium thiosulfate (100 mL) and water (50 mL), dried (on phase separation paper), and concentrated under vacuum to give the title compound (619 mg, 91%) as a grayish-white solid. The crude material was used in the next step without further purification. 1 ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 5.33 (s, 2H), 2.48 (q, J = 1.1 Hz, 3H). NMR contains 30 mol% succinimide; only data for the major components are recorded.

[0206] Step 4: 8-Bromo-7-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine The title compound is given by condensing 3-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine with chloroacetaldehyde using a method similar to general method C. 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.74 (d, J=1.3Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 2.62 (q, J=1.3 Hz, 3H).

[0207] Intermediate 18: 8-chloro-7-cyclopropylimidazo[1,2-a]pyridine

[0208] Step 1: 4-Bromo-3-chloropyridine-2-amine 4-Bromo-3-chloro-2-fluoropyridine (1.12 g, 5.32 mmol) in ammonium hydroxide solution (35%, 7 mL, 69.2 mmol) was heated at 110 °C for 2 hours in a reinforced 40 mL tube, then cooled. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (40 mL). The aqueous layer was extracted with ethyl acetate (40 mL), and the combined organic layers were dried (on phase separation paper) and concentrated under vacuum to give a colorless solid (710 mg). The mixture was redissolved in ammonium hydroxide solution (35%, 7.0 mL, 69.2 mmol), stirred, and heated at 115 °C for 4 hours in a reinforced 40 mL tube, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (40 mL). The aqueous layer was extracted with ethyl acetate (40 mL), and the combined organic layers were dried (on phase separation paper) and concentrated under vacuum to give the title compound as a colorless solid. (559 mg, 63% purity, residue starting material) It was used in the next step without further purification. 1 ¹H NMR (400 MHz, CDCl₃) δ 7.77 (δ, J=5.3 Hz, 1H), 6.92 (d, J=5.4 Hz, 1H), 5.00 (s, 2H). Only data for the major components were recorded.

[0209] Step 2: 3-Chloro-4-cyclopropylpyridine-2-amine The reaction mixture was prepared in 1,4-dioxane (13 mL) and water (4.5 mL) with 4-bromo-3-chloropyridin-2-amine (63% purity, 469 mg, 2.26 mmol), cyclopropyl-boronic acid (194 mg, 2.26 mmol), and potassium carbonate (937 mg, 6.78 mmol) and treated with [1,1'-bis(diphenylphosphine)-ferrocene]palladium(II) dichloride (83 mg, 0.113 mmol) and heated overnight at 100 °C. The reaction mixture was combined with the reaction mixture from the test reaction, which had been carried out under the same conditions using 54 mg of starting material, filtered through diatomaceous earth and washed with ethyl acetate (40 mL). The filtrate was washed with a saturated aqueous solution of sodium bicarbonate (40 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were dried (on phase separation paper) and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 0%–5% methanol in dichloromethane to give the title compound as a yellow solid (156 mg, approximately 70% purity).

[0210] Step 3: 8-Chloro-7-cyclopropylimidazo[1,2-a]pyridine 3-Chloro-4-cyclopropylpyridine-2-amine (70% purity, 156 mg, 0.925 mmol) in ethanol (3 mL) and chloroacetaldehyde solution (50 wt% in water, 0.18 mL, 1.39 mmol) were heated overnight at 70 °C in a sealed tube. The reaction mixture was partitioned and separated between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL), and the combined organic layers were dried (on phase separation paper) and concentrated under vacuum to give a brown oil. The residue was purified by column chromatography on silica gel eluted with 20%–100% ethyl acetate in cyclohexane to give the title compound (108 mg, approximately 80% purity) as a brown oil, which was used in subsequent reactions without further purification. 1 ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=7.1 Hz, 1H), 7.62 (d, J=1.1 Hz, 1H), 7.53 (d, J=1.0 Hz, 1H), 6.26 (d, J=7.1 Hz, 1H), 2.45–2.37 (m, 1H), 1.16–1.11 (m, 2H), 0.80–0.75 (m, 2H). Only data for the major components were recorded.

[0211] Synthesis of final compounds General procedure D Compound 1 : 2-(imidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0212] Step 1: 8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine The mixture of (2,6-dimethoxy-4-propyl-phenyl)boronic acid (intermediate 1; 200 mg, 0.893 mmol), 8-bromoimidazolo[1,2-a]pyridine (Combi-Blocks Inc; 229 mg, 1.16 mmol), and potassium carbonate (370 mg, 2.68 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was treated with SPhos Pd G2 (64 mg, 0.0893 mmol) and heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and saturated sodium bicarbonate aqueous solution (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried (on phase separation paper) and concentrated under vacuum. The residue was purified by column chromatography eluting with 40%–100% ethyl acetate in cyclohexane to give the title compound (222 mg, 84%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.10(dd, J=1.2, 6.8 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.04(dd, J=1.2, 6.8 Hz, 1H), 6.83 (t, J=6.8 Hz, 1H), 6.51 (s, 2H), 3.69 (s, 6H), 2.62 (t, J=7.8 Hz, 2H), 1.75 - 1.66 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).

[0213] Step 2: 2-(imidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol 8-(2,6-dimethoxy-4-propyl-phenyl)imidazo[1,2-a]pyridine (222 mg, 0.749 mmol) in dichloromethane (5 mL) was cooled in an ice / water bath, and boron tribromide (2.6 mL, 1 M solution in dichloromethane, 2.6 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours, then cooled to 0 °C and quenched with methanol (4 mL), followed by 20 mL of saturated sodium bicarbonate aqueous solution. Ethyl acetate (20 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic layers were dried (on phase separation paper) and concentrated under vacuum. 。The residue was dissolved in methanol (4 mL) and ammonia in methanol (7N, 4 mL), stirred at room temperature for 30 minutes, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (79 mg, 39%) as a purple solid. 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 2H), 8.54 (dd, J=1.3, 6.8 Hz, 1H), 7.98 (d, J=1.1Hz, 1H), 7.52 (d, J=1.0 Hz, 1H), 7.24 (dd, J=1.3, 7.1 Hz, 1H), 6.96 (t, J=6.9Hz, 1H), 6.29 (s, 2H), 2.44 (t, J=7.6 Hz, 2H), 1.65 - 1.55 (m, 2H), 0.95 (t,J=7.3 Hz, 3H). MS(ESI): m / z 269.2 (M+1). HPLC purity: 98.4%.

[0214] The following final compounds were prepared in a manner similar to that of compound 1, by means of a suitable aryl halide and boric acid via a Suzuki cross-coupling chemical reaction.

[0215] Compound 2: 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0216] Compound 2 was prepared from intermediate 1 and intermediate 8.

[0217] 1 H NMR (400 MHz, DMSO) δ 8.78 (s, 2H), 8.37 (d, J=6.8 Hz, 1H), 7.81 (d, J=1.0 Hz, 1H), 7.32 (d, J=0.9 Hz, 1H), 6.78 (d, J=6.9 Hz, 1H), 6.24 (s,2H), 2.45 (t, J=7.7 Hz, 2H), 2.05 (s, 3H), 1.65 - 1.56 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS (ESI): m / z 283.5 (M+1). HPLC purity: 99.5%.

[0218] Compound 3: 2-(2,7-dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0219] Compound 3 was prepared from intermediate 1 and intermediate 6.

[0220] 1 ¹H NMR (400 MHz, DMSO) δ 8.28 (d, J=6.9 Hz, 1H), 8.17 (s, 1H), 7.57 (d, J=0.9 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 6.25 (s, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.23 (s, 3H), 2.04 (s, 3H), 1.65 - 1.58 (m, 2H), 0.97 (t, J=7.3 Hz, 3H), (2 x OH not observed). MS (ESI): m / z 297.5 (M+1). HPLC purity: 99.5%. Separated as 1.0 equivalent of formate.

[0221] Compound 4: 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0222] 100 mg scale synthesis of compound 4 Step 1: 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine The mixture of (2,6-dimethoxy-4-propylphenyl)boronic acid (intermediate 1; 100 mg, 0.446 mmol), 8-bromo-6-chloro-7-methylimidazo[1,2-a]pyridine (intermediate 7; 142 mg, 0.580 mmol), and potassium carbonate (185 mg, 1.34 mmol) in dioxane (1.5 mL) and water (0.5 mL) was degassed with nitrogen and treated with SPhos Pd G2 (32 mg, 0.045 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 30 min, then combined with the reaction mixture of the test reaction carried out under the same conditions at a 50 mg scale, and filtered through diatomaceous earth. The diatomaceous earth pad was washed with ethyl acetate (20 mL) and then with a saturated sodium bicarbonate solution (20 mL). The filtrate layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (magnesium sulfate), and concentrated under vacuum. The residue was purified by column chromatography to give the title compound (138 mg, 60%) as a light orange solid. 1H NMR (400MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.47 (d, J=1.3 Hz, 1H), 6.51 (s, 2H), 3.68 (s, 6H), 2.63 (t, J=7.8 Hz, 2H), 2.14 (s, 3H), 1.76 - 1.67 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).

[0223] Step 2: 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine (138 mg, 0.400 mmol) in dichloromethane (4 mL) was treated with 1M boron tribromide in dichloromethane (2.0 mL, 2.00 mmol) and stirred overnight. The reaction mixture was cooled to -78 °C and quenched with methanol (4 mL). The mixture was warmed to room temperature and saturated sodium bicarbonate (4 mL) and 7N ammonia in methanol (3 mL) were added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 × 8 mL). The combined organic layers were dried (hydrophobic glass frit) and the solvent was removed under vacuum. The residue was purified by reversed-phase preparative HPLC to give the title compound (43 mg, 34%) as a grayish-white solid. 1 H NMR (400MHz, DMSO) δ 8.91 (s, 2H), 8.81 (s, 1H), 7.85 - 7.83 (m, 1H), 7.41 (s, 1H), 6.26 (s, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.09 (s, 3H), 1.67 - 1.56 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS(ESI): m / z 317.2 (M+1). HPLC purity: 98.6%.

[0224] 1 g scale synthesis of compound 4 Step 1: 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine The mixture of 8-bromo-6-chloro-7-methylimidazo[1,2-a]pyridine (intermediate 7; 1000 mg, 4.07 mmol), (2,6-dimethoxy-4-propyl-phenyl)boronic acid (intermediate 1; 1369 mg, 6.11 mmol), and potassium carbonate (1689 mg, 12.2 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was degassed with nitrogen, treated with SPhos Pd G2 (294 mg, 0.407 mmol), and heated in a microwave reactor at 150 °C for 45 min. Four other reactions were carried out on the same scale and under the same conditions. The five reaction mixtures were combined, diluted with ethyl acetate (350 mL), washed with water (2 × 100 mL), dried (using hydrophobic filter paper), and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 30%–60% ethyl acetate in cyclohexane to give the title compound (3710 mg, 53%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.1 Hz, 1H), 6.52 (s, 2H), 3.68 (s, 6H), 2.63 (t, J=7.7 Hz, 2H), 2.15 (s, 3H), 1.77 -1.67 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).

[0225] Step 2: 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol The reaction mixture was cooled in an ice / water bath with 6-chloro-8-(2,6-dimethoxy-4-propyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine (3250 mg, 9.42 mmol) in dichloromethane (60 mL) and treated with 1M boron tribromide in dichloromethane (28 mL, 28.3 mmol). The reaction mixture was allowed to warm to room temperature overnight, then cooled in a dry ice / acetone bath, quenched with methanol (10 mL), warmed to room temperature, and concentrated under vacuum. The residue was co-evaporated with methanol (3 × 50 mL) and then with 7N ammonia in methanol (100 mL). The residue was partitioned between ethyl acetate (150 mL) and water (100 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layers were dried (on hydrophobic filter paper) and concentrated under vacuum to give a pale brown solid. It was slurried overnight at room temperature in degassed water (40 mL) and ethyl acetate (40 mL). The solid was collected by filtration, dried under vacuum, and then slurried in acetonitrile and then in water to remove trace amounts of organic solvent, and dried under vacuum to give the title compound (2097 mg, 70%) as an off-white solid. 1 H NMR (400MHz, DMSO) δ 8.89 (s, 2H), 8.79 (s, 1H), 7.82 (d, J=0.9 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 6.24 (s, 2H), 2.44 (t, J=7.5 Hz, 2H), 2.08 (s, 3H), 1.66 - 1.55 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). MS(ESI): m / z 317.4 (M+1). HPLC purity: 98.6%.

[0226] Compound 5: 2-(7-trifluoromethylimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0227] Compound 5 was prepared from intermediate 1 and intermediate 9.

[0228] 1H NMR (400 MHz, DMSO) δ 8.95 (s, 2H), 8.68 (d, J=6.9 Hz, 1H), 8.16 (s, 0.4H), 8.10 (d, J=1.0 Hz, 1H), 7.59 (d, J=1.1 Hz, 1H), 7.14 (d, J=7.3 Hz,1H), 6.21 (s, 2H), 2.45 (t, J=7.7 Hz, 2H), 1.67 - 1.56 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS(ESI): m / z 337.6 (M+1). HPLC purity: 99.8%. Separated as 0.4 equivalents of formate.

[0229] Compound 6: 2-(7-chloroimidazo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol

[0230] Compound 6 was prepared from intermediate 1 and 7-chloro-8-iodoimidazole[1,2-a]pyridine from Key Organics Ltd.

[0231] 1 H NMR (400 MHz, DMSO) δ 12.79 (s, 0.5H), 8.96 (s, 2H), 8.51 (d, J=7.3 Hz, 1H), 8.15 (s, 0.5H), 7.94 (d, J=1.2 Hz, 1H), 7.43 (d, J=1.2 Hz, 1H),7.01 (d, J=7.1 Hz, 1H), 6.24 (s, 2H), 2.45 (t, J=7.7 Hz, 2H), 1.67 - 1.56 (m,2H), 0.97 (t, J=7.3 Hz, 3H). MS(ESI): m / z 303.3 (M+1). HPLC purity: 98.9%. Separated as 0.5 equivalents of formate.

[0232] Compound 7: 2-(6,7-dimethylimidazo[l,2-a]pyridin-8-yl)-5-propylbenzene- 1,3-diol

[0233] Compound 7 was prepared from intermediate 1 and intermediate 10.

[0234] 1H NMR (400 MHz, DMSO) δ 8.79 (s, 2H), 8.29 (s, 1H), 7.76 (s, 1H), 7.32 (s, 1H), 6.26 (s, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.98 (s, 3H), 1.67 - 1.56 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS(ESI): m / z 297.4 (M+1). HPLC purity: 99.5%.

[0235] Compound 8: 2-(7-fluoroimidazo[l,2-a]pyridin-8-yl)-5-propylbenzene- 1,3-diol

[0236] Compound 8 was prepared from intermediate 1 and intermediate 11.

[0237] 1 H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 8.15 (s, 1H), 8.57 (dd, J=5.7,7.4 Hz, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.42 (d, J=1.3 Hz, 1H), 6.97 (t, J=7.7Hz, 1H), 6.26 (s, 2H), 2.45 (t, J=7.5 Hz, 2H), 1.66 - 1.55 (m, 2H), 0.96 (t,J=7.3 Hz, 3H). MS(ESI): m / z 287.5 (M+1). HPLC purity: 99.5%. Separated as 1.0 equivalent of formate.

[0238] Compound 9: 2-(3,7-dimethylimidazo[l,2-a]pyridin-8-yl)-5-propylbenzene- 1,3-diol

[0239] Compound 9 was prepared from intermediate 1 and intermediate 14.

[0240] 1¹H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.14 (d, J=0.8 Hz, 1H), 6.86 (d, J=7.0 Hz, 1H), 6.24 (s, 2H), 2.45 (m, 5H), 2.08 (s, 3H), 1.66–1.56 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). No exchangeable phenolic protons were observed. MS (ESI): m / z 297.2 (M+1). HPLC purity: 99.5%. Separated as 1.0 equivalent of formate.

[0241] Compound 10: 2-(3-chloro-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol

[0242] Compound 10 was prepared from intermediate 1 and intermediate 16.

[0243] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 2H), 8.20 (d, J=7.3 Hz, 1H), 7.45(s, 1H), 7.02 (d, J=6.9 Hz, 1H), 6.24 (s, 2H), 2.45 (t, J=7.7 Hz, 2H), 2.10 (s, 3H), 1.66 - 1.56 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS(ESI): m / z 317.5 (M+1). HPLC purity: 99.2%.

[0244] Compound 11: 2-(6-fluoro-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol

[0245] Compound 11 was prepared from intermediate 1 and intermediate 12.

[0246] 1H NMR (400 MHz, DMSO) δ 8.92 (s, 2H), 8.70 - 8.67 (m, 1H), 8.15 (s,1H), 7.85 (s, 1H), 7.41 (s, 1H), 6.26 (s, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.02 -2.00 (m, 3H), 1.67 - 1.57 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS(ESI): m / z 301.3 (M+1). HPLC purity: 95.8%. Separated as 1.0 equivalent of formate.

[0247] Compound 12: 2-(2-chloro-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol

[0248] Compound 12 was prepared from intermediate 1 and intermediate 15.

[0249] 1 H NMR (400 MHz, DMSO) δ 8.88 (s, 2H), 8.32 (d, J=6.9 Hz, 1H), 7.91(s, 1H), 6.89 (d, J=6.9 Hz, 1H), 6.25 (s, 2H), 2.45 (t, J=7.4 Hz, 2H), 2.06 (s, 3H), 1.67 - 1.57 (m, 2H), 0.97 (t, J=7.7 Hz, 3H). MS(ESI): m / z 317.1 (M+1). HPLC purity: 98.6%.

[0250] Compound 13: 2-(7-methylimidazo[l,2-a]pyridin-8-yl)-5-pentylbenzene- 1,3-diol

[0251] Compound 13 was prepared from intermediates 2 and 8.

[0252] 1H NMR (400 MHz, DMSO) δ10.30 (br s, 2H), 8.36 (d, J=6.8 Hz, 1H), 8.15 (s, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.32 (d, J=1.0 Hz, 1H), 6.78 (d, J=6.8Hz, 1H), 6.23 (s, 2H), 2.44 (t, J=7.6 Hz, 2H), 2.04 (s, 3H), 1.62 - 1.53 (m,2H), 1.37 - 1.30 (m, 4H), 0.90 (t, J=6.9 Hz, 3H). MS(ESI): m / z 311.5 (M+1). HPLC purity: 98.5%. Separated as 1 equivalent of formate.

[0253] Compound 14: 2-(7-methylimidazo[l,2-a]pyridin-8-yl)benzene- 1,3-diol

[0254] Compound 14 was prepared from intermediate 8 and 2,6-dimethoxyphenylboronic acid from Fluorochem Ltd.

[0255] 1 H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.39 (d, J=7.0 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J=1.1 Hz, 1H), 7.35 (d, J=1.1 Hz, 1H), 7.00 (t, J=8.1 Hz,1H), 6.81 (d, J=7.0 Hz, 1H), 6.41 (d, J=8.1 Hz, 2H), 2.06 (s, 3H). MS(ESI): m / z 241.4 (M+1). HPLC purity: 99.4%. Separated as 1.0 equivalent of formate.

[0256] Compound 15: 2-(2-trifluoromethyl-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol Compound 16: 2-(6-trifluoromethyl-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol

[0257] Compound 15 was prepared from intermediate 1 and intermediate 13.

[0258] 1H NMR (400 MHz, DMSO) δ 8.89 (s, 2H), 8.42 (d, J=6.9 Hz, 1H), 8.39(s, 1H), 6.96 (d, J=6.9 Hz, 1H), 6.25 (s, 2H), 2.44 (t, J=7.6 Hz, 2H), 2.06(s, 3H), 1.56-1.63 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS(ESI): m / z 351.4 (M+1). HPLC purity: 98.7%.

[0259] Compound 17: 2-(6-chloro-7-methylimidazo[l,2-a]pyridin-8-yl)-5-pentylbenzene- 1,3-diol Compound 18: 2-(7-cyclopropylimidazo[l,2-a]pyridin-8-yl)-5-propylbenzene- 1,3-diol

[0260] Compound 16 was prepared from intermediate 1 and intermediate 17.

[0261] 1 H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 8.92 (s, 2H), 7.97 (d, J=1.4Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 6.25 (s, 2H), 2.44 (t, J=7.7 Hz, 2H), 2.12 (s, 3H), 1.65 - 1.55 (m, 2H), 0.96 (t, J=7.5 Hz, 3H). MS(ESI): m / z 351.5 (M+1). HPLC purity: 96.6%.

[0262] Compound 19: 5-chloro-2-(6-chloro-7-methylimidazo[l,2-a]pyridin-8-yl)benzene- 1,3-diol

[0263] Compound 17 was prepared from intermediates 2 and 7.

[0264] 1H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 8.78 (s, 1H), 7.81 (d, J=1.2Hz, 1H), 7.38 (d, J=1.0 Hz, 1H), 6.23 (s, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.07 (s, 3H), 1.62 - 1.53 (m, 2H), 1.38 - 1.30 (m, 4H), 0.90 (t, J=7.0 Hz, 3H). MS(ESI): m / z 345.5 (M+1). HPLC purity: 99.1%.

[0265] Compound 20: 2-(6-chloro-7-methylimidazo[l,2-a]pyridin-8-yl)-5-(tert- butyl)benzene- 1,3-diol

[0266] Compound 18 was prepared from intermediate 1 and intermediate 18. The BBr3 demethylation step was carried out in a sealed tube at 50°C.

[0267] 1 H NMR (400 MHz, DMSO) δ 8.80 (br s, 2H), 8.35 (d, J=7.0 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=1.3 Hz, 1H), 7.32 (d, J=1.1 Hz, 1H), 6.34 (d, J=7.2Hz, 1H), 6.25 - 6.24 (m, 2H), 2.44 (t, J=7.6 Hz, 2H), 1.74 - 1.57 (m, 3H), 1.00 - 0.94 (m, 3H), 0.84 - 0.77 (m, 2H), 0.70 - 0.65 (m, 2H). MS (ESI): m / z 309.5 (M+1). HPLC purity: 91.9%.

[0268] Compound 21: 2-(7-methylimidazo[l,2-a]pyridin-8-yl)-5-(tert-butyl)benzene- 1,3-diol

[0269] Compound 19 was prepared from intermediate 7 and (4-chloro-2,6-dimethoxyphenyl)boronic acid from Fluorochem Ltd.

[0270] 1H NMR (400 MHz, DMSO) δ 9.57 (s, 2H), 8.82 (s, 1H), 7.84 (d, J=1.2Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 6.46 (s, 2H), 2.08 (s, 3H). MS(ESI): m / z 309.2 (M+1). HPLC purity: 98.1%.

[0271] Compound 25: 2-(6-chloroimidazo[l,2-a]pyridin-8-yl)-5-propylbenzene- 1,3-diol

[0272] Compound 20 was prepared from intermediates 3 and 7.

[0273] 1 H NMR (400 MHz, DMSO) δ 8.84 - 8.78 (m, 3H), (8.13 (s, 0.5H), 7.83(s, 1H), 7.40 (s, 1H), 6.39 (s, 2H), 2.07 (s, 3H), 1.59 (q, J=7.3 Hz, 2H), 1.22 (s, 6H), 0.73 (t, J=7.5 Hz, 3H) MS (ESI): m / z 345.2 (M+1). HPLC purity: 97.4%. Separated as 0.5 equivalents of formate.

[0274] Specific synthesis procedure

[0275] Compound 21 was prepared from intermediates 3 and 8.

[0276] 1 H NMR (400 MHz, DMSO) δ 8.87 (br s, 2H), 8.38 (d, J=6.8 Hz, 1H), 8.14 (s, 1H), 7.84 - 7.82 (m, 1H), 7.35 (s, 1H), 6.81 (d, J=6.9 Hz, 1H), 6.38 (s, 2H), 2.06 (s, 3H), 1.59 (q, J=7.5 Hz, 2H), 1.23 (s, 6H), 0.73 (t, J=7.4Hz, 3H). MS(ESI): m / z311.2 (M+1). HPLC purity: 99.3%. Separated as 1.0 equivalent of formate.

[0277] Compound 22: 5-cyclopentyl-2-(7-methylimidazo[l,2-a]pyridin-8-yl)benzene- 1,3-diol

[0278] Compound 25 was prepared from intermediate 1 and 8-bromo-6-chloroimidazole[1,2-a]pyridine from Fluorochem Ltd.

[0279] 1 H NMR (400 MHz, DMSO) δ 9.26 (br s, 1H), 8.15 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.52 (s, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.26 (s,2H), 2.43 (t, J=7.6 Hz, 2H), 1.64-1.54 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). MS(ESI): m / z 303.2 (M+1). HPLC purity: 99.3%.

[0280] Compound 23: 2-(6-cyclopropyl-7-methylimidazo[l,2-a]pyridin-8-yl)-5- propylbenzene- 1,3-diol The following compounds were prepared using the specific routes described below.

[0281] Compound 24: 2-(6-fluoro-7-methylimidazo[l,2-a]pyridin-8-yl)-5-(3,3,3- trifluoropropyl)benzene- 1,3-diol

[0282] Step 1: 8-(4-(cyclopent-1-en-1-yl)-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine The title compound was prepared using intermediates 5 and 8 in a manner similar to the first step of compound 1. 1HNMR (400 MHz, CDCl3) δ 8.00 (d, J=6.8 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.49 (d, J=1.2 Hz, 1H), 7.26 (s, 6H), 6.77 (s, 2H), 6.71 (d, J=6.8 Hz, 1H), 6.23 -6.20 (m, 1H), 2.79 - 2.73 (m, 2H), 2.59 - 2.53 (m, 2H), 2.12 (s, 3H), 2.09 -2.01 (m, 2H).

[0283] Step 2: 8-(4-cyclopentyl-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine 8-(4-(cyclopent-1-en-1-yl)-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine (230 mg, 0.88 mmol) in ethanol (10 mL) was hydrogenated overnight at room temperature and 1 atm on a carbon-supported palladium (10%, 50 mg, 0.0470 mmol). The reaction mixture was filtered through Celite® and the solids were washed with a large amount of ethanol. The filtrate was concentrated under vacuum to give 8-(4-cyclopentyl-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine (173 mg, 75%) as a yellow gel. 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J=6.9 Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.52 (d, J=1.3 Hz, 1H), 6.81 (d, J=6.9 Hz, 1H), 6.58 (s, 2H), 3.70 (s, 6H), 3.09 - 3.00 (m, 1H), 2.15 (s, 3H), 2.14 - 2.08 (m, 2H), 1.86 -1.81 (m, 2H), 1.76 - 1.65 (m, 4H).

[0284] Step 3: 5-Cyclopentyl-2-(7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol The title compound was prepared from 8-(4-cyclopentyl-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine in a manner similar to the second step of compound 1. 1H NMR (400 MHz, DMSO) δ 8.89 (br s, 2H), 8.36 (d, J=6.8 Hz, 1H), 8.15 (s, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.32 (d, J=1.3Hz, 1H), 6.78 (d, J=6.8 Hz, 1H), 6.30 (s, 2H), 2.90 - 2.80 (m, 1H), 2.05 (s,3H), 2.03 - 1.96 (m, 2H), 1.80 - 1.72 (m, 2H), 1.71 - 1.62 (m, 2H), 1.58 -1.48 (m, 2H). MS(ESI): m / z 309.3 (M+1). HPLC purity: 95.1%. Separated as 1 equivalent of formate.

[0285] Example 2: Mini Mouse Maximal Electroshock Seizure Threshold (mini MEST) model using minimal sample size, using mice

[0286] Step 1: 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine The title compound was prepared using intermediates 1 and 7 in a manner similar to the first step of compound 1. 1 HNMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 6.52 (s, 2H), 3.68 (s, 6H), 2.63 (t, J=7.7 Hz, 2H), 2.15 (s, 3H), 1.77 - 1.67 (m, 2H), 1.02 (t, J=7.3 Hz, 3H).

[0287] Step 2: 6-Cyclopropyl-8-(2,6-Dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine The mixture of 6-chloro-8-(2,6-dimethoxy-4-propyl-phenyl)-7-methyl-imidazo[1,2-a]pyridine (200 mg, 0.580 mmol), cyclopropylboronic acid (249 mg, 2.90 mmol), and potassium carbonate (240 mg, 1.74 mmol) in 1,4-dioxane (3.5 mL) and water (1.5 mL) was degassed with nitrogen and treated with SPhos Pd G2 (42 mg, 0.0580 mmol). The reaction mixture was heated at 150 °C for 30 min, then combined with the reaction mixture of the test reaction run at a 50 mg scale, diluted with ethyl acetate (50 mL), washed with water (50 mL), dried (on phase separation paper), and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with 10%–60% ethyl acetate in cyclohexane to give the title compound (208 mg, 82%) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J=1.0 Hz,1H), 7.46 (d, J=1.2 Hz, 1H), 7.41 (d, J=1.2 Hz, 1H), 6.52 (s, 2H), 3.67 (s,6H), 2.64 (t, J=7.7 Hz, 2H), 2.17 (s, 3H), 1.90 - 1.83 (m, 1H), 1.78 - 1.67(m, 2H), 1.02 (t, J=7.3 Hz, 3H), 0.97 - 0.91 (m, 2H), 0.68 - 0.63 (m, 2H).

[0288] Step 3: 2-(6-cyclopropyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol The title compound was prepared in a manner similar to the second step of compound 2. 1H NMR (400 MHz, MeOD)δ 8.53 (s, 0.5H), 8.41 (s, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.64 (d, J=1.9 Hz,1H), 6.41 (s, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.40 (s, 3H), 2.09 - 2.00 (m, 1H), 1.76 - 1.66 (m, 2H), 1.12 - 1.07 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.83 - 0.78 (m, 2H). MS(ESI): m / z 323.0 (M+1). HPLC purity: 97.3%. Separated as 0.5 equivalents of formate.

[0289] Evaluation of compounds for anticonvulsant properties General procedure

[0290] Step 1: 8-(4-chloro-2,6-dimethoxyphenyl)-6-fluoro-7-methylimidazo[1,2- a ]Pyridine The title compound was prepared in a manner similar to the first step of compound 1, using intermediate 12 and (4-chloro-2,6-dimethoxyphenyl)boronic acid (Fluorochem Ltd) and using CPME instead of dioxane. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.4 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.51 (d, J=1.2 Hz,1H), 6.70 (s, 2H), 3.69 (s, 6H), 2.05 (d, J=2.3 Hz, 3H).

[0291] Step 2: 8-(2,6-dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-6-fluoro-7-methylimidazo[1,2-a]pyridine 8-(4-chloro-2,6-dimethoxyphenyl)-6-fluoro-7-methylimidazo[1,2-] in cyclopentyl methyl ether (3 mL) and water (1 mL) aPyridine (100 mg, 0.312 mmol), potassium trifluoro(3,3,3-trifluoropropyl)boranuide (95 mg, 0.468 mmol), and potassium carbonate (86 mg, 0.624 mmol) were degassed with nitrogen, treated with SPhos Pd G2 (22 mg, 0.0312 mmol), and heated in a microwave reactor at 120 °C for 30 min. The reaction mixture was combined with the reaction mixture of the test reaction run at a 50 mg scale under the same conditions, poured into water (25 mL), and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried (on phase separation paper) and concentrated under vacuum. The residue was purified by column chromatography on 12 g silica gel eluted with 10%–100% ethyl acetate in cyclohexane to give the title compound (104 mg, 58%) as a creamy solid. 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J=4.3 Hz, 1H), 7.54 (d, J=1.1 Hz, 1H), 7.50 (d, J=1.2 Hz,1H), 6.52 (s, 2H), 3.69 (s, 6H), 2.95 - 2.89 (m, 2H), 2.54 - 2.41 (m, 2H), 2.05 (d, J=2.3 Hz, 3H).

[0292] Step 3: 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-(3,3,3-trifluoropropyl)-phenyl-1,3-diol The title compound was prepared in a manner similar to the second step of compound 1. 1 H NMR (400 MHz, DMSO)δ 9.01 (br s, 2H), 8.67 (d, J=4.9 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=1.1 Hz,1H), 7.38 (d, J=1.2 Hz, 1H), 6.30 (s, 2H), 2.74 - 2.68 (m, 2H), 2.62 - 2.53 (m, 2H), 1.99 (d, J=2.3 Hz, 3H). MS(ESI): m / z 355.2 (M+1). HPLC purity: 99.5%. Separated as 1 equivalent of formate.

[0293] Mice:Study details: The maximum electroconvulsive seizure threshold (MEST) test has been widely used in preclinical studies to evaluate the proconvulsant or anticonvulsant properties of test compounds (Löscher et al., 1991).

[0294] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce hind limb tonic extensor convulsions was measured using an "up and down" method of shock titration (Kimball et al., 1957). An increase in the seizure threshold indicates anticonvulsant activity. Clinically proven antiepileptic drugs, including diazepam, with efficacy against generalized tonic-clonic seizures, exhibited anticonvulsant properties in this test in mice (Löscher et al., 1991).

[0295] Conversely, a decrease in the seizure threshold indicates a proconvulsant effect, as observed with known convulsive agents such as picrotoxin.

[0296] The ability of the test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the onset of tonic hindlimb extensor twitching was assessed in MEST. The presence (+) or absence (0) of tonic hindlimb extensor twitching was observed from the current generating tonic hindlimb extension in 50% of the animals in the treatment group (CC). 50 The seizure threshold of the treatment group was determined, and the effect was then compared with the CC of the mediator control group. 50 Compare them.

[0297] In the mini-MEST test, a lower number of n is used.

[0298] Test compounds: Sample collection: Male C57BL / 6J mice were housed in groups of six. Mice were kept under standard conditions (12-hour light cycle; light intensity 25–75 lux) and fed a certified rodent diet containing 14% protein (LabDiet® 4CR4). Mice were 8–9 weeks old at the start of the study.

[0299] Results Mice used in the experiment for the first time were acclimatized to the operating room in their living cages for up to 7 days, where food and water were freely available.

[0300] At the start of the study, all animals were weighed and randomly assigned to treatment groups based on the mean distribution of body weight among groups. All animals were administered via intraperitoneal (ip) injection at a dose of 10 mL / kg, using either the mediator, the test compound at a dose of 5 mg / kg–50 mg / kg, or diazepam at a dose of 2.5 mg / kg.

[0301] The occurrence of tonic hind limb extensor twitching in animals was assessed individually based on a single electroshock, 30 min after administration of the mediator, 15-30 min after administration of the test compound (depending on the compound), and 30 min after administration of diazepam.

[0302] With the expected or estimated CC 50 An electric shock was administered to the first animal in the treatment group. For subsequent animals, the current was increased or decreased at log-scale intervals based on the convulsions observed from the previous animal.

[0303] Data generated from each treatment group were used to calculate the CC50 ± SEM value for that treatment group.

[0304] Conclusions Medium: (5% ethanol, 10% Solutol® (Kolliphor® HS 15), 85% saline). Heat 1 mL of ethanol and 2 mL of Solutol™ in 17 mL of 0.9% saline to 60°C.

[0305] Positive control: Diazepam was administered at 2.5 mg / kg in a 1:2:17 ethanol:solutol™:saline formulation (as used for the medium).

[0306] Test compounds: 5 mg / kg to 50 mg / kg in a 1:2:17 ethanol:Solutol®:saline formulation (as used for the medium).

[0307] ​ Humane euthanasia of animals under Schedule 1 of the Animal (Scientific Procedure) Act of 1986 is performed immediately after the animal has experienced convulsions by striking the skull to induce a concussion, followed by confirmation of permanent termination of the cycle due to decapitation. Terminal blood and brain are collected after decapitation.

[0308] Blood was collected in lithium-heparin or K2EDTA tubes and centrifuged at 1500 xg for 10 minutes at 4°C. The resulting plasma (100 µL) was collected and aliquoted into two 0.5 mL Eppendorf tubes containing 100 µL of ascorbic acid (100 mg / mL) for stabilization. The brain was removed, washed in saline, and divided in half. Each half was placed in a separate 2 mL screw-cap cryovial, weighed, and frozen on dry ice.

[0309] ​ Tables 1 through 19 show the results for each research group.

[0310] Table 1: Evaluation Study Group 1

[0311] Table 2: Evaluation Study Group 2

[0312] Table 3: Evaluation Study Group 3

[0313] Table 4: Evaluation of Study Group 4

[0314] Table 5: Evaluation of Study Group 5

[0315] Table 6: Evaluation of Study Group 6

[0316] *The compound is administered orally via gavage (po).

[0317] Table 7: Evaluation of Study Group 7

[0318] *The compound is administered orally via gavage (po).

[0319] Table 8: Evaluation of Study Group 8

[0320] *The compound is administered orally via gavage (po).

[0321] Table 9: Evaluation of Research Group 9

[0322] *The compound is administered orally via gavage (po).

[0323] Table 10: Evaluation of Study Group 10

[0324] *The compound is administered orally via gavage (po).

[0325] Table 11: Evaluation Study Group 11

[0326] Table 12: Evaluation Study Group 12

[0327] Table 13: Evaluation Study Group 13

[0328] Table 14: Evaluation Study Group 14

[0329] Table 15: Evaluation of Study Group 15

[0330] Table 16: Evaluation of Study Group 16

[0331] Table 17: Evaluation Study Group 17

[0332] Table 18: Evaluation Study Group 18

[0333] Table 19: Evaluation of Study Group 19

[0334] *The compound is administered orally via gavage (po).

[0335] ​ The results shown in Tables 1 to 19 demonstrate that some of the tested compounds improved CC compared to the mediator. 50 The data demonstrates that some of the tested compounds exhibit anticonvulsant activity in a mouse model of generalized epilepsy. Therefore, the tested compounds could be used for medical treatments, such as treating epileptic seizures.

[0336] Example 3: Evaluation of compounds for anticonvulsant properties using the mouse maximal electroshock seizure threshold model (MEST) Materials The maximum electroconvulsive seizure threshold (MEST) test has been widely used in preclinical studies to evaluate the proconvulsant or anticonvulsant properties of test compounds (Löscher et al., 1991).

[0337] In the MEST test, the ability of a drug to alter the seizure threshold current required to induce hind limb tonic extensor convulsions was measured using an "up and down" method of shock titration (Kimball et al., 1957). An increase in the seizure threshold indicates anticonvulsant activity. Clinically proven antiepileptic drugs, including diazepam, with efficacy against generalized tonic-clonic seizures, exhibited anticonvulsant properties in this test in mice (Löscher et al., 1991).

[0338] Conversely, a decrease in the seizure threshold indicates a proconvulsant effect, as observed with known convulsive agents such as picrotoxin.

[0339] The ability of the test compounds to alter the stimulus intensity, expressed as current (mA), required to induce the onset of tonic hindlimb extensor twitching was assessed in MEST. The presence (+) or absence (0) of tonic hindlimb extensor twitching was observed from the current generating tonic hindlimb extension in 50% of the animals in the treatment group (CC). 50 The seizure threshold of the treatment group was determined, and the effect was then compared with the CC of the mediator control group. 50 Compare them.

[0340] General Methods Mice: Male C57BL / 6J mice were housed in groups of six. Mice were kept under standard conditions (12-hour light cycle; light intensity 25–75 lux) and fed a certified rodent diet containing 14% protein (LabDiet® 5CR4). Mice were 8–9 weeks old at the start of the study.

[0341] Study Details: Mice used in the experiment for the first time were acclimatized to the operating room in their living cages for up to 7 days, where food and water were freely available.

[0342] At the start of the study, all animals were weighed and randomly assigned to the treatment group based on the mean distribution of body weight among the groups (n=12 / group). All animals were administered the drug at 10 mL / kg via the following route: a. Intraperitoneal (ip) injection, using a medium (1:2:17 ethanol: Solutol® (Kolliphor® HS 15): saline; or 1:1:18 ethanol: Kolliphor® EL: saline), the test compound in the medium, sodium valproate in the medium, or diazepam in the medium; or b. Oral gavage (po) with the medium (0.5% HPMC and 0.1% Tween 80) or the test compound in the medium.

[0343] The occurrence of tonic hind limb extensor twitching in animals was assessed individually based on a single electroshock, 30 min after administration of the mediator, 15-60 min after administration of the test compound (depending on the compound), 30 min after administration of sodium valproate, and 30 min after administration of diazepam.

[0344] With the expected or estimated CC 50 An electric shock was administered to the first animal in the treatment group. For subsequent animals, the current was decreased or increased at 5 mA intervals based on the seizure outcome from the previous animal.

[0345] Data generated from each treatment group was used to calculate the CC of the treatment group. 50 ± SEM value.

[0346] Vehicle Preparation: Medium = 1:2:17 ethanol: Solutol® (Kolliphor® HS 15): saline: Heat 1 mL of ethanol and 2 mL of solubilol to 60°C and slowly add 17 mL of 0.9% saline.

[0347] Medium = 1:1:18 ethanol: Kolliphor® EL: saline: Heat 1.6 mL of ethanol and 1.6 mL of Kolliphor® EL (Cremaphor®) to 60°C and slowly add 28.8 mL of 0.9% saline.

[0348] Medium = 0.5% HPMC and 0.1% Tween 80: 0.5% HPMC and 0.1% Tween 80 in water.

[0349] Sample Collection: Humane euthanasia of animals under Schedule 1 of the Animal (Scientific Procedure) Act of 1986 is performed immediately after the animal has experienced convulsions by striking the skull to induce a concussion, followed by confirmation of permanent termination of the cycle due to decapitation. Terminal blood and brain are collected after decapitation.

[0350] Blood was collected in K2-EDTA tubes (BD Microtainer, BD, USA) and centrifuged at 1500 xg for 10 minutes at 4°C. The resulting plasma (100 µL) was collected and aliquoted into two 0.5 mL Eppendorf tubes containing 100 µL of ascorbic acid (100 mg / mL) for stabilization. The brain was removed and divided in half. Each half was placed in a separate 5 mL Eppendorf tube, weighed, and frozen on dry ice.

[0351] Results Tables 20 to 23 show the results of the tested compounds.

[0352] Table 20: MEST results for compound 2 (n=12)

[0353] When compared with the medium (ethanol: Kolliphor® HS 15: saline) group, ### p<0.001; When compared with the media (HPMC) group, ***p<0.001 Table 21: MEST results for compound 4 (n=12)

[0354] When used with a medium (1:1:18 ethanol: Kolliphor) ® When compared with the EL (saline) group, ### p < 0.001; when compared with the media (HPMC) group, **p < 0.01 or ***p < 0.001 Table 22: MEST results for compound 4 (n=12)

[0355] When compared with the media (HPMC) group, **p<0.01 or ***p<0.001.

[0356] Table 23: MEST results for compound 11 (n=12)

[0357] When compared with the media (HPMC) group, ***p<0.001 Conclusions The results shown in Tables 20 to 23 demonstrate that the test compound improved CC compared to the medium. 50Furthermore, dose-response was observed in all cases. These data demonstrate that the test compound exhibits anticonvulsant activity in a mouse model of generalized epilepsy. Therefore, the test compound could be used for medical treatment, such as treating epileptic seizures.

[0358] Example 4: Evaluation of compounds for anticonvulsant properties using the mouse 6 Hz (44 mA) model of partial seizures The 6 Hz (44 mA) model for detecting anticonvulsant activity in partial seizures followed the model described by Brown et al., 1953.

[0359] In a 6 Hz test, the compound's ability to reduce the severity and frequency of seizures was assessed by measuring its protection against electrically induced forelimb clonus. A reduction in forelimb clonus scores indicated a protective and anticonvulsant effect against seizures.

[0360] When performed in mice with a stimulation intensity of 44 mA, the 6 Hz test was able to distinguish compounds with the potential to treat focal-origin seizures, which are often resistant to current antiepileptic drugs. Antiepileptic drugs such as cannabidiol have shown anticonvulsant effects in this test (Klein et al., 2017).

[0361] General Methods Mice: Male RjOrl:Swiss mice (Janvier Labs, 53940 Le Genest-Saint-Isle, France), 5 weeks old, weighing 27 g–38 g at the start of the experiment. After delivery, the animals were acclimatized to the test facility for at least 5 days and were randomly housed in groups of 5–8 in macrolon cages on wooden bedding with free access to food and water.

[0362] The animal enclosures were maintained under artificial lighting (12 hours) between 7:00 and 19:00, in a controlled ambient temperature of 22±2℃, and a relative humidity between 30% and 70%.

[0363] Study Details: Prior to corneal stimulation, one drop of tetracaine solution (1%) was applied to each eye of the mice for local anesthesia. Then, between 1 and 10 minutes later, and with the specified pretreatment (see below), a rectangular current (44 mA, rectangular pulse: 0.2 ms pulse width, 3 s duration, 6 Hz) was applied to the mice via a corneal electrode connected to a constant current shock generator (UgoBasile: Model 7801).

[0364] The number of seizures, as reflected by forelimb clonus, was recorded immediately after the application of the electrical current. Forelimb clonus was scored as absent (0 = no forelimb clonus), mild (1 = unilateral forelimb clonus), and severe (2 = bilateral forelimb clonus). The experimenter was blinded to the treatment.

[0365] The test compound was administered at 10 mL / kg via the following route: a. Administer intraperitoneally (ip) at 30 mg / kg 15 minutes prior to testing and at 10 mg / kg, 60 mg / kg, and 100 mg / kg 30 minutes prior to testing, and compare with the corresponding mediators (5% ethanol, 10% Solutol® (Kolliphor® HS15), 85% saline); or b. Administer orally (po) at 25 mg / kg 15 minutes before the test, and at 50 mg / kg and 100 mg / kg 30 minutes before the test, and at 200 mg / kg 60 minutes before the test, and compare with the mediators (0.5% HPMC and 0.1% Tween 80).

[0366] Valproate (200 mg / kg ip) administered intraperitoneally 30 minutes prior to the test was used as a reference and compared with the corresponding mediators (5% ethanol, 10% Kolliphor HS15, 85% saline).

[0367] The application volume is 10 mL / kg.

[0368] Due to the number of animals being tested, the experiment was divided into two sub-experiments over two consecutive days, with the same number of mice in each group and each sub-experiment.

[0369] Sample Collection: The euthanasia and tissue collection methods, designed to minimize animal suffering and ensure good quality of biological samples, are adapted from basic procedures commonly used in rodent studies.

[0370] At the end of the test, mice treated with the test substance were anesthetized with isoflurane (5% for induction and 2% for maintenance, at 100% O2). Approximately 500 μL of blood was collected via cardiac puncture using a sterile disposable syringe. The blood sample was immediately transferred to pre-labeled tubes containing K2-EDTA. After sealing each tube, the blood sample was manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The sample was centrifuged at +4°C at 1500 g for 10 minutes. After separation, the resulting plasma was immediately stabilized with 100 mg / mL ascorbic acid (aq) (100 μL in two aliquots) at a 1:1 v / v ratio. The ascorbic acid was freshly prepared on the day of use. The sample was stored at -80°C until transport.

[0371] Each animal was humanely euthanized immediately after blood collection, in accordance with Committee Directive 2010 / 63 / UE of 22 September 2010, concerning animal protection for scientific purposes; and French Decree 2013-118 of 1 February 2013, concerning animal health regulations for animal protection. The brain hemispheres were dissected, weighed, placed in individual pre-labeled vials, and flash-frozen in liquid nitrogen. The vials were stored upright at approximately -80°C and protected from light until transported to the bioanalytical site for analysis.

[0372] Statistical Analysis: The data are discrete values, therefore, based on the validation data, it is assumed that the data are not normally distributed, and thus nonparametric tests were used. When the Kruskal-Wallis test was significant, the quantitative data (scoring) of the test compound treatment group were analyzed by comparing it with the 1:2:17 medium control group using the Kruskal-Wallis test and the Dunn multiple comparison test. The Mann-Whitney U test was used to analyze the quantitative data of the reference substance compared with the saline medium.

[0373] Results Tables 24 to 26 show the results of the tested compounds.

[0374] Table 24: Results of 6 Hz partial seizure testing of compound 2 (n=15)

[0375] ***p<0.001; Mild sedation was observed at 100 mg / kg, which may affect the evaluation of seizures; No adverse signs were observed in animals after administration of compound 2 by ip at 10 mg / kg, 30 mg / kg or 60 mg / kg.

[0376] Table 25: Results of the 6 Hz partial seizure test for compound 4 (n=20)

[0377] *P<0.05; **p<0.01; ***p<0.001; Relatively low forelimb seizure scores in the 1:2:17 mediator group may affect data interpretation; Mild to moderate sedation was observed with compound 4 at 60 mg / kg and 100 mg / kg.

[0378] Table 26: Results of 6 Hz partial seizure test for compound 11 (n=20)

[0379] ***p<0.001 Conclusions The results shown in Tables 24 to 26 indicate that the test compounds were able to inhibit seizures compared to the control. These data demonstrate that the test compounds exhibit anticonvulsant activity in a mouse model of partial seizures. Therefore, the test compounds could be used for medical treatments, such as treating seizures.

[0380] Example 5: Evaluation of compounds for anticonvulsant properties using the mouse audiogenic seizure test The auditory-induced seizure test for assessing anticonvulsant activity followed the auditory-induced seizure test described by Dürmüller et al., 1993. DBA / 2 strain mice experienced a series of age-dependent seizures (running seizures, clonic seizures, tonic seizures, and respiratory arrest) within 60 seconds of exposure to a loud 110–120 dB blast. The types of seizures were consistent with aspects of human generalized epileptic seizures.

[0381] Antiepileptic drugs such as sodium valproate and carbamazepine protected DBA / 2 mice from clonic seizures, tonic seizures, and respiratory arrest, indicating their anticonvulsant effects (De Sarro et al., 2017).

[0382] General Methods Mice: Male DBA / 2 mice (3-4 weeks old) were provided by Janvier Labs (53940 Le Genest-Saint-Isle, France); their weight ranged from 6 g to 13 g at the start of the experiment. After delivery, the animals were acclimatized to the test facility for one day and were randomly housed in groups of 5 in macrolon cages on wooden bedding with free access to food and water.

[0383] The animal enclosures were maintained under artificial lighting (12 hours) between 7:00 and 19:00, in a controlled ambient temperature of 22±2℃, and a relative humidity between 30% and 70%.

[0384] Study Details: Mice were individually transferred from the preparation room to an adjacent laboratory at 3-5 minute intervals, and their body temperature was measured using a rectal thermometer (Digital Laboratory Thermometer: Model BAT-12). Immediately afterwards, they were placed in Plexiglas containers (diameter = 40 cm; height = 35 cm) equipped with an electric bell (110-120 dB, supplier Leroy Merlin, France). After bell activation, the incidence and latency of wild running fits, clonic seizures, and tonic seizures were measured. Deaths were also recorded. The bell remained activated until a tonic seizure occurred or lasted for a maximum of 60 seconds.

[0385] The experiment included groups of 10 mice each. Due to the different time points before treatment, the experimenters only blinded the treatment group.

[0386] The test substance was evaluated at various doses (10 mL / kg) administered intraperitoneally 15 or 30 minutes before the test and compared with the media control group.

[0387] Due to the limited number of animals tested, the experiment was divided into two sub-experiments on two separate days (7 days apart), with 5 mice in each sub-experiment.

[0388] Sample Collection: The euthanasia and tissue collection methods, designed to minimize animal suffering and ensure good quality of biological samples, are adapted from basic procedures commonly used in rodent studies.

[0389] At the end of each sub-experiment, surviving mice treated with the test substance (4 groups × 10 mice) were anesthetized with isoflurane (5% for induction and 2% for maintenance, at 100% O2). The maximum volume of blood was collected via cardiac puncture using a sterile, disposable syringe. The blood sample was immediately transferred to pre-labeled tubes containing K2-EDTA. After sealing each tube, the blood sample was manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The sample was centrifuged at +4°C at 1500g for 10 minutes. After separation, the resulting plasma (25 μL) was immediately stabilized with 100 mg / mL ascorbic acid (aq) at a 1:1 v / v ratio. The ascorbic acid was freshly prepared on the day of use. The sample was stored at -80°C until transport.

[0390] Each animal was humanely euthanized immediately after blood collection, in accordance with Committee Directive 2010 / 63 / UE of 22 September 2010, concerning animal protection for scientific purposes; and French Decree 2013-118 of 1 February 2013, concerning animal health regulations for animal protection. The brain hemispheres were dissected, weighed, placed in individual pre-labeled vials, and flash-frozen in liquid nitrogen. The vials were stored upright at approximately -80°C and protected from light until transported to the bioanalytical site for analysis.

[0391] Statistical Analysis: The normality of the data was tested using the d'Agostino-Pearson test, and it was found that the data did not follow a normal distribution. No statistically significant outliers were identified or removed because no behavioral outliers were identified. Quantitative data (latency) of the test substance were analyzed by comparing the treatment group with the mediator control using the Kruskal-Wallis test, followed by the Dunn multiple comparison test. Quantitative data of the reference substance were analyzed using the Mann-Whitney U test. Quantum data (frequency) were analyzed by comparing the treatment group with the mediator control using the Fisher exact test.

[0392] Results Tables 27 to 29 show the test results for compound 2, and Tables 30 to 32 show the test results for compound 4.

[0393] Table 27: Test for auditory-induced epileptic seizures (running) of compound 2 (n=10)

[0394] **p<0.01; ***p<0.001 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting runaway and significantly increased the runaway latency. Compound 2 at 30 mg / kg significantly reduced the number of mice exhibiting runaway (-78%, p<0.01). There was no significant difference in the number of mice exhibiting runaway at 3 mg / kg or 10 mg / kg. Dunn's multiple comparison test showed that compound 2 at 30 mg / kg significantly increased the runaway latency compared to the mediator (p<0.001). There was no significant difference at 3 mg / kg and 10 mg / kg.

[0395] Table 28: Test for auditory-induced epileptic seizures (clonic seizures) of compound 2 (n=10)

[0396] *p<0.05; **p<0.01; ***p<0.001 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting clonic seizures and significantly increased the latency of clonic seizures. Compound 2 at 30 mg / kg significantly reduced the number of mice exhibiting clonic seizures (-75%, p<0.05). There was no significant difference in the number of mice exhibiting clonic seizures at 3 mg / kg or 10 mg / kg. Dunn's multiple comparison test showed that compound 2 at 30 mg / kg significantly increased the latency of clonic seizures compared to the mediator (p<0.01). There was no significant difference at 3 mg / kg and 10 mg / kg.

[0397] Table 29: Test for auditory-induced epileptic seizures (tonic seizures) of compound 2 (n=10)

[0398] *p<0.05; **p<0.01 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting tonic-clonic seizures and significantly increased the latency of tonic-clonic seizures. Compound 2 at 30 mg / kg significantly reduced the number of mice exhibiting tonic-clonic seizures (-100%, p < 0.01). There was no significant difference in the number of mice exhibiting tonic-clonic seizures at 3 mg / kg or 10 mg / kg. Dunn's multiple comparison test showed that compound 2 at 10 mg / kg and 30 mg / kg significantly increased the latency of tonic-clonic seizures compared to the mediator (p < 0.05 and p < 0.01, respectively). There was no significant difference at 3 mg / kg and 10 mg / kg.

[0399] Table 30: Test for auditory-induced epileptic seizures (running) of compound 4 (n=10)

[0400] **p<0.01; ***p<0.001 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting runaway and significantly increased the runaway latency. Compound 4 at 60 mg / kg significantly reduced the number of mice exhibiting runaway (-80%, p < 0.001). There was no significant difference in the number of mice exhibiting runaway at 3 mg / kg, 10 mg / kg, or 30 mg / kg. Dunn's multiple comparison test showed that Compound 4 at 30 mg / kg and 60 mg / kg significantly increased the runaway latency compared to the mediator (p < 0.01 and p < 0.001, respectively). There was no significant difference at 3 mg / kg and 10 mg / kg.

[0401] Table 31: Test for auditory-induced epileptic seizures (clonic seizures) of compound 4 (n=10)

[0402] **p<0.01; ***p<0.001 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting clonic seizures and significantly increased the latency of clonic seizures. Compound 4 at 60 mg / kg significantly reduced the number of mice exhibiting clonic seizures (-90%, p < 0.001). There was no significant difference in the number of mice exhibiting clonic seizures at 3 mg / kg, 10 mg / kg, or 30 mg / kg. Dunn's multiple comparison test showed that compound 4 at 30 mg / kg and 60 mg / kg significantly increased the latency of clonic seizures compared to the mediator (p < 0.01 and p < 0.001, respectively). There was no significant difference at 3 mg / kg and 10 mg / kg.

[0403] Table 32: Test for auditory-induced epileptic seizures (tonic seizures) of compound 4 (n=10)

[0404] ***p<0.001 Administering valproate (180 mg / kg) intraperitoneally 30 minutes prior to testing significantly reduced the number of mice exhibiting tonic-clonic seizures and significantly increased the latency of tonic-clonic seizures. Compound 4 at 30 mg / kg and 60 mg / kg significantly reduced the number of mice exhibiting tonic-clonic seizures (-90% and -100%, respectively, p < 0.01). There was no significant difference in the number of mice exhibiting tonic-clonic seizures at 3 mg / kg or 10 mg / kg. Dunn's multiple comparison test showed that compound 4 at 30 mg / kg and 60 mg / kg significantly increased the latency of tonic-clonic seizures compared to the mediator (p < 0.001). There was no significant difference at 3 mg / kg or 10 mg / kg.

[0405] Conclusions The results shown in Tables 27 to 32 indicate that the test compounds exhibit anticonvulsant activity in a generalized seizure model using mice prone to auditory-induced seizures. The test compounds protected mice from multiple seizure endpoints (runaway, clonic, and tonic seizures). Therefore, the test compounds could be used for medical treatment, such as for the treatment of epilepsy. Biological Test - Conclusions

[0406] The results described in Examples 2 through 5 indicate that the test compounds exhibit anticonvulsant activity in several different and complementary mouse seizure models (mini-MEST, MEST, 6Hz, and auditory-induced seizure models). Therefore, the compounds of formula (I) can be used for medical treatments, such as treating seizures. References

[0407] Numerous publications have been cited above to more fully describe and disclose the invention and the current state of the art to which it pertains. Full citations of these references are provided below. The contents of each of these references are incorporated herein by reference.

[0408]

[0409] .

Claims

1. A compound of formula (I) or a salt thereof: (I) in, R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl or halogen.

2. The compound according to claim 1, wherein R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups or halogens; such as hydrogen, methyl, CF3 or chlorine.

3. The compound according to claim 1, wherein R 1 It is hydrogen.

4. The compound according to any one of claims 1 to 3, wherein R 2 It is hydrogen, C 1-3 Alkyl or halogen; such as hydrogen, methyl or chlorine.

5. The compound according to any one of claims 1 to 3, wherein R 2 It is hydrogen.

6. The compound according to any one of claims 1 to 5, wherein R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or halogen; such as hydrogen, methyl, CF3, cyclopropyl, fluorine or chlorine.

7. The compound according to any one of claims 1 to 5, wherein R 3 It is hydrogen, fluorine, or chlorine.

8. The compound according to any one of claims 1 to 7, wherein R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or halogen; such as hydrogen, methyl, CF3, cyclopropyl, fluorine or chlorine.

9. The compound according to any one of claims 1 to 7, wherein R 4 It is methyl, CF3, cyclopropyl, fluorine or chlorine.

10. The compound according to any one of claims 1 to 7, wherein R 4 It is a methyl group.

11. The compound according to any one of claims 1 to 10, wherein R 5 yes: a. C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 cycloalkyl or halogen; b. C 3-6 Alkyl, C 3-6 Haloalkyl, C 3-6 cycloalkyl or halogen; or c. C 3-5 Alkyl, C 3-5 Halogenated alkyl, cyclopentyl or chlorinated.

12. The compound according to any one of claims 1 to 10, wherein R 5 It is propyl, pentyl, 1,1-dimethylpropyl, 3,3,3-trifluoropropyl, cyclopentyl, or chlorine.

13. The compound according to any one of claims 1 to 10, wherein R 5 It is propyl.

14. The compound according to claim 1, wherein the compound is a compound of any one of formulas (IA) to (IF): ， Where R 1 R 2 R 3 R 4 and R 5 It is as defined in any one of claims 1 to 13.

15. The compound according to claim 14, wherein the compound is a compound of formula (IC): (IC) in, R 3 It is hydrogen, fluorine, or chlorine; and R 5 It is C 3-6 alkyl.

16. The compound according to claim 15, wherein R 5 It is propyl.

17. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds and their salts: 2-(imidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(2,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-trifluoromethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Clomidazolo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Fluorimidazolo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(3,7-Dimethylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-Cyclopropylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(3-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(2-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-pentylphenyl-1,3-diol; 5-Cyclopentyl-2-(7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(2-trifluoromethyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-Cyclopropyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-trifluoromethyl-7-methylimidazo[1,2-a]pyridin-8-yl)-5-propylphenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-pentylphenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(7-methylimidazo[1,2-a]pyridin-8-yl)-5-(tert-amyl)phenyl-1,3-diol; 2-(6-chloro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-(tert-amyl)phenyl-1,3-diol; 5-Chloro-2-(6-Chloro-7-methylimidazo[1,2-a]pyridin-8-yl)phenyl-1,3-diol; 2-(6-fluoro-7-methylimidazo[1,2-a]pyridin-8-yl)-5-(3,3,3-trifluoropropyl)benzene-1,3-diol; and 2-(6-chloroimidazolo[1,2-a]pyridin-8-yl)-5-propylbenzene-1,3-diol.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and one or more components selected from the group consisting of: carriers, diluents, excipients, excipients, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, colorants, flavoring agents, and sweeteners.

19. The compound, salt thereof, or pharmaceutical composition according to any one of claims 1 to 17, for use in a treatment method.

20. The compound or pharmaceutical composition for use according to claim 19, wherein the treatment is for a condition associated with epileptic seizures.

21. The compound or pharmaceutical composition for use according to claim 20, wherein the condition associated with the seizure is selected from focal seizures, generalized seizures, and seizures of unknown origin.

22. The compound or pharmaceutical composition for use according to claim 20, wherein the condition associated with the epileptic seizure is selected from the following types of epileptic seizures: absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, febrile seizures, focal seizures progressing to bilateral tonic-clonic seizures, laughing and crying seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, and epileptic (or infantile) spasms.

23. The compound or pharmaceutical composition for use according to claim 20, wherein the condition associated with epileptic seizures is selected from focal epilepsy, generalized epilepsy, and epilepsy that combines generalized and focal epilepsy.

24. The compound or pharmaceutical composition for use according to claim 20, wherein the condition associated with epileptic seizures is selected from the following epileptic syndromes: neonatal and infancy-onset syndromes, childhood-onset syndromes, syndromes with onset at different ages, and idiopathic generalized epilepsy syndrome (IGE).

25. The compound or pharmaceutical composition for use according to claim 20, wherein the condition associated with epileptic seizures is epilepsy with an etiology selected from structural, genetic, infectious, metabolic, and autoimmune factors.

26. A treatment method comprising administering to a subject requiring treatment a therapeutically effective amount of the compound, salt thereof, or pharmaceutical composition according to any one of claims 1 to 17, or according to claim 18.

27. The method of claim 26, wherein the treatment is for a condition associated with epileptic seizures.

28. The method of claim 27, wherein the seizure-related condition is selected from focal seizures, generalized seizures, and seizures of unknown origin.

29. The method of claim 27, wherein the condition associated with the epileptic seizure is selected from the following types of epileptic seizures: absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, febrile seizures, focal seizures progressing to bilateral tonic-clonic seizures, laughing and crying seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, and epileptic (or infantile) spasms.

30. The method of claim 27, wherein the condition associated with the epileptic seizure is selected from focal epilepsy, generalized epilepsy, and combined generalized and focal epilepsy.

31. The method of claim 27, wherein the condition associated with epileptic seizures is selected from the following epilepsy syndromes: neonatal and infancy-onset syndromes, childhood-onset syndromes, syndromes with onset at different ages, and idiopathic generalized epilepsy syndrome (IGE).

32. The method of claim 27, wherein the condition associated with epileptic seizures is epilepsy with an etiology selected from structural, genetic, infectious, metabolic, and autoimmune factors.

33. Use of the compound, salt thereof, or pharmaceutical composition according to any one of claims 1 to 17 for the preparation of a medicament.

34. Use of the compound, salt thereof, or pharmaceutical composition according to any one of claims 1 to 17 in a treatment method.

35. A method for preparing a compound of formula (I) according to claim 1, the method comprising: (1a) React the compound of formula (II) with the compound of formula (III) to give the compound of formula (IV): in: R 1 R 2 R 3 R 4 and R 5 As defined in claim 1; X is chlorine, bromine, iodine, or trifluoromethanesulfonate; R 6 and R 7 It is hydrogen, alkyl, or phenyl; or R 6 and R 7 Linked to form cyclic boronic esters (such as pinacol boronic acid ester, neopentyl boronic acid ester, or catechol boronic acid ester); and R 8 and R 9 Suitable alcohol protecting groups, such as methyl or benzyl; and (1b) Convert the compound of formula (IV) into the compound of formula (I).

36. The method of claim 35, wherein R 6 and R 7 Both are hydrogen; or R 6 and R 7 Together .

37. The method according to claim 35 or claim 36, wherein R 8 and R 9 Both are methyl groups; or R 8 and R 9 All are benzyl groups.

38. The method according to any one of claims 35 to 37, wherein step (1a) comprises reacting the compound of formula (II) with the compound of formula (III) and a palladium catalyst and optionally a base.

39. The method according to any one of claims 35 to 38, wherein step (1a) is performed at a temperature of 60°C to 140°C.

40. A compound obtained or available by the method according to any one of claims 35 to 39.

41. A compound of formula (II): (II) Where R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; and X is chlorine, bromine, iodine, or trifluoromethanesulfonate.

42. The compound of formula (II) according to claim 41, selected from: 8-Bromo-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-6-chloro-7-methylimidazo[1,2-a]pyridine; 8-Chloro-7-(trifluoromethyl)imidazo[1,2-a]pyridine; 8-Bromo-6,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-7-fluoroimidazole[1,2-a]pyridine; 8-Bromo-3,7-dimethylimidazo[1,2-a]pyridine; 8-Bromo-7-cyclopropylimidazo[1,2-a]pyridine; 8-Bromo-3-chloro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-6-fluoro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2-chloro-7-methylimidazo[1,2-a]pyridine; 8-Bromo-2-(trifluoromethyl)-7-methylimidazo[1,2-a]pyridine; and 8-Bromo-6-(trifluoromethyl)-7-methylimidazo[1,2-a]pyridine.

43. A compound of formula (IV): (IV) Where R 1 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or halogens; R 2 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogen; R 3 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 4 It is hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 cycloalkyl or halogen; R 5 It is hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 cycloalkyl or halogen; and R 8 and R 9 It is a suitable alcohol protecting group (such as methyl or benzyl).

44. The compound of formula (IV) according to claim 43, selected from: 8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-2,7-dimethylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-trifluoromethylimidazo[1,2-a]pyridine; 7-Chloro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-6,7-dimethylimidazo[1,2-a]pyridine; 7-Fluoro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-3,7-dimethylimidazo[1,2-a]pyridine; 3-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Fluoro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 2-Chloro-8-(2,6-dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-pentylphenyl)7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-2-trifluoromethyl-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-propylphenyl)-6-trifluoromethyl-7-methylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-Dimethoxy-4-propylphenyl)-7-cyclopropylimidazo[1,2-a]pyridine; 6-Chloro-8-(4-Chloro-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Chloro-8-(2,6-dimethoxy-4-tert-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-tert-pentylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(4-cyclopentyl-2,6-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridine; 6-Cyclopropyl-8-(2,6-Dimethoxy-4-propylphenyl)-7-methylimidazo[1,2-a]pyridine; 8-(2,6-dimethoxy-4-(3,3,3-trifluoropropyl)phenyl)-6-fluoro-7-methylimidazo[1,2-a]pyridine; and 6-Chloro-8-(2,6-dimethoxy-4-propylphenyl)imidazo[1,2-a]pyridine.

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